Angela Rogers

All Publications

• Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress Syndrome Patients not Distinguished by Prior Latent Class Analyses Using Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized Clinical Trials. Critical care medicine Moore, A. R., Pienkos, S. M., Sinha, P., Guan, J., O'Kane, C. M., Levitt, J. E., Wilson, J. G., Shankar-Hari, M., Matthay, M. A., Calfee, C. S., Baron, R. M., McAuley, D. F., Rogers, A. J. 2023

  Abstract

  Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications.Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup.Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients.Six hundred eighty-three patients in SAILS and 511 patients in HARP-2.None.We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009).Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.

  View details for DOI 10.1097/CCM.0000000000006028

  View details for PubMedID 37695136

• Evaluation of acebilustat, a selective inhibitor of leukotriene B4 biosynthesis, for treatment of outpatients with mild-moderate COVID-19 disease: A randomized, double-blind, placebo- controlled Phase 2 trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Levitt, J. E., Hedlin, H., Duong, S., Lu, D., Lee, J., Bunning, B., Elkarra, N., Pinsky, B. A., Heffernan, E., Springman, E., Moss, R. B., Bonilla, H. F., Parsonnet, J., Zamanian, R. T., Langguth, J. J., Bollyky, J., Khosla, C., Nicolls, M. R., Desai, M., Rogers, A. J. 2023

  Abstract

  The vast majority of COVID-19 disease occurs in outpatients where treatment is limited to anti-virals for high-risk subgroups. Acebilustat, a leukotriene B4 (LTB4) inhibitor, has potential to reduce inflammation and symptom duration.In a single-center trial spanning Delta and Omicron variants, outpatients were randomized to 100 mg of oral acebilustat or placebo for 28 days. Patients reported daily symptoms via electronic query through Day 28 with phone follow-up on Day 120 and collected nasal swabs on Days 1-10. The primary outcome was sustained symptom resolution to Day 28. Secondary 28-day outcomes included time to first symptom resolution, area under the curve (AUC) of longitudinal daily symptom scores; duration of viral shedding through Day 10; and symptoms on Day 120.Sixty participants were randomized to each study arm. At enrollment, median duration and number of symptoms were 4 (IQR 3-5) days and 9 (IQR 7-11) symptoms. Most patients (90%) were vaccinated with 73% having neutralizing antibodies. A minority (44%) of participants (35% in the acebilustat arm and 53% in placebo) had sustained symptom resolution at Day 28 (HR 0.6, 95% CI 0.34-1.04, p = 0.07 favoring placebo). There was no difference in mean AUC of symptom scores over 28 days (difference in mean of AUC 9.4, 95% CI -42.1-60.9, p=0.72). Acebilustat did not impact viral shedding or symptoms at Day 120.Sustained symptoms through Day 28 were common in this low-risk population. Despite this, LTB4 antagonism with acebilustat did not shorten symptom duration in outpatients with COVID-19.

  View details for DOI 10.1093/cid/ciad187

  View details for PubMedID 36996150

• The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19. Annals of internal medicine 2022

  Abstract

  Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.114 centers in 10 countries.Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

  View details for DOI 10.7326/M22-0924

  View details for PubMedID 36037469

  View details for PubMedCentralID PMC9447373

• Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI insight Wilson, J. G., Simpson, L. J., Ferreira, A., Rustagi, A., Roque, J. A., Asuni, A., Ranganath, T., Grant, P. M., Subramanian, A. K., Rosenberg-Hasson, Y., Maecker, H., Holmes, S., Levitt, J. E., Blish, C., Rogers, A. J. 2020

  Abstract

  BACKGROUND: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.METHODS: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTS: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONS: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDING: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.

  View details for DOI 10.1172/jci.insight.140289

  View details for PubMedID 32706339

• A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nature medicine Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020

  Abstract

  There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.

  View details for DOI 10.1038/s41591-020-0944-y

  View details for PubMedID 32514174

• Association of Elevated Plasma Interleukin 18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome. Critical care medicine Rogers, A. J., Guan, J., Trtchounian, A., Hunninghake, G. M., Kaimal, R., Desai, M., Kozikowski, L., DeSouza, L., Mogan, S., Liu, K. D., Matthay, M. A., Steingrub, J., Wheeler, A., Yoon, J. H., Nakahira, K., Choi, A. M., Baron, R. M. 2019

  Abstract

  OBJECTIVE: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial.DESIGN: Retrospective analysis of randomized controlled clinical trial.SETTING: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis.PATIENTS: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population.INTERVENTIONS: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge.MEASUREMENTS AND MAIN RESULTS: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however.CONCLUSIONS: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.

  View details for DOI 10.1097/CCM.0000000000003816

  View details for PubMedID 31206358

• Profiling of ARDS Pulmonary Edema Fluid Identifies a Metabolically Distinct Subset. American journal of physiology. Lung cellular and molecular physiology Rogers, A. J., Contrepois, K., Wu, M., Zheng, M., Peltz, G., Ware, L. B., Matthay, M. A. 2017: ajplung 00438 2016-?

  Abstract

  There is considerable biologic and physiologic heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a sub-group of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Non-targeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal components analysis (PCA) and partial least squares discriminant analysis (PLSDA) were conducted to find discriminant metabolites. 760 unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared to edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This "high metabolite" endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus, metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biologic heterogeneity among ARDS patients who meet standard clinical and physiologic criteria for ARDS.

  View details for DOI 10.1152/ajplung.00438.2016

  View details for PubMedID 28258106

• Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., Phillips, A., Poulakou, G., Price, D. A., Robinson, P., Rogers, A. J., Sandkovsky, U., Shaw-Saliba, K., Sturek, J. M., Trautner, B. W., Waters, M., Reilly, C. 2024

  Abstract

  Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models.Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time.Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

  View details for DOI 10.1093/cid/ciad780

  View details for PubMedID 38376212

• The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia. American journal of respiratory and critical care medicine Chouchane, O., Schuurman, A. R., Reijnders, T. D., Peters-Sengers, H., Butler, J. M., Uhel, F., Schultz, M. J., Bonten, M. J., Cremer, O. L., Calfee, C. S., Matthay, M. A., Langley, R. J., Alipanah-Lechner, N., Kingsmore, S. F., Rogers, A., Weeghel, M. v., Vaz, F. M., van der Poll, T. 2024

  Abstract

  The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups, or focused on lipids as prognosticators.To map the plasma lipidome during sepsis due to community-acquired pneumonia (CAP), and determine disease-specificity and associations with clinical features.We analyzed 1833 lipid species, across 33 classes, in 169 patients admitted to the intensive care unit (ICU) with sepsis due to CAP, 51 non-infected ICU patients and 48 outpatient controls. In a paired analysis we reanalyzed patients still in the ICU four days after admission (n=82).58% of plasma lipids were significantly lower in CAP-sepsis patients compared to outpatient controls (6% higher, 36% not different). We found strong, lipid class-specific associations with disease severity, validated across two external cohorts, and inflammatory biomarkers, in which triacylglycerols, cholesterol esters, and lysophospholipids exhibited the strongest associations. 36% of lipids increased over time, stratification by survival revealed diverging lipid recovery, which was confirmed in an external cohort; specifically, a 10% increase in cholesterol ester levels was related to a lower odds ratio (OR 0.84, p=0.006) for 30-day mortality (absolute mortality: 18/82). Comparison with non-infected ICU patients delineated a substantial common illness response (57.5%), and a lipidomic signal distinct for patients with CAP-sepsis (37%).Patients with sepsis due to CAP display a time-dependent and partially disease-specific shift in their plasma lipidome that correlates with disease severity and systemic inflammation, and is associated with higher mortality.

  View details for DOI 10.1164/rccm.202308-1321OC

  View details for PubMedID 38240721

• IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition. Nature communications Haslund-Gourley, B. S., Woloszczuk, K., Hou, J., Connors, J., Cusimano, G., Bell, M., Taramangalam, B., Fourati, S., Mege, N., Bernui, M., Altman, M. C., Krammer, F., van Bakel, H., IMPACC Network, Maecker, H. T., Rouphael, N., Diray-Arce, J., Wigdahl, B., Kutzler, M. A., Cairns, C. B., Haddad, E. K., Comunale, M. A., Ozonoff, A., Ehrlich, L. I., Melamed, E., Sesma, A. F., Simon, V., Pulendran, B., Nadeau, K. C., Davis, M. M., McCoey, G. A., Sekaly, R., Baden, L. R., Levy, O., Schaenman, J., Reed, E. F., Shaw, A. C., Hafler, D. A., Montgomery, R. R., Kleinstein, S. H., Becker, P. M., Augustine, A. D., Calfee, C. S., Erle, D. J., DeBakey, M. E., Corry, D. B., Kheradmand, F., Atkinson, M. A., Brakenridge, S. C., Higuita, N. I., Metcalf, J. P., Hough, C. L., Messer, W. B., Kraft, M., Bime, C., Peters, B., Milliren, C. E., Syphurs, C., McEnaney, K., Barton, B., Lentucci, C., Saluvan, M., Chang, A. C., Hoch, A., Albert, M., Shaheen, T., Kho, A. T., Liu, S., Thomas, S., Chen, J., Murphy, M. D., Cooney, M., Hayati, A. N., Bryant, R., Abraham, J., Jayavelu, N. D., Presnell, S., Jancsyk, T., Maguire, C., Qi, J., Lee, B., Fourati, S., Esserman, D. A., Guan, L., Gygi, J., Pawar, S., Brito, A., Fragiadakis, G. K., Patel, R., Overton, J. A., Vita, R., Westendorf, K., Shannon, C. P., Tebbutt, S. J., Thyagarajan, R. V., Rousseau, J. F., Wylie, D., Triplett, T. A., Kojic, E., Chinthrajah, S., Ahuja, N., Rogers, A. J., Artandi, M., Geng, L., Yendewa, G., Powell, D. L., Kim, J. N., Simmons, B., Goonewardene, I. M., Smith, C. M., Martens, M., Sherman, A. C., Walsh, S. R., Issa, N. C., Salehi-Rad, R., Dela Cruz, C., Farhadian, S., Iwasaki, A., Ko, A. I., Anderson, E. J., Mehta, A. K., Sevransky, J. E., Seyfert-Margolis, V., Leligdowicz, A., Matthay, M. A., Singer, J. P., Kangelaris, K. N., Hendrickson, C. M., Krummel, M. F., Langelier, C. R., Woodruff, P. G., Corry, D. B., Kheradmand, F., Anderson, M. L., Guirgis, F. W., Drevets, D. A., Brown, B. R., Siegel, S. A., Lu, Z., Mosier, J., Kimura, H., Khor, B., van Bakel, H., Rahman, A., Stadlbauer, D., Dutta, J., Xie, H., Kim-Schulze, S., Gonzalez-Reiche, A. S., van de Guchte, A., Carreno, J. M., Singh, G., Raskin, A., Tcheou, J., Bielak, D., Kawabata, H., Kelly, G., Patel, M., Nie, K., Yellin, T., Fried, M., Sullivan, L., Morris, S., Sieg, S., Steen, H., van Zalm, P., Fatou, B., Mendez, K., Lasky-Su, J., Hutton, S. R., Michelotti, G., Wong, K., Jha, M., Viode, A., Kanarek, N., Petrova, B., Zhao, Y., Bosinger, S. E., Boddapati, A. K., Tharp, G. K., Pellegrini, K. L., Beagle, E., Cowan, D., Hamilton, S., Ribeiro, S. P., Hodder, T., Rosen, L. B., Lee, S., Wilson, M. R., Dandekar, R., Alvarenga, B., Rajan, J., Eckalbar, W., Schroeder, A. W., Tsitsiklis, A., Mick, E., Guerrero, Y. S., Love, C., Maliskova, L., Adkisson, M., Siles, N., Geltman, J., Hurley, K., Saksena, M., Altman, D., Srivastava, K., Eaker, L. Q., Bermudez-Gonzalez, M. C., Beach, K. F., Sominsky, L. A., Azad, A. R., Mulder, L. C., Kleiner, G., Lee, A. S., Do, E., Fernandes, A., Manohar, M., Hagan, T., Blish, C. A., Din, H. N., Roque, J., Yang, S., Sigal, N., Chang, I., Tribout, H., Harris, P., Consolo, M., Edwards, C., Lee, E., Lin, E., Croen, B., Semenza, N. C., Rogowski, B., Melnyk, N., Bell, M. R., Furukawa, S., McLin, R., Schearer, P., Sheidy, J., Tegos, G. P., Nagle, C., Smolen, K., Desjardins, M., van Haren, S., Mitre, X., Cauley, J., Li, X., Tong, A., Evans, B., Montesano, C., Licona, J. H., Krauss, J., Chang, J. B., Izaguirre, N., Rooks, R., Elashoff, D., Brook, J., Ramires-Sanchez, E., Llamas, M., Rivera, A., Perdomo, C., Ward, D. C., Magyar, C. E., Fulcher, J. A., Pickering, H. C., Sen, S., Chaudhary, O., Coppi, A., Fournier, J., Mohanty, S., Muenker, C., Nelson, A., Raddassi, K., Rainone, M., Ruff, W. E., Salahuddin, S., Schulz, W. L., Vijayakumar, P., Wang, H., Wunder, E. J., Young, H. P., Rothman, J., Konstorum, A., Chen, E., Cotsapas, C., Grubaugh, N. D., Wang, X., Xu, L., Asashima, H., Bristow, L., Hussaini, L., Hellmeister, K., Samaha, H., Wimalasena, S. T., Cheng, A., Spainhour, C., Scherer, E. M., Johnson, B., Bechnak, A., Ciric, C. R., Hewitt, L., Carter, E., Mcnair, N., Panganiban, B., Huerta, C., Usher, J., Vaysman, T., Holland, S. M., Abe-Jones, Y., Asthana, S., Beagle, A., Bhide, S., Carrillo, S. A., Chak, S., Ghale, R., Gonzalez, A., Jauregui, A., Jones, N., Lea, T., Lee, D., Lota, R., Milush, J., Nguyen, V., Pierce, L., Prasad, P. A., Rao, A., Samad, B., Shaw, C., Sigman, A., Sinha, P., Ward, A., Willmore, A., Zhan, J., Rashid, S., Rodriguez, N., Tang, K., Altamirano, L. T., Betancourt, L., Curiel, C., Sutter, N., Paz, M. T., Tietje-Ulrich, G., Leroux, C., Thakur, N., Vasquez, J. J., Santhosh, L., Song, L., Nelson, E., Moldawer, L. L., Borresen, B., Roth-Manning, B., Ungaro, R. F., Oberhaus, J., Booth, J. L., Sinko, L. A., Brunton, A., Sullivan, P. E., Strnad, M., Lyski, Z. L., Coulter, F. J., Micheleti, C., Conway, M., Francisco, D., Molzahn, A., Erickson, H., Wilson, C. C., Schunk, R., Sierra, B., Hughes, T. 2024; 15 (1): 404

  Abstract

  The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.

  View details for DOI 10.1038/s41467-023-44211-0

  View details for PubMedID 38195739

• Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study. Nature communications Ozonoff, A., Jayavelu, N. D., Liu, S., Melamed, E., Milliren, C. E., Qi, J., Geng, L. N., McComsey, G. A., Cairns, C. B., Baden, L. R., Schaenman, J., Shaw, A. C., Samaha, H., Seyfert-Margolis, V., Krammer, F., Rosen, L. B., Steen, H., Syphurs, C., Dandekar, R., Shannon, C. P., Sekaly, R. P., Ehrlich, L. I., Corry, D. B., Kheradmand, F., Atkinson, M. A., Brakenridge, S. C., Higuita, N. I., Metcalf, J. P., Hough, C. L., Messer, W. B., Pulendran, B., Nadeau, K. C., Davis, M. M., Sesma, A. F., Simon, V., van Bakel, H., Kim-Schulze, S., Hafler, D. A., Levy, O., Kraft, M., Bime, C., Haddad, E. K., Calfee, C. S., Erle, D. J., Langelier, C. R., Eckalbar, W., Bosinger, S. E., Peters, B., Kleinstein, S. H., Reed, E. F., Augustine, A. D., Diray-Arce, J., Maecker, H. T., Altman, M. C., Montgomery, R. R., Becker, P. M., Rouphael, N. 2024; 15 (1): 216

  Abstract

  Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

  View details for DOI 10.1038/s41467-023-44090-5

  View details for PubMedID 38172101

  View details for PubMedCentralID PMC10764789

• Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS). Thorax Mehta, P., Samanta, R. J., Wick, K., Coll, R. C., Mawhinney, T., McAleavey, P. G., Boyle, A. J., Conlon, J., Shankar-Hari, M., Rogers, A., Calfee, C. S., Matthay, M. A., Summers, C., Chambers, R. C., McAuley, D. F., O'Kane, C. M. 2023

  Abstract

  Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS.Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality.Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality.Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

  View details for DOI 10.1136/thorax-2023-220292

  View details for PubMedID 38148147

• The transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure. Nature communications Morrell, E. D., Holton, S. E., Lawrance, M., Orlov, M., Franklin, Z., Mitchem, M. A., DeBerg, H., Gersuk, V. H., Garay, A., Barnes, E., Liu, T., Peltan, I. D., Rogers, A., Ziegler, S., Wurfel, M. M., Mikacenic, C. 2023; 14 (1): 7443

  Abstract

  The transcriptional and phenotypic characteristics that define alveolar monocyte and macrophage subsets in acute hypoxemic respiratory failure (AHRF) are poorly understood. Here, we apply CITE-seq (single-cell RNA-sequencing and cell-surface protein quantification) to bronchoalveolar lavage and blood specimens longitudinally collected from participants with AHRF to identify alveolar myeloid subsets, and then validate their identity in an external cohort using flow cytometry. We identify alveolar myeloid subsets with transcriptional profiles that differ from other lung diseases as well as several subsets with similar transcriptional profiles as reported in healthy participants (Metallothionein) or patients with COVID-19 (CD163/LGMN). We use information from CITE-seq to determine cell-surface proteins that distinguish transcriptional subsets (CD14, CD163, CD123, CD71, CD48, CD86 and CD44). In the external cohort, we find a higher proportion of CD163/LGMN alveolar macrophages are associated with mortality in AHRF. We report a parsimonious set of cell-surface proteins that distinguish alveolar myeloid subsets using scalable approaches that can be applied to clinical cohorts.

  View details for DOI 10.1038/s41467-023-43223-0

  View details for PubMedID 37978185

• Right Ventricular Dysfunction Patterns Among Patients with COVID-19 in the Intensive Care Unit - a Retrospective Cohort Analysis. Annals of the American Thoracic Society Sanchez, P. A., O'Donnell, C. T., Francisco, N., Santana, E. J., Moore, A. R., Pacheco-Navarro, A., Roque, J., Lebold, K. M., Parmer, C. M., Pienkos, S. M., Celestin, B. E., Levitt, J. E., Collins, W. J., Lanspa, M. J., Ashley, E. A., Wilson, J. G., Haddad, F., Rogers, A. J. 2023

  Abstract

  Right ventricular (RV) dysfunction is common among patients hospitalized with COVID-19; however, its epidemiology may depend on the echocardiographic parameters used to define it.To evaluate the prevalence of abnormalities in three common echocardiographic parameters of RV function among COVID-19 patients admitted to the intensive care unit, as well as the effect of RV dilatation on differential parameter abnormality and the association of RV dysfunction with 60-day mortality.Retrospective cohort study of COVID-19 ICU patients between March 4th,2020 to March 4th, 2021, who received a transthoracic echocardiogram within 48 hours before to at most 7 days after ICU admission. RV dysfunction and dilatation respectively defined by guideline thresholds for tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RVFAC), RV free wall longitudinal strain (RVFWS), and RV basal dimension or RV end-diastolic area. Association of RV dysfunction with 60-day mortality assessed through logistic regression adjusting for age, prior history of congestive heart failure, invasive ventilation at time of TTE and APACHE II score.116 patients were included, of which 69% had RV dysfunction by > 1 parameter and 36.3% of these had RV dilatation. The three most common patterns of RV dysfunction included: Presence of 3 abnormalities, the combination of abnormal RVFWS and TAPSE, and isolated TAPSE abnormality. Patients with RV dilatation had worse RVFAC (24% vs 36%, p = 0.001), worse RVFWS (16.3% vs 19.1%, p = 0.005), higher RVSP (45mmHg vs 31mmHg, p = 0.001) but similar TAPSE (13mm vs 13mm, p = 0.30) compared to those with normal RV size. After multivariable adjustment, 60-day mortality was significantly associated with RV dysfunction (OR 2.91, 95% CI 1.01 - 9.44), as was the presence of at least 2 parameter abnormalities.ICU patients with COVID-19 had significant heterogeneity in RV function abnormalities present with different patterns associated with RV dilatation. RV dysfunction by any parameter was associated with increased mortality. Therefore, a multiparameter evaluation may be critical in recognizing RV dysfunction in COVID-19.

  View details for DOI 10.1513/AnnalsATS.202303-235OC

  View details for PubMedID 37478340

• Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. The Lancet. Respiratory medicine Brown, S. M., Barkauskas, C. E., Grund, B., Sharma, S., Phillips, A. N., Leither, L., Peltan, I. D., Lanspa, M., Gilstrap, D. L., Mourad, A., Lane, K., Beitler, J. R., Serra, A. L., Garcia, I., Almasri, E., Fayed, M., Hubel, K., Harris, E. S., Middleton, E. A., Barrios, M. A., Mathews, K. S., Goel, N. N., Acquah, S., Mosier, J., Hypes, C., Salvagio Campbell, E., Khan, A., Hough, C. L., Wilson, J. G., Levitt, J. E., Duggal, A., Dugar, S., Goodwin, A. J., Terry, C., Chen, P., Torbati, S., Iyer, N., Sandkovsky, U. S., Johnson, N. J., Robinson, B. R., Matthay, M. A., Aggarwal, N. R., Douglas, I. S., Casey, J. D., Hache-Marliere, M., Georges Youssef, J., Nkemdirim, W., Leshnower, B., Awan, O., Pannu, S., O'Mahony, D. S., Manian, P., Awori Hayanga, J. W., Wortmann, G. W., Tomazini, B. M., Miller, R. F., Jensen, J. U., Murray, D. D., Bickell, N. A., Zatakia, J., Burris, S., Higgs, E. S., Natarajan, V., Dewar, R. L., Schechner, A., Kang, N., Arenas-Pinto, A., Hudson, F., Ginde, A. A., Self, W. H., Rogers, A. J., Oldmixon, C. F., Morin, H., Sanchez, A., Weintrob, A. C., Cavalcanti, A. B., Davis-Karim, A., Engen, N., Denning, E., Taylor Thompson, B., Gelijns, A. C., Kan, V., Davey, V. J., Lundgren, J. D., Babiker, A. G., Neaton, J. D., Lane, H. C. 2023

  Abstract

  There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure.TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761.Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10).Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy.National Institutes of Health.

  View details for DOI 10.1016/S2213-2600(23)00147-9

  View details for PubMedID 37348524

• Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients. Cell reports. Medicine Diray-Arce, J., Fourati, S., Doni Jayavelu, N., Patel, R., Maguire, C., Chang, A. C., Dandekar, R., Qi, J., Lee, B. H., van Zalm, P., Schroeder, A., Chen, E., Konstorum, A., Brito, A., Gygi, J. P., Kho, A., Chen, J., Pawar, S., Gonzalez-Reiche, A. S., Hoch, A., Milliren, C. E., Overton, J. A., Westendorf, K., Cairns, C. B., Rouphael, N., Bosinger, S. E., Kim-Schulze, S., Krammer, F., Rosen, L., Grubaugh, N. D., van Bakel, H., Wilson, M., Rajan, J., Steen, H., Eckalbar, W., Cotsapas, C., Langelier, C. R., Levy, O., Altman, M. C., Maecker, H., Montgomery, R. R., Haddad, E. K., Sekaly, R. P., Esserman, D., Ozonoff, A., Becker, P. M., Augustine, A. D., Guan, L., Peters, B., Kleinstein, S. H. 2023: 101079

  Abstract

  The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention.

  View details for DOI 10.1016/j.xcrm.2023.101079

  View details for PubMedID 37327781

• Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial. JAMA network open Berger, J. S., Neal, M. D., Kornblith, L. Z., Gong, M. N., Reynolds, H. R., Cushman, M., Althouse, A. D., Lawler, P. R., McVerry, B. J., Kim, K. S., Baumann Kreuziger, L., Solomon, S. D., Kosiborod, M. N., Berry, S. M., Bochicchio, G. V., Contoli, M., Farkouh, M. E., Froess, J. D., Gandotra, S., Greenstein, Y., Hade, E. M., Hanna, N., Hudock, K., Hyzy, R. C., Ibáñez Estéllez, F., Iovine, N., Khanna, A. K., Khatri, P., Kirwan, B. A., Kutcher, M. E., Leifer, E., Lim, G., Lopes, R. D., Lopez-Sendon, J. L., Luther, J. F., Nigro Maia, L., Quigley, J. G., Wahid, L., Wilson, J. G., Zarychanski, R., Kindzelski, A., Geraci, M. W., Hochman, J. S. 2023; 6 (5): e2314428

  Abstract

  Platelet activation is a potential therapeutic target in patients with COVID-19.To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.ClinicalTrials.gov Identifier: NCT04505774.

  View details for DOI 10.1001/jamanetworkopen.2023.14428

  View details for PubMedID 37227729

• Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. JAMA Self, W. H., Shotwell, M. S., Gibbs, K. W., de Wit, M., Files, D. C., Harkins, M., Hudock, K. M., Merck, L. H., Moskowitz, A., Apodaca, K. D., Barksdale, A., Safdar, B., Javaheri, A., Sturek, J. M., Schrager, H., Iovine, N., Tiffany, B., Douglas, I. S., Levitt, J., Busse, L. W., Ginde, A. A., Brown, S. M., Hager, D. N., Boyle, K., Duggal, A., Khan, A., Lanspa, M., Chen, P., Puskarich, M., Vonderhaar, D., Venkateshaiah, L., Gentile, N., Rosenberg, Y., Troendle, J., Bistran-Hall, A. J., DeClercq, J., Lavieri, R., Joly, M. M., Orr, M., Pulley, J., Rice, T. W., Schildcrout, J. S., Semler, M. W., Wang, L., Bernard, G. R., Collins, S. P., ACTIV-4 Host Tissue Investigators, Becker, R. C., Del Zoppo, G., Henke, P., Holubkov, R., Johnson, M., Kerr, K., Lipman, H. I., Lurie, F., Pitt, B., Vesely, S. K., Fleg, J. L., Aamodt, D., Ayers, J., Clark, D., Collins, J., Cook, M., Dixon, S., Graves, J., Jordan, C., Lindsell, C. J., Lopez, I., McKeel, D., Orozco, D., Prato, N., Qi, A., Qutab, M., Stoughton, C., Vermillion, K., Walsh, K., Winchell, S., Young, T., Franklin, R., Wagner, E., Walther, T., Demitrack, M., Johnson, J., Walsh, R., Bales, B., Miller, K., Torr, D., Barot, H., Landreth, L., LaRose, M., Parks, L., Teixeira, J. P., Cardenas, S., Ceniceros, J. A., Cunningham, A. G., Kunkel, S., Lovato, D. M., Zimmerman, B., Nguyen, T., Zeger, W., Nichols, H., Wiedel, N., Javaheri, A., Stilinovic, S., Brokowski, C., Lu, J., Solberg, M., Lee, D., Roach, K., Tiffany, B., Tanner, C., Taylor, A., Zumbahl, J., Syed, A., Mason, J., Jackson, P. E., Coleman, R. W., Haughey, H. M., Cherabuddi, K., James, N., Wakeman, R., Duncan, C., Montero, C., Rogers, A. J., Wilson, J. G., Vojnik, R., Perez, C., Wyles, D., Hiller, T. D., Oakes, J. L., Garcia, A. Z., Gong, M., Mohamed, A., Andrea, L., Nair, R., Nkemdirim, W., Lopez, B., Boujid, S., Torres, M., Garcia, O., Martinez, F., Baduashvili, A., Bastman, J., Chauhan, L., Douin, D. J., Finck, L., Licursi, A., Ten Lohuis, C., Zhang, S., Bender, W., Tovar, S., Hayes, S., Kurtzman, N., Rosseto, E., Scaffidi, D., Shapiro, N., Pak, J., Allada, G., Briceno, G., Pena, J., Oh, M., Ali, H., Beselman, S., Eby, Y., Klimov, V., Hite, R. D., Tanzeem, H., Droege, C., Winter, J., Jackman, S., Caudill, A., Bayoumi, E., Pascual, E., Chen, P., Mucha, S., Thiruchelvam, N., Siuba, M., Mehkri, O., Driver, B. E., Hendrickson, A. F., Kaus, O. R., Ontiveros, C., Riehm, A., Laudun, S., Hudock, D., Ensley, C., Shaner, V., Gentile, N., Isenberg, D., Reimer, H., Cincola, P., Harris, E. S., Callahan, S. J., Yamane, M. B., Barrios, M. A., Desai, N., Bharara, A., Keller, M., Majumder, P., Dohe, C., D'Armiento, J., Goldklang, M., Wagener, G., Fonseca, L., Valezquez-Sanchez, I., Johnson, N. J., Petersen, E., Fuentes, M., Newton, M., Gundel, S., Srinivasan, V., Steel, T., Robinson, B. 2023; 329 (14): 1170-1182

  Abstract

  Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

  View details for DOI 10.1001/jama.2023.3546

  View details for PubMedID 37039791

• Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials. Critical care (London, England) Pienkos, S. M., Moore, A. R., Guan, J., Levitt, J. E., Matthay, M. A., Baron, R. M., Conlon, J., McAuley, D. F., O'Kane, C. M., Rogers, A. J. 2023; 27 (1): 126

  Abstract

  Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins.Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher's exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality.There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06-4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17-1.07, p = 0.06; interaction p = 0.22).Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.

  View details for DOI 10.1186/s13054-023-04387-9

  View details for PubMedID 36978134

  View details for PubMedCentralID 6201750

• Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness. JCI insight Feng, A., Yang, E. Y., Moore, A. R., Dhingra, S., Chang, S. E., Yin, X., Pi, R., Mack, E. K., Völkel, S., Geßner, R., Gündisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P. C., Asuni, A. A., Levitt, J. E., Wilson, J. G., Leong, M., Lumb, J. H., Mao, R., Pinedo, K., Roque, J., Richards, C. M., Stabile, M., Swaminathan, G., Salagianni, M. L., Triantafyllia, V., Bertrams, W., Blish, C. A., Carette, J. E., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T. T., Luning Prak, E. T., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A. J., Utz, P. J. 2023; 8 (3)

  Abstract

  The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

  View details for DOI 10.1172/jci.insight.163150

  View details for PubMedID 36752204

• Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS. American journal of physiology. Lung cellular and molecular physiology Alipanah-Lechner, N., Neyton, L., Mick, E., Willmore, A., Leligdowicz, A., Contrepois, K., Jauregui, A., Zhuo, H., Hendrickson, C., Gomez, A., Sinha, P., Kangelaris, K. N., Liu, K. D., Matthay, M. A., Rogers, A. J., Calfee, C. S. 2023

  Abstract

  Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed amongst patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 ARDS patients with sepsis enrolled in a multi-center prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Hyperinflammatory ARDS patients had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Hyperinflammatory ARDS patients may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biologic profiling may identify key differences in pathogenesis among patients with ARDS and lead to novel targeted therapies.

  View details for DOI 10.1152/ajplung.00278.2022

  View details for PubMedID 36648136

• The Metabolomics of Critical Illness. Handbook of experimental pharmacology Pacheco-Navarro, A. E., Rogers, A. J. 2022

  Abstract

  Critical illness is associated with dramatic changes in metabolism driven by immune, endocrine, and adrenergic mediators. These changes involve early activation of catabolic processes leading to increased energetic substrate availability; later on, they are followed by a hypometabolic phase characterized by deranged mitochondrial function. In sepsis and ARDS, these rapid clinical changes are reflected in metabolomic profiles of plasma and other fluids, suggesting that metabolomics could one day be used to assist in the diagnosis and prognostication of these syndromes. Some metabolites, such as lactate, are already in clinical use and define patients with septic shock, a high-mortality subtype of sepsis. Larger-scale metabolomic profiling may ultimately offer a tool to identify subgroups of critically ill patients who may respond to therapy, but further work is needed before this type of precision medicine is readily employed in the clinical setting.

  View details for DOI 10.1007/164_2022_622

  View details for PubMedID 36376705

• Circulating N-formylmethionine and metabolic shift in critical illness: a multicohort metabolomics study. Critical care (London, England) Sigurdsson, M. I., Kobayashi, H., Amrein, K., Nakahira, K., Rogers, A. J., Pinilla-Vera, M., Baron, R. M., Fredenburgh, L. E., Lasky-Su, J. A., Christopher, K. B. 2022; 26 (1): 321

  Abstract

  BACKGROUND: Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality.METHODS: We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women's Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models.RESULTS: Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5-4.0; P=0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4-18.7; P=0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites.CONCLUSIONS: The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway.

  View details for DOI 10.1186/s13054-022-04174-y

  View details for PubMedID 36261854

• Using a 29-mRNA Host Response Classifier To Detect Bacterial Coinfections and Predict Outcomes in COVID-19 Patients Presenting to the Emergency Department. Microbiology spectrum Ram-Mohan, N., Rogers, A. J., Blish, C. A., Nadeau, K. C., Zudock, E. J., Kim, D., Quinn, J. V., Sun, L., Liesenfeld, O., Yang, S. 2022: e0230522

  Abstract

  Clinicians in the emergency department (ED) face challenges in concurrently assessing patients with suspected COVID-19 infection, detecting bacterial coinfection, and determining illness severity since current practices require separate workflows. Here, we explore the accuracy of the IMX-BVN-3/IMX-SEV-3 29 mRNA host response classifiers in simultaneously detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and bacterial coinfections and predicting clinical severity of COVID-19. A total of 161 patients with PCR-confirmed COVID-19 (52.2% female; median age, 50.0 years; 51% hospitalized; 5.6% deaths) were enrolled at the Stanford Hospital ED. RNA was extracted (2.5 mL whole blood in PAXgene blood RNA), and 29 host mRNAs in response to the infection were quantified using Nanostring nCounter. The IMX-BVN-3 classifier identified SARS-CoV-2 infection in 151 patients with a sensitivity of 93.8%. Six of 10 patients undetected by the classifier had positive COVID tests more than 9 days prior to enrollment, and the remaining patients oscillated between positive and negative results in subsequent tests. The classifier also predicted that 6 (3.7%) patients had a bacterial coinfection. Clinical adjudication confirmed that 5/6 (83.3%) of the patients had bacterial infections, i.e., Clostridioides difficile colitis (n = 1), urinary tract infection (n = 1), and clinically diagnosed bacterial infections (n = 3), for a specificity of 99.4%. Two of 101 (2.8%) patients in the IMX-SEV-3 "Low" severity classification and 7/60 (11.7%) in the "Moderate" severity classification died within 30 days of enrollment. IMX-BVN-3/IMX-SEV-3 classifiers accurately identified patients with COVID-19 and bacterial coinfections and predicted patients' risk of death. A point-of-care version of these classifiers, under development, could improve ED patient management, including more accurate treatment decisions and optimized resource utilization. IMPORTANCE We assay the utility of the single-test IMX-BVN-3/IMX-SEV-3 classifiers that require just 2.5 mL of patient blood in concurrently detecting viral and bacterial infections as well as predicting the severity and 30-day outcome from the infection. A point-of-care device, in development, will circumvent the need for blood culturing and drastically reduce the time needed to detect an infection. This will negate the need for empirical use of broad-spectrum antibiotics and allow for antibiotic use stewardship. Additionally, accurate classification of the severity of infection and the prediction of 30-day severe outcomes will allow for appropriate allocation of hospital resources.

  View details for DOI 10.1128/spectrum.02305-22

  View details for PubMedID 36250865

• Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase atrial LANCET RESPIRATORY MEDICINE Holland, T. L., Ginde, A. A., Paredes, R., Murray, T. A., Engen, N., Grandits, G., Vekstein, A., Ivey, N., Mourad, A., Sandkovsky, U., Gottlieb, R. L., Berhe, M., Jain, M. K., Marines-Price, R., Agbor, B., Mateu, L., Espana-Cueto, S., Llados, G., Mylonakis, E., Rogers, R., Shehadeh, F., Filbin, M. R., Hibbert, K. A., Kim, K., Tran, T., Morris, P. E., Cassity, E. P., Trautner, B., Pandit, L. M., Knowlton, K. U., Leither, L., Matthay, M. A., Rogers, A. J., Drake, W., Jones, B., Poulakou, G., Syrigos, K. N., Fernandez-Cruz, E., Di Natale, M., Almasri, E., Balerdi-Sarasola, L., Bhagani, S. R., Boyle, K. L., Casey, J. D., Chen, P., Douin, D. J., Files, D., Gunthard, H. F., Hite, R., Hyzy, R. C., Khan, A., Kibirige, M., Kidega, R., Kimuli, I., Kiweewa, F., Jensen, J., Leshnower, B. G., Lutaakome, J. K., Manian, P., Morales-Rull, J., O'Mahony, D., Overcash, J., Ramachandruni, S., Steingrub, J. S., Taha, H. S., Waters, M., Young, B. E., Phillips, A. N., Murray, D. D., Jensen, T. O., Padilla, M. L., Sahner, D., Shaw-Saliba, K., Dewar, R. L., Teitelbaum, M., Natarajan, V., Rehman, M., Pett, S., Hudson, F., Touloumi, G., Brown, S. M., Self, W. H., Chang, C. C., Sanchez, A., Weintrob, A. C., Hatlen, T., Grund, B., Sharma, S., Reilly, C. S., Garbes, P., Esser, M. T., Templeton, A., Babiker, A. G., Davey, V. J., Gelijns, A. C., Higgs, E. S., Kan, V., Matthews, G., Thompson, B., Neaton, J. D., Lane, C., Lundgren, J. D., ACTIV-3-Therapeutics Inpatients CO 2022; 10 (10): 972-984

  View details for DOI 10.1016/S2213-2600(22)00215-6

  View details for Web of Science ID 000898650900016

• Functional, imaging, and respiratory evaluation (FIRE) of patients post-hospitalization for COVID-19: protocol for a pilot observational study. Pilot and feasibility studies Mayer, K. P., Palakshappa, J. A., Peltan, I. D., Andrew, J. S., Gundel, S. J., Ringwood, N. J., Mckeehan, J., Hope, A. A., Rogers, A. J., Biehl, M., Hayden, D. L., Caldwell, E., Mehkri, O., Lynch, D. J., Burham, E. L., Hough, C. L., Jolley, S. E., NHLBI PETAL Network 2022; 8 (1): 212

  Abstract

  INTRODUCTION: We describe a protocol for FIRE CORAL, an observational cohort study that examines the recovery from COVID-19 disease following acute hospitalization with an emphasis on functional, imaging, and respiratory evaluation.METHODS AND ANALYSIS: FIRE CORAL is a multicenter prospective cohort study of participants recovering from COVID-19 disease with in-person follow-up for functional and pulmonary phenotyping conducted by the National Heart, Lung and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. FIRE CORAL will include a subset of participants enrolled in Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study (BLUE CORAL), an NHLBI-funded prospective cohort study describing the clinical characteristics, treatments, biology, and outcomes of hospitalized patients with COVID-19 across the PETAL Network. FIRE CORAL consists of a battery of in-person assessments objectively measuring pulmonary function, abnormalities on lung imaging, physical functional status, and biospecimen analyses. Participants will attend and perform initial in-person testing at 3 to 9months after hospitalization. The primary objective of the study is to determine the feasibility of longitudinal assessments investigating multiple domains of recovery from COVID-19. Secondarily, we will perform descriptive statistics, including the prevalence and characterization of abnormalities on pulmonary function, chest imaging, and functional status. We will also identify potentialclinical and biologic factors that predict recovery or the occurrence of persistent impairment of pulmonary function, chest imaging, and functional status.ETHICS AND DISSEMINATION: FIRE CORAL is approved via the Vanderbilt University central institutional review board (IRB) and via reliance agreement with the site IRBs. Results will be disseminated via the writing group for the protocol committee and reviewed by the PETAL Network publications committee prior to publication. Data obtained via the study will subsequently be made publicly available via NHLBI's biorepository.STRENGTHS AND LIMITATIONS OF THE STUDY: Strengths: First US-based multicenter cohort of pulmonary and functional outcomes in patients previously hospitalized for COVID-19 infection Longitudinal biospecimen measurement allowing for biologic phenotyping of abnormalities Geographically diverse cohort allowing for a more generalizable understanding of post-COVID pulmonary sequela Limitations: Selected cohort given proximity to a participating center Small cohort which may be underpowered to identify small changes in pulmonary function.

  View details for DOI 10.1186/s40814-022-01151-8

  View details for PubMedID 36123599

• Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy. Nature communications Parikh, V. N., Ioannidis, A. G., Jimenez-Morales, D., Gorzynski, J. E., De Jong, H. N., Liu, X., Roque, J., Cepeda-Espinoza, V. P., Osoegawa, K., Hughes, C., Sutton, S. C., Youlton, N., Joshi, R., Amar, D., Tanigawa, Y., Russo, D., Wong, J., Lauzon, J. T., Edelson, J., Mas Montserrat, D., Kwon, Y., Rubinacci, S., Delaneau, O., Cappello, L., Kim, J., Shoura, M. J., Raja, A. N., Watson, N., Hammond, N., Spiteri, E., Mallempati, K. C., Montero-Martín, G., Christle, J., Kim, J., Kirillova, A., Seo, K., Huang, Y., Zhao, C., Moreno-Grau, S., Hershman, S. G., Dalton, K. P., Zhen, J., Kamm, J., Bhatt, K. D., Isakova, A., Morri, M., Ranganath, T., Blish, C. A., Rogers, A. J., Nadeau, K., Yang, S., Blomkalns, A., O'Hara, R., Neff, N. F., DeBoever, C., Szalma, S., Wheeler, M. T., Gates, C. M., Farh, K., Schroth, G. P., Febbo, P., deSouza, F., Cornejo, O. E., Fernandez-Vina, M., Kistler, A., Palacios, J. A., Pinsky, B. A., Bustamante, C. D., Rivas, M. A., Ashley, E. A. 2022; 13 (1): 5107

  Abstract

  The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

  View details for DOI 10.1038/s41467-022-32397-8

  View details for PubMedID 36042219

• Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO). Med (New York, N.Y.) Mylonakis, E., Lutaakome, J., Jain, M. K., Rogers, A. J., Molto, J., Benet, S., Mourad, A., Files, D. C., Mugerwa, H., Kityo, C., Kiweewa, F., Nalubega, M. G., Kitonsa, J., Nabenkema, E., Murray, D. D., Braun, D., Kamel, D., Higgs, E. S., Hatlen, T. J., Kan, V. L., Sanchez, A., Tierney, J., Denner, E., Wentworth, D., Babiker, A. G., Davey, V. J., Gelijns, A. C., Matthews, G. V., Thompson, B. T., Lane, H. C., Neaton, J. D., Lundgren, J. D. 2022; 3 (8): 531-537

  Abstract

  The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.

  View details for DOI 10.1016/j.medj.2022.07.003

  View details for PubMedID 35963234

• Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study. EBioMedicine Ozonoff, A., Schaenman, J., Jayavelu, N. D., Milliren, C. E., Calfee, C. S., Cairns, C. B., Kraft, M., Baden, L. R., Shaw, A. C., Krammer, F., van Bakel, H., Esserman, D. A., Liu, S., Sesma, A. F., Simon, V., Hafler, D. A., Montgomery, R. R., Kleinstein, S. H., Levy, O., Bime, C., Haddad, E. K., Erle, D. J., Pulendran, B., Nadeau, K. C., Davis, M. M., Hough, C. L., Messer, W. B., Higuita, N. I., Metcalf, J. P., Atkinson, M. A., Brakenridge, S. C., Corry, D., Kheradmand, F., Ehrlich, L. I., Melamed, E., McComsey, G. A., Sekaly, R., Diray-Arce, J., Peters, B., Augustine, A. D., Reed, E. F., Altman, M. C., Becker, P. M., Rouphael, N. 2022; 83: 104208

  Abstract

  Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed.The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63- 4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC.Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19.NIH.

  View details for DOI 10.1016/j.ebiom.2022.104208

  View details for PubMedID 35952496

• Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post-COVID-19 syndrome. JCI insight Jia, X., Cao, S., Lee, A. S., Manohar, M., Sindher, S. B., Ahuja, N., Artandi, M., Blish, C. A., Blomkalns, A. L., Chang, I., Collins, W. J., Desai, M., Din, H. N., Do, E., Fernandes, A., Geng, L. N., Rosenberg-Hasson, Y., Mahoney, M. R., Glascock, A. L., Chan, L. Y., Fong, S. Y., Phelps, M., Raeber, O., Purington, N., Röltgen, K., Rogers, A. J., Snow, T., Wang, T. T., Solis, D., Vaughan, L., Verghese, M., Maecker, H., Wittman, R., Puri, R., Kistler, A., Yang, S., Boyd, S. D., Pinsky, B. A., Chinthrajah, S., Nadeau, K. C. 2022; 7 (13)

  Abstract

  BACKGROUNDProlonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODSAdult SARS-CoV-2 reverse transcription PCR-positive (RT-PCR-positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTSOur cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSIONWe found that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATIONClinicalTrials.gov, NCT04373148.FUNDINGNIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

  View details for DOI 10.1172/jci.insight.156713

  View details for PubMedID 35801588

• COVID-19 Acute Respiratory Distress Syndrome: One Pathogen, Multiple Phenotypes. Critical care clinics Empson, S., Rogers, A. J., Wilson, J. G. 2022; 38 (3): 505-519

  Abstract

  Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome arising from multiple causes with a range of clinical severity. In recent years, the potential for prognostic and predictive enrichment of clinical trials has been increased with identification of more biologically homogeneous subgroups or phenotypes within ARDS. COVID-19 ARDS also exhibits significant clinical heterogeneity despite a single causative agent. In this review the authors summarize the existing literature on COVID-19 ARDS phenotypes, including physiologic, clinical, and biological subgroups as well as the implications for improving both prognostication and precision therapy.

  View details for DOI 10.1016/j.ccc.2022.02.001

  View details for PubMedID 35667740

• Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death: an analysis of population-wide data from 63 countries. European journal of epidemiology Geldsetzer, P., Mukama, T., Jawad, N. K., Riffe, T., Rogers, A., Sudharsanan, N. 2022

  Abstract

  Men are more likely than women to die due to coronavirus disease 2019 (COVID-19). An open question is whether these sex differences reflect men's generally poorer health and lower life expectancy compared to women of similar ages or if men face a unique COVID-19 disadvantage. Using age-specific data on COVID-19 mortalityas well as cause-specific and all-cause mortality for 63 countries, we compared the sex difference in COVID-19 mortality to sexdifferences in all-causemortality and mortality fromother common causes of death to determine the magnitude of theexcess male mortalitydisadvantage for COVID-19. We found that sex differences in the age-standardized COVID-19 mortality rate were substantially larger than for the age-standardized all-cause mortality rate and mortality rate formost other common causes of death. Theexcess male mortality disadvantage for COVID-19 was especially large in the oldest age groups. Our findings suggest that the causal pathways that link male sex to a higher mortality from a SARS-CoV-2 infection may be specific to SARS-CoV-2, rather than shared with the pathways responsible for the shorter life expectancy among men or sex differences for other common causes of death. Understanding these causal chains could assist in the development of therapeutics and preventive measures for COVID-19 and, possibly, other coronavirus diseases.

  View details for DOI 10.1007/s10654-022-00866-5

  View details for PubMedID 35737205

• Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections. JCI insight Kratochvil, M. J., Kaber, G., Demirdjian, S., Cai, P. C., Burgener, E. B., Nagy, N., Barlow, G. L., Popescu, M., Nicolls, M. R., Ozawa, M. G., Regula, D. P., Pacheco-Navarro, A. E., Yang, S., de Jesus Perez, V. A., Karmouty-Quintana, H., Peters, A. M., Zhao, B., Buja, M. L., Johnson, P. Y., Vernon, R. B., Wight, T. N., Stanford COVID-19 Biobank Study Group, Milla, C. E., Rogers, A. J., Spakowitz, A. J., Heilshorn, S. C., Bollyky, P. L. 2022; 7 (12)

  Abstract

  Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.

  View details for DOI 10.1172/jci.insight.152629

  View details for PubMedID 35730564

• Machine learning approaches to the human metabolome in sepsis identify metabolic links with survival. Intensive care medicine experimental Kosyakovsky, L. B., Somerset, E., Rogers, A. J., Sklar, M., Mayers, J. R., Toma, A., Szekely, Y., Soussi, S., Wang, B., Fan, C. S., Baron, R. M., Lawler, P. R. 2022; 10 (1): 24

  Abstract

  BACKGROUND: Metabolic predictors and potential mediators of survival in sepsis have been incompletely characterized. We examined whether machine learning (ML) tools applied to the human plasma metabolome could consistently identify and prioritize metabolites implicated in sepsis survivorship, and whether these methods improved upon conventional statistical approaches.METHODS: Plasma gas chromatography-liquid chromatography mass spectrometry quantified 411 metabolites measured≤72h of ICU admission in 60 patients with sepsis at a single center (Brigham and Women's Hospital, Boston, USA). Seven ML approaches were trained to differentiate survivors from non-survivors. Model performance predicting 28day mortality was assessed through internal cross-validation, and innate top-feature (metabolite) selection and rankings were compared across the 7 ML approaches and with conventional statistical methods (logistic regression). Metabolites were consensus ranked by a summary, ensemble ML ranking procedure weighing their contribution to mortality risk prediction across multiple ML models.RESULTS: Median (IQR) patient age was 58 (47, 62) years, 45% were women, and median (IQR) SOFA score was 9 (6, 12). Mortality at 28days was 42%. The models' specificity ranged from 0.619 to 0.821. Partial least squares regression-discriminant analysis and nearest shrunken centroids prioritized the greatest number of metabolites identified by at least one other method. Penalized logistic regression demonstrated top-feature results that were consistent with many ML methods. Across the plasma metabolome, the 13 metabolites with the strongest linkage to mortality defined through an ensemble ML importance score included lactate, bilirubin, kynurenine, glycochenodeoxycholate, phenylalanine, and others. Four of these top 13 metabolites (3-hydroxyisobutyrate, indoleacetate, fucose, and glycolithocholate sulfate) have not been previously associated with sepsis survival. Many of the prioritized metabolites are constituents of the tryptophan, pyruvate, phenylalanine, pentose phosphate, and bile acid pathways.CONCLUSIONS: We identified metabolites linked with sepsis survival, some confirming prior observations, and others representing new associations. The application of ensemble ML feature-ranking tools to metabolomic data may represent a promising statistical platform to support biologic target discovery.

  View details for DOI 10.1186/s40635-022-00445-8

  View details for PubMedID 35710638

• A Retrospective Analysis of Medical Student Performance Evaluations, 2014-2020: Recommend with Reservations. Journal of general internal medicine Tisdale, R. L., Filsoof, A. R., Singhal, S., Caceres, W., Nallamshetty, S., Rogers, A. J., Verghese, A. C., Harrington, R. A., Witteles, R. M. 2022

  Abstract

  BACKGROUND: The Medical Student Performance Evaluations (MSPE) is a cornerstone of residency applications. Little is known regarding adherence to Association of American Medical Colleges (AAMC) MSPE recommendations and longitudinal changes in MSPE content.OBJECTIVES: Evaluate current MSPE quality and longitudinal changes in MSPE and grading practices.DESIGN: Retrospective analysis.PARTICIPANTS: Students from all Liaison Committee on Medical Education (LCME)-accredited medical schools from which the Stanford University Internal Medicine residency program received applications between 2014-2015 and 2019-2020.MAIN MEASURES: Inclusion of key words to describe applicant performance and metrics thereof, including distribution among students and key word assignment explanation; inclusion of clerkship grades, grade distributions, and grade composition; and evidence of grade inflation over time.KEY RESULTS: MSPE comprehensiveness varied substantially among the 149 schools analyzed. In total, 25% of schools provided complete information consistent with AAMC recommendations regarding key word/categorization of medical students and clerkship grades in 2019-2020. Seventy-seven distinct key word terms appeared across the 139 schools examined in 2019-2020. Grading practices markedly varied, with 2-83% of students receiving the top internal medicine clerkship grade depending on the year and school. Individual schools frequently changed key word and grading practices, with 33% and 18% of schools starting and/or stopping use of key words and grades, respectively. Significant grade inflation occurred over the 6-year study period, with an average 14% relative increase in the proportion of students receiving top clerkship grades.CONCLUSIONS: A minority of schools complies with AAMC MSPE guidelines, and MSPEs are inconsistent across time and schools. These practices may impair evaluation of students within and between schools.

  View details for DOI 10.1007/s11606-022-07502-8

  View details for PubMedID 35710660

• Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial. Critical care (London, England) Boyle, A. J., Ferris, P., Bradbury, I., Conlon, J., Shankar-Hari, M., Rogers, A. J., O'Kane, C. M., McAuley, D. F. 2022; 26 (1): 164

  Abstract

  BACKGROUND: Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18.METHODS: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1beta compared.RESULTS: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥800pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30-2.73]; p=0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p=0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1beta.CONCLUSION: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.

  View details for DOI 10.1186/s13054-022-04025-w

  View details for PubMedID 35672834

• Influence of the COVID-19 Pandemic on Author Gender and Manuscript Acceptance Rates among Pulmonary and Critical Care Journals. Annals of the American Thoracic Society Gershengorn, H. B., Vranas, K. C., Ouyang, D., Cheng, S., Rogers, A. J., Schweiger, L., Cooke, C. R., Slatore, C. G. 2022

  Abstract

  RATIONALE: The COVID-19 pandemic has negatively affected women more than men and may influence the publication of non-COVID research.OBJECTIVES: Evaluate whether the COVID-19 pandemic is associated with changes in manuscript acceptance rates among pulmonary/critical care journals, and gender-based disparities in these rates.METHODS: We analyzed first, senior, and corresponding-author gender (female vs. male, identified by matching first names in a validated Genderize database) of manuscripts submitted to four pulmonary/critical care journals between 1/1/18-12/31/20. We constructed interrupted time series regression models to evaluate whether the proportion of female first and senior authors of non-COVID-19 original research manuscripts changed with the pandemic. Next, we performed multivariable logistic regressions to evaluate the association of author gender with acceptance of original research manuscripts.RESULTS: Among 8,332 original research submissions, women comprised 39.9% and 28.3% of first and senior authors, respectively. We found no change in the proportion of female first or senior-authors of non-COVID-19 or COVID-19-submitted research manuscripts during the COVID-era. Non-COVID-19 manuscripts submitted during the COVID-era had reduced odds of acceptance, regardless of author gender (first-author: adjustedOR [aOR]0.46 [95%CI0.36-0.59]; senior-author: aOR0.46 [95%CI0.37-0.57]). Female senior-authorship was associated with decreased acceptance of non-COVID research manuscripts (crude rates: 14.4% [male] vs 13.2% [female]; aOR0.84, 95%CI0.71-0.99).CONCLUSIONS: Although female author submissions were not disproportionately influenced by COVID-19, we found evidence suggesting gender disparities in manuscript acceptance rates. Journals may need to consider strategies to reduce this disparity and academic institutions may need to factor our findings, including lower acceptance rates for non-COVID manuscripts, into promotion decisions.

  View details for DOI 10.1513/AnnalsATS.202203-277OC

  View details for PubMedID 35588358

• The Influence of the COVID-19 Pandemic on Author Gender and Manuscript Acceptance Rates Among Pulmonary and Critical Care Journals Vranas, K. C., Gershengorn, H. B., Ouyang, D., Cheng, S., Rogers, A., Schweiger, L., Cooke, C. R., Slatore, C. G. AMER THORACIC SOC. 2022

  View details for Web of Science ID 000792480403562

• Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial LANCET INFECTIOUS DISEASES Self, W. H., Sandkovsky, U., Reilly, C. S., Vock, D. M., Gottlieb, R. L., Mack, M., Golden, K., Dishner, E., Vekstein, A., Ko, E. R., Der, T., Franzone, J., Almasri, E., Fayed, M., Filbin, M. R., Hibbert, K. A., Rice, T. W., Casey, J. D., Hayanga, J., Badhwar, V., Leshnower, B. G., Sharifpour, M., Knowlton, K. U., Peltan, I. D., Bakowska, E., Kowalska, J., Bowdish, M. E., Sturek, J. M., Rogers, A. J., Files, D., Mosier, J. M., Gong, M. N., Douin, D. J., Hite, R., Trautner, B. W., Jain, M. K., Gardner, E. M., Khan, A., Jensen, J., Matthay, M. A., Ginde, A. A., Brown, S. M., Higgs, E. S., Pett, S., Weintrob, A. C., Chang, C. C., Murrary, D. D., Gunthard, H. F., Moquete, E., Grandits, G., Engen, N., Grund, B., Sharma, S., Cao, H., Gupta, R., Osei, S., Margolis, D., Zhu, Q., Polizzotto, M. N., Babiker, A. G., Davey, V. J., Kan, V., Thompson, B., Gelijns, A. C., Neaton, J. D., Lane, H., Lundgren, J. D., ACTIV-3 Theropeutics Inpatients CO 2022; 22 (5): 622-635

  Abstract

  We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.US National Institutes of Health and Operation Warp Speed.

  View details for DOI 10.1016/S1473-3099(21)00751-9

  View details for Web of Science ID 000821471300027

  View details for PubMedID 34953520

  View details for PubMedCentralID PMC8700279

• Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19. Open forum infectious diseases Ram-Mohan, N., Kim, D., Rogers, A. J., Blish, C. A., Nadeau, K. C., Blomkalns, A. L., Yang, S. 2022; 9 (2): ofab646

  Abstract

  Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, worst disease severity, and length of symptoms.

  View details for DOI 10.1093/ofid/ofab646

  View details for PubMedID 35111870

  View details for PubMedCentralID PMC8802799

• Anti-type I interferon antibodies as a cause of severe COVID-19. Faculty reviews Fajgenbaum, D. C., Hayday, A. C., Rogers, A. J., Towers, G. J., Wack, A., Zanoni, I. 2022; 11: 15

  Abstract

  COVID-19 ranges from asymptomatic through to respiratory failure and death. Although specific pre-existing conditions such as age and male sex have been associated with poor outcomes, we remain largely ignorant of the mechanisms predisposing to severe disease. In this study, the authors discovered that approximately 10% of 987 patients with life-threatening COVID-19 harbored neutralizing antibodies to Type I interferons (IFNs)1. They demonstrated that these antibodies could neutralize high concentrations of the corresponding IFN and could rescue SARS-CoV-2 infection from inhibition by IFN in vitro. Importantly, anti-IFN antibodies were associated with low levels of serum IFN. These observations suggest that disease severity in these individuals results from a failure to control SARS-CoV-2 replication because of antibody-mediated IFN inhibition. The study suggests specific treatments and diagnostics for this class of severe COVID-19.

  View details for DOI 10.12703/r-01-0000010

  View details for PubMedID 35812362

• Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. The New England journal of medicine REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, E. C., Bradbury, C. A., McVerry, B. J., Lawler, P. R., Berger, J. S., Gong, M. N., Carrier, M., Reynolds, H. R., Kumar, A., Turgeon, A. F., Kornblith, L. Z., Kahn, S. R., Marshall, J. C., Kim, K. S., Houston, B. L., Derde, L. P., Cushman, M., Tritschler, T., Angus, D. C., Godoy, L. C., McQuilten, Z., Kirwan, B., Farkouh, M. E., Brooks, M. M., Lewis, R. J., Berry, L. R., Lorenzi, E., Gordon, A. C., Berry, S. M., McArthur, C. J., Neal, M. D., Hochman, J. S., Webb, S. A., Zarychanski, R., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y. M., Aryal, D., Baumann Kreuziger, L., Beane, A., Bhimani, Z., Bihari, S., Billett, H. H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L. A., Chekuri, S., Chen, J., Cheng, A. C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T. W., de Brouwer, S., Detry, M. A., Duggal, A., Dzavik, V., Effron, M. B., Eng, H. F., Escobedo, J., Estcourt, L. J., Everett, B. M., Fergusson, D. A., Fitzgerald, M., Fowler, R. A., Froess, J. D., Fu, Z., Galanaud, J. P., Galen, B. T., Gandotra, S., Girard, T. D., Goodman, A. L., Goossens, H., Green, C., Greenstein, Y. Y., Gross, P. L., Haniffa, R., Hegde, S. M., Hendrickson, C. M., Higgins, A. M., Hindenburg, A. A., Hope, A. A., Horowitz, J. M., Horvat, C. M., Huang, D. T., Hudock, K., Hunt, B. J., Husain, M., Hyzy, R. C., Jacobson, J. R., Jayakumar, D., Keller, N. M., Khan, A., Kim, Y., Kindzelski, A., King, A. J., Knudson, M. M., Kornblith, A. E., Kutcher, M. E., Laffan, M. A., Lamontagne, F., Le Gal, G., Leeper, C. M., Leifer, E. S., Lim, G., Gallego Lima, F., Linstrum, K., Litton, E., Lopez-Sendon, J., Lother, S. A., Marten, N., Saud Marinez, A., Martinez, M., Mateos Garcia, E., Mavromichalis, S., McAuley, D. F., McDonald, E. G., McGlothlin, A., McGuinness, S. P., Middeldorp, S., Montgomery, S. K., Mouncey, P. R., Murthy, S., Nair, G. B., Nair, R., Nichol, A. D., Nicolau, J. C., Nunez-Garcia, B., Park, J. J., Park, P. K., Parke, R. L., Parker, J. C., Parnia, S., Paul, J. D., Pompilio, M., Quigley, J. G., Rosenson, R. S., Rost, N. S., Rowan, K., Santos, F. O., Santos, M., Santos, M. O., Satterwhite, L., Saunders, C. T., Schreiber, J., Schutgens, R. E., Seymour, C. W., Siegal, D. M., Silva, D. G., Singhal, A. B., Slutsky, A. S., Solvason, D., Stanworth, S. J., Turner, A. M., van Bentum-Puijk, W., van de Veerdonk, F. L., van Diepen, S., Vazquez-Grande, G., Wahid, L., Wareham, V., Widmer, R. J., Wilson, J. G., Yuriditsky, E., Zhong, Y., Manax, V., Connor, J., Bion, J., Gates, S., Reynolds, J., van der Poll, T., Al-Beidh, F., Angus, D., Annane, D., Arabi, Y., Beane, A., van Bentum-Pujik, W., Berry, S., Bhimani, Z., Bonten, M., Bradbury, C., Brunkhorst, F., Buxton, M., Cheng, A., Derde, L., Estcourt, L., Goossens, H., Gordon, A., Green, C., Haniffa, R., Lamontagne, F., Lawler, P., Linstrum, K., Litton, E., Marshall, J., McArthur, C., McAuley, D., McGuinness, S., McVerry, B., Montgomery, S., Mouncey, P., Murthy, S., Nichol, A., Parke, R., Parker, J., Rowan, K., Santos, M., Seymour, C., Turgeon, A., Turner, A., van de Veerdonk, F., Webb, S., Zarychanski, R., Campbell, L., Forbes, A., Gattas, D., Heritier, S., Kruger, P., Peake, S., Presneill, J., Seppelt, I., Trapani, T., Young, P., Cuthbertson, B., Fowler, R., Manoharan, V., Aryal, D., Dondrop, A. M., Hashmi, M., Jayakumar, D., Tolppa, T., Singh, V., Brillinger, N., Cecconi, M., Ermann, S., Francois, B., Hullegie, S., Markgraff, R., Pletz, M., Povoa, P., Rohde, G., Parker, L., Scheepstra-Beukers, I., Alexander, B., Basile, K., Girard, T., Horvat, C., Huang, D., Mayr, F., Beasley, R., Daneman, N., Fowler, R., McGloughlin, S., Morpeth, S., Paterson, D., Venkatesh, A. N., de Jong, M., Uyeki, T., Baillie, K., Duffy, E., Hills, T., Orr, K., Patanwala, A., Tong, S., Cooper, N., Cremer, O., Galea, J., King, A., Leavis, H., Netea, M., Ogungbenro, K., Patawala, A., Pettila, V., Rademaker, E., Saxena, M., Sligl, W., Tong, S., Youngstein, T., Seymour, C. W., Aryal, D. A., Bihari, S., Carrier, M., Fergusson, D., Goligher, E., Hunt, B., Jayakumar, D., Kumar, A., Laffan, M., Lother, S., Middeldorp, S., McQuilten, Z., Neal, M., Schutgens, R., Stanworth, S., Adhikari, N., Anstey, M., Brant, E., de Man, A., Lamonagne, F., Masse, M., Udy, A., Arnold, D., Begin, P., Charlewood, R., Chasse, M., Coyne, M., Cooper, J., Daly, J., Gosbell, I., Harvala-Simmonds, H., Hills, T., MacLennan, S., Menon, D., McDyer, J., Pridee, N., Roberts, D., Shankar-Hari, M., Thomas, H., Tinmouth, A., Triulzi, D., Walsh, T., Wood, E., Calfee, C., O'Kane, C., Shyamsundar, M., Sinha, P., Thompson, T., Young, I., Haidar, G., Lawless, P., Weissman, A., Ferguson, N., Hodgson, C., Laffey, J., Orford, N., Neto, A., Baron, R., Epelman, S., Frankfurter, C., Gommans, F., Kim, E., Leaf, D., Vaduganathan, M., van Kimmenade, R., Detry, M., Fitzgerald, M., Lewis, R., McGlothlin, A., Sanil, A., Saunders, C., Berry, L., Lorenzi, E., Buzgau, A., Higgins, A., Parker, P., Zammit, C., Groeneveld, E., Peters, S., Okundaye, C., van Hout, D., Smit, A., Rikkert, L., Bari, S., Raymakers, K., Kwakkenbos-Craanen, M., Post, S., Schreuder, G., Markgraf, R., Ainscough, K., Brickell, K., Doran, P., Anjum, A., Lane, J., Fagbodun, E., Miller, L., Parry-Billings, K., Peters, S., Richards-Belle, A., Saull, M., Sprinckmoller, S., Wiley, D., Wunderley, R., van Beurden, M., Effelaar, E., Schotsman, J., Boyd, C., Harland, C., Shearer, A., Wren, J., Clermont, G., Garrard, W., Kalchthaler, K., Ricketts, D., Malakoutis, S., Marroquin, O., Music, E., Quinn, K., Attanayaka, U., Darshana, S., Ishani, P., Jawad, I., Pabasara, U., Udayanga, I., Gilmour, K., Pearson, K., Siewerski, C., Hurford, S., Marsh, E., Campbell, D., Williams, P., Shirley, K., Logan, M., Hanson, J., Dilley, B., Phillips, L., Oliver, A., Sutu, M., Murphy, S., Aravindan, L., Collins, J., Monaghan, H., Unsworth, A., Beddows, S., Dawson, L. A., Dyas, S., Asghar, A., Donaldson, K., Skinner, T., Mguni, N., Muzengi, N., Luo, J., O'Reilly, J., Levett, C., Potter, A., Porter, D., Lockett, T., Bartholomew, J., Rook, C., McKay, R., Williams, H., Hall, A., Campbell, H., Speight, H., Halden, S., Harrison, S., Naz, M., Lomme, K., Sharratt, P., Sheffield, J., Van't Hoff, W., Williamson, J. D., Barnard, A., Birch, C., Brend, M., Chambers, E., Crawshaw, S., Drake, C., Duckles-Leech, H., Graham, J., Harper, H., Lock, S., McMillan, N., O'Flaherty, C., OKell, E., Hayes, A., Sam, S., Slade, H., Walker, S., Wilding, K., Goodwin, J., Hodgson, H., Ellis, Y., Williamson, D., Bayne, M., Jackson, S., Byrne, R., McKenna, S., Clinton, A., McCracken, P., Young, M., Board, J., Martin, E., El-Khawas, K., Richardson, A., Hill, D., Commons, R. J., Abdelkharim, H., Knott, C., Smith, J., Boschert, C., Affleck, J., Apte, Y., Subbanna, U., Bartholdy, R., Frakking, T., Keat, K., Bhonagiri, D., Sanghavi, R., Nema, J., Ford, M., Parikh, H. G., Avard, B., Nourse, M., Cheung, W., Kol, M., Wong, H., Shah, A., Wagh, A., Simpson, J., Duke, G., Chan, P., Carter, B., Hunter, S., Laver, R. D., Shrestha, T., Jin, X., Regli, A., Pellicano, S., Palermo, A., Eroglu, E., French, C., Bates, S., Towns, M., Yang, Y., McGain, F., McCullough, J., Tallott, M., Kumar, N., Panwar, R., Brinkerhoff, G., Koppen, C., Cazzola, F., Brain, M., Mineall, S., Fischer, R., Biradar, V., Soar, N., White, H., Estensen, K., Morrison, L., Sutton, J., Cooper, M., Shehabi, Y., Al-Bassam, W., Hulley, A., Kadam, U., Sathianathan, K., Whitehead, C., Lowrey, J., Gresham, R., Masters, K., Walsham, J., Meyer, M. 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J., Nery, E., Saporito, W., Pereira, T., Mancini, B., Kowalski Neto, E., Andrade, B., Santos, J., Pompilio, M., Pompilio, R., Grava, S., Koga, K., Silva, M., Lemos, D., Villegas, B., Garcia, E. M., Cortes Vazquez, M. A., Perez Gonzalez, Y. S., Carreno Perez, P., Valenzuela, J., Santillan, J. A. 2021

  Abstract

  BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

  View details for DOI 10.1056/NEJMoa2103417

  View details for PubMedID 34351722

• Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. The New England journal of medicine ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, P. R., Goligher, E. C., Berger, J. S., Neal, M. D., McVerry, B. J., Nicolau, J. C., Gong, M. N., Carrier, M., Rosenson, R. S., Reynolds, H. R., Turgeon, A. F., Escobedo, J., Huang, D. T., Bradbury, C. A., Houston, B. L., Kornblith, L. Z., Kumar, A., Kahn, S. R., Cushman, M., McQuilten, Z., Slutsky, A. S., Kim, K. S., Gordon, A. C., Kirwan, B., Brooks, M. M., Higgins, A. M., Lewis, R. J., Lorenzi, E., Berry, S. M., Berry, L. R., Angus, D. C., McArthur, C. J., Webb, S. A., Farkouh, M. E., Hochman, J. S., Zarychanski, R., Aday, A. W., Al-Beidh, F., Annane, D., Arabi, Y. M., Aryal, D., Baumann Kreuziger, L., Beane, A., Bhimani, Z., Bihari, S., Billett, H. H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L. A., Chekuri, S., Chen, J., Cheng, A. 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R., Henderson, S., Van Der Heyden, K., Mehrtens, J., Morris, A., Morgan, S., Williams, T., Kazemi, A., Song, R., Lai, V., Girijadevi, D., Everitt, R., Russell, R., Hackin, D., Buehner, U., Williams, E., Browne, T., Grimwade, K., Goodson, J., Keet, O., Callender, O., Martynoga, R., Trask, K., Butler, A., Young, C., Lesona, E., Olatunji, S., Navarra, L., Sol Cruz, R., Perry, K., Fuchs, R., Lambert, B., Albrett, J., Jackson, C., Kirkham, S., Amaro Dos Santos Catorze, N. J., Lima Pereira, T. N., Castro Ferreira, R. M., Pereira Sousa Bastos, J. M., Oliveira Batista, T. M., Florescu, S. A., Stanciu, D., Zaharia, M. F., Kosa, A. G., Codreanu, D., Arabi, Y. M., Qasim, E. A., Tlayjeh, H., Alswaidan, L., Naidu, B., Munoz-Bermudez, R., Marin-Corral, J., Salazar Degracia, A., Parrilla Gomez, F., Mateo Lopez, M. I., Lopez, R. L., Rodriguez, J., Carcel, S., Carmona, R., de la Fuente, C., Rodriguez, M., Kaye, C., Allan, A., Summers, C., Polgarova, P., McWilliam, S. J., Hawcutt, D. B., Rad, L., O'Malley, L., Whitbread, J., Kelsall, O., Cowley, N., Wild, L., Thrush, J., Wood, H., Austin, K., Donnelly, A., Kelly, M., Smyth, N., O'Kane, S., McClintock, D., Warnock, M., Campbell, R., McCallion, E., Johnson, P., McKenna, S., Hanley, J., Currierbara Allen, A., McGoldrick, C., McMaster, M., Jha, R., Kalogirou, M., Ellis, C., Krishnamurthy, V., Deelchand, V., O'Connor, A., Silversides, J., McGuigan, P., Ward, K., O'Neill, A., Finn, S., Phillips, B., Ortiz-Ruiz de Gordoa, L., Bewley, J., Thomas, M., Sweet, K., Grimmer, L., Johnson, R., Pinnell, J., Robinson, M., Gledhill, L., Wood, T., Morgan, M., Cole, J., Hill, H., Davies, M., Williams, A., Thomas, E., Davies, R., Wise, M., Antcliffe, D., Templeton, M., Rojo, R., Coghlan, P., Smee, J., Mackay, E., Cort, J., Whileman, A., Spencer, T., Spittle, N., Beavis, S., Padmakumar, A., Dale, K., Hawes, J., Moakes, E., Gascoyne, R., Pritchard, K., Stevenson, L., Cooke, J., Nemeth-Roszpopa, K., Kasipandian, V., Patel, A., Allibone, S., Mary-Genetu, R., Ramali, M., Ghosh, A., Osagie, R., Jayasinghe Arachchige, M., Hartley, M., Bamford, P., London, E., Cawley, K., Faulkner, M., Jeffrey, H., Sundar Raj, A., Tsinaslanidis, G., Nair Khade, R., Nwajei Agha, G., Nalumansi Sekiwala, R., Smith, T., Brewer, C., Gregory, J., Limb, J., Cowton, A., O'Brien, J., Postlethwaite, K., Nikitas, N., Wells, C., Lankester, L., McMillan, H., Pulletz, M., Birch, J., Wiseman, S., Horton, S., Alegria, A., Turki, S., Elsefi, T., Crisp, N., Allen, L., Smith, M., Chukkambotla, S., Goddard, W., Duberley, S., McCullagh, I. J., Robinson, P., Patel, B., Kelly, S., Touma, O., Holland, S., Hodge, C., Taylor, H., Alderman, M., Barnes, N., Da Rocha, J., Smith, C., Brooks, N., Weerasinghe, T., Sinclair, J., Abusamra, Y., Doherty, R., Cudlipp, J., Singh, R., Yu, H., Daebis, A., Ng, C., Kendrick, S., Saran, A., Makky, A., Greener, D., Rowe-Leete, L., Edwards, A., Bland, Y., Dolman, R., Foster, T., Linnett, V., Sanderson, A., Ritzema, J., Wild, H., Khare, D., Pinder, M., Selvamoni, S., Gopinath, A., Pugh, R., Menzies, D., Lean, R., Qiu, X., Scanlon, J. J., Puxty, K., Cathcart, S., McGovern, C., Carmichael, S., Rimmer, D., Yusuff, H., Isgro, G., Brightling, C., Bourne, M., Craner, M., Boyles, R., Szakmany, T., Cherian, S., Williams, G., James, C., Waters, A., Watters, M., Prout, R., Davies, L., Pegler, S., Kyeremeh, L., Mian, A., Ostermann, M., Marotti, M., Grau Novellas, N., Bociek, A., Brett, S., Sousa Arias, S., Hall, R. E., Jain, S., Gupta, A., Holbrook, C., Henning, J., Bonner, S., Hugill, K., Cirstea, E., Wilkinson, D., Jones, J., Karlikowski, M., Sutherland, H., Wilhelmsen, E., Woods, J., North, J., Sundaran, D., Hollos, L., Coburn, S., Williams, A., Saunders, S., Hopkins, P., Smith, J., Noble, H., Depante, M. T., Clarey, E., Laha, S., Verlander, M., Williams, A., Paramasivam, E., Wilby, E., Ogg, B., Howcroft, C., Aspinwall, A., Charlton, S., Gould, R., Mistry, D., Awan, S., Bedford, C., Hall, A., Cooke, J., Gardiner-Hill, C., Maloney, C., Brunskill, N., QureshiI, H. R., Flint, N., Nicholson, S., Southin, S., Nicholson, A., Ghattaoraya, A., Harding, D., O'Halloran, S., Collins, A., Smith, E., Trues, E., Borgatta, B., Turner-Bone, I., Reddy, A., Wilding, L., Wilson, C., Surti, Z., Chamara Warnapura, L., Agno, R., Sathianathan, P., Shaw, D., Ijaz, N., Burns, D., Nisar, M., Quick, V., Alexander, C., Patel, S., Hussain, N., Croucher, Y., Langnu Rudran, E., Gilani, S., Wieder, T., Tate, M. L., Golden, D., Davey, M., Seaman, R., Felton, T., Bannard-Smith, J., Henry, J., Clark, R., Birchall, K., Pomeroy, F., Quayle, R., Wylie, K., Sukuraman, A., McNamarra, J., Makowski, A., Misztal, B., Ahmed, I., Neicker, K., Millington, S., Squires, R., Phulpoto, M., Stewart, R., Mwaura, E., Mew, L. E., Wren, L., Willams, F., Oborska, A., Maeda, R., Kalchko-Veyssal, S., Orat Prabakaran, R., Hadebe, B., Makmur, E., Nicholls, G., Innes, R., Doble, P., Graham, L., Shovelton, C., Hamlyn, V., Hawkins, N., Roynon-Reed, A., Cutler, S., Lewis, S., Lazaro, J. M., Newman, T., Austin, P., Chapman, S., Cabrelli, L., Fletcher, S., Nortje, J., Fottrell-Gould, D., Randell, G., Stammers, K., Zaman, M., Elmahi, E., Jones, A., Hall, K., Mills, G. H., Ryalls, K., Harrington, K., Bowler, H., Sall, J., Bourne, R., Borrill, Z., Duncan, T., Lamb, T., Shaw, J., Fox, C., Smith, K., Holland, S., Blackledge, B., McMorrow, L., Durrans, L., Harris, J., Moreno Cuesta, J., Xavier, K., Purohit, D., Elhassan, M., Haldeos, A., Vincent, R., Abdelrazik, M., Jenkins, S., Ganesan, A., Kumar, R., Carter, D., Bakthavatsalam, D., Rowland, M., Hutton, P., Bashyal, A., Davidson, N., Hird, C., Beer, S., Chhablani, M., Phalod, G., Kirkby, A., Archer, S., Netherton, K., Philips, B., Mullan, D., Skinner, D., Gaylard, J., Newman, J., Sathe, S. A., Roche, L., Davies, E., Turner, K., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Pogson, D., Rose, S., Daly, Z., Brimfield, L., Nown, A., Parekh, D., Bergin, C., Bates, M., McGhee, C., Lynch, D., Bhandal, K., Tsakiridou, K., Bamford, A., Cooper, L., Whitehouse, T., Veenith, T., Sim, M. A., Kennedy Hay, S., Henderson, S., Nygren, M., Valentine, E., Katary, A., Bell, G., Wilcox, L., English, K., Adams, A., Phull, M., Zaidi, A., Pogreban, T., Rosaroso, L. P., Harvey, D., Lowe, B., Meredith, M., Ryan, L., Hormis, A., Walker, R., Collier, D., Kimpton, S., Oakley, S., Rooney, K., Rodden, N., Hughes, E., Thomson, N., McGlynn, D., Clark, C., Clark, P., Walden, A., Keating, L., Frise, M., Okeke, T., Jacques, N., Coles, H., Tilney, E., Vowell, E., Schuster-Bruce, M., Pitts, S., Miln, R., Purandare, L., Vamplew, L., Patel, B., Dempster, D., Gummadi, M., Dormand, N., Wang, S. F., Spivey, M., Bean, S., Burt, K., Moore, L., Day, C., Gibson, C., Gordon, E., Zitter, L., Keenan, S., Singh, J., Lynch, C., Mikusek, J., Deacon, B., Baker, E., Hickey, J., Champanerkar, S., Aitken, L., Lewis Prosser, L., Raithatha, A., Bauchmuller, K., Ahmad, N., Wiles, M., Willson, J., Grecu, I., Martin, J., Wrey Brown, C., Arias, A., Bevan, E., Craven, T. H., Hope, D., Singleton, J., Clark, S., McCulloch, C., Welters, I. D., Hamilton, D. O., Williams, K., Waugh, V., Shaw, D., Mulla, S., Waite, A., Fernandez Roman, J., Lopez Martinez, M., Puthucheary, Z., Martin, T., Santos, F., Uddin, R., Fernandez, M., Seidu, F., Somerville, A., Pakats, M. L., Dias, P., Begum, S., Shahid, T., Bhagani, S., De Neef, M., Filipe, H., Mingos, S., Maharajh, A., Pakou, G., Nandani, A., Tatham, K. C., Jhanji, S., Blackurs, E., Dela Rosaurs, A., Howle, R., Baikady, R. R., Tully, R. P., Drummond, A., Dearden, J., Philbin, J. E., Munt, S., Gopal, S., Pooni, J., Ganguly, S., Smallwood, A., Metherell, S., Vuylsteke, A., Chan, C., Victor, S., Hospital, P., Matsa, R., Gellamucho, M., Creagh-Brown, B., Tooley, J., Montague, L., De Beaux, F., Bullman, L., Kerslake, I., Demetriou, C., Mitchard, S., Ramos, L., White, K., Reay, M., Jenkins, S., Tuckwell, C., Watts, A., Traverse, E., Jennings, S., Donnison, P., Johns, M., Casey, R., Mattocks, L., Salisbury, S., Dark, P., Harvey, A., Reece, R., Doonan, D., Knowles, K., Hulme, J., Kannan, S., Joseph, S., Kinney, F., Senya, H. J., Ratnam, V., Gill, M., Kirk, J., Shelton, S., Frey, C., Scano, R., McKee, M., Murphy, P., Thomas, M., Worner, R., Faulkner, B., Gendall, E., Hayes, K., Hayley, H., Blakemore, B., Borislavova, B., Hamilton-Davies, C., Chan, C., Mfuko, C., Abbass, H., Mandadapu, V., Leaver, S., Patel, K., Farnell-Ward, S., Pepermans Saluzzio, R., Rawlins, J., Banach, D., Fernandez de Pinedo Artaraz, Z., Cabreros, L., White, I., Croft, M., Holland, N., Pereira, R., Zaki, A., Johnson, D., Jackson, M., Garrard, H., Juhaz, V., Brown, L., Roy, A., Rostron, A., Woods, L., Cornell, S., Pillai, S., Harford, R., Ivatt, H., Evans, D., Richards, S., Roberts, E., Bowen, J., Ainsworth, J., Clark, T., Foulds, A., Atkins, S., Lee, K., Barber, R., Hilldrith, A., Hewitt, C., Bremmer, P., Ward, G., Bassford, C., Brohi, F., Jagannath, V., Clark, M., Purvis, S., Wetherill, B., Dushianthan, A., Cusack, R., de Courcy-Golder, K., Salmon, K., Burnish, R., Smith, S., Jackson, S., Ruiz, W., Duke, Z., Johns, M., Male, M., Gladas, K., Virdee, S., Swabe, J., Tomlinson, H., Attwood, B., Parsons, P., Campbell, B., Smith, A., Page, V. J., Zhao, X. B., Oza, D., Abrahamson, G., Sheath, B., Ellis, C., Rhodes, J., Anderson, T., Morris, S., Xia Le Tai, C., Thomas, A., Keen, A., Tridente, A., Shuker, K., Anders, J., Greer, S., Scott, P., Millington, A., Buchanan, P., Kirk, J., Denmade, C., Sadera, G., Jacob, R., Jones, C., Hughes, D., Digby, S., Southern, D., Reddy, H., Hulse, S., Campbell, A., Garton, M., Watkins, C., Smuts, S., Quinn, A., Simpson, B., McMillan, C., Finch, C., Hill, C., Cooper, J., Budd, J., Small, C., O'Leary, R., Birch, J., Collins, E., Alexander, P. D., Ferguson, S., Sellers, K., Bradley-Potts, J., Yates, D., Birkinshaw, I., Kell, K., Scott, Z., Pearson, H., Adams, P., Vita, T., Buhay, M., Winters, J., Doherty, K., Ghaffari, M., Bagavathy, K., Donadee, C., Bryan-Morris, K., Arnold, J., Reynolds, B., Beard, G., McAdams, D., Walker, G., Gingo, M., Dunsavage, D., Saiyed, S., Hernandez, E., Goldman, J., Brown, C., Comp, S., Raczek, J., Morris, J. L., Vargas, J. J., Weiss, D., Hensley, J. W., Kochert, E., Wnuk, C., Nemeth, C., Mowery, B., Hutchinson, C., Winters, L., Martin, E., Bariola, R., Viehman, A., Daley, J., Lopus, A., Schmidhofer, M., Sackrowitz, R., Skrtich, A., Minnier, T., Wisniewski, M. K., Mayak, K., Ambrosino, R., Keen, S., Della Toffalo, S., Stambaugh, M., Trimmer, K., Perri, R., Casali, S., Medva, R., Massar, B., Beyerl, A., Burkey, J., Keeler, S., Lowery, M., Oncea, L., Daugherty, J., Sevilla, C., Woelke, A., Dice, J., Weber, L., Roth, J., Ferringer, C., Beer, D. 2021

  Abstract

  BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT02735707, and NCT04359277.).

  View details for DOI 10.1056/NEJMoa2105911

  View details for PubMedID 34351721

• Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. The Journal of experimental medicine Wilk, A. J., Lee, M. J., Wei, B., Parks, B., Pi, R., Martinez-Colon, G. J., Ranganath, T., Zhao, N. Q., Taylor, S., Becker, W., Stanford COVID-19 Biobank, Jimenez-Morales, D., Blomkalns, A. L., O'Hara, R., Ashley, E. A., Nadeau, K. C., Yang, S., Holmes, S., Rabinovitch, M., Rogers, A. J., Greenleaf, W. J., Blish, C. A. 2021; 218 (8)

  Abstract

  Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-kappaB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

  View details for DOI 10.1084/jem.20210582

  View details for PubMedID 34128959

• Plasma Metabolites in Early Sepsis Identify Distinct Clusters Defined by Plasma Lipids. Critical care explorations Rogers, A. J., Leligdowicz, A., Contrepois, K., Jauregui, A., Vessel, K., Deiss, T. J., Belzer, A., Liu, T., Lippi, M., Ke, S., Ross, E., Zhou, H., Hendrickson, C., Gomez, A., Sinha, P., Kangelaris, K. N., Liu, K. D., Calfee, C. S., Matthay, M. A. 2021; 3 (8): e0478

  Abstract

  Unbiased global metabolomic profiling has not been used to identify distinct subclasses in patients with early sepsis and sepsis-associated acute respiratory distress syndrome. In this study, we examined whether the plasma metabolome reflects systemic illness in early sepsis and in acute respiratory distress syndrome.DESIGN: Plasma metabolites were measured in subjects with early sepsis.SETTING: Patients were admitted from the emergency department to the ICU in a plasma sample collected within 24 hours of ICU admission. Metabolic profiling of 970 metabolites was performed by Metabolon (Durham, NC). Hierarchical clustering and partial least squares discriminant clustering were used to identify distinct clusters among patients with early sepsis and sepsis-associated acute respiratory distress syndrome.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Among critically ill patients with early sepsis (n = 197), three metabolically distinct subgroups were identified, with metabolic subtype driven by plasma lipids. Group 1, with 45 subjects (23% of cohort), had increased 60-day mortality (odds ratio, 2; 95% CI, 0.99-4.0; p = 0.04 for group 1 vs all others). This group also had higher rates of vasopressor-dependent shock, acute kidney injury, and met Berlin acute respiratory distress syndrome criteria more often (all p < 0.05). Conversely, metabolic group 3, with 76 subjects (39% of cohort), had the lowest risk of 60-day mortality (odds ratio, 0.44; 95% CI, 0.22-0.86; p = 0.01) and lower rates of organ dysfunction as reflected in a lower Simplified Acute Physiology Score II (p < 0.001). In contrast, global metabolomic profiling did not separate patient with early sepsis with moderate-to-severe acute respiratory distress syndrome (n = 78) from those with sepsis without acute respiratory distress syndrome (n = 75).CONCLUSIONS: Plasma metabolomic profiling in patients with early sepsis identified three metabolically distinct groups that were characterized by different plasma lipid profiles, distinct clinical phenotypes, and 60-day mortality. Plasma metabolites did not distinguish patients with early sepsis who developed acute respiratory distress syndrome from those who did not.

  View details for DOI 10.1097/CCE.0000000000000478

  View details for PubMedID 34345827

• The COVID-19 Outpatient Pragmatic Platform Study (COPPS): Study design of a multi-center pragmatic platform trial. Contemporary clinical trials Bunning, B., Hedlin, H., Purington, N., Sundaram, V., Kapphahn, K., Weng, Y., Cunanan, K., Maldonado, Y., Singh, U., Khosla, C., O'Hara, R., Nicolls, M., Springman, E., Parsonnet, J., Rogers, A., Levitt, J., Desai, M. 2021: 106509

  Abstract

  More than 3000 clinical trials related to COVID-19 have been registered through clinicaltrials.gov. With so many trials, there is a risk that many will be inconclusive due to being underpowered or due to an inability to recruit patients. At academic medical centers, multiple trials are competing for the same resources; the success of one may come at the expense of another. The COVID-19 Outpatient Pragmatic Protocol Study (COPPS) is a flexible phase 2, multi-site, randomized, blinded trial based at Stanford University designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. This approach reduces the overall number of patients required for statistical power, while improving the likelihood that any enrolled patient receives active treatment. The platform study has two main domains designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain), measured with self-collected nasal swabs, or improve clinical outcomes (Clinical Domain), measured through self-reported symptomology data. Data are collected on both domains for all participants enrolled. Participants are followed over a 28-day period. COPPS has the advantage of pragmatism created around its workflow that is also appealing to potential participants because of a lower probability of inactive treatment. At the conclusion of this clinical trial we expect to have identified potentially effective therapeutic strategy/ies for treating COVID-19 in the outpatient setting, which will have a transformative impact on medicine and public health.

  View details for DOI 10.1016/j.cct.2021.106509

  View details for PubMedID 34274494

• Prospective validation of an 11-gene mRNA host response score for mortality risk stratification in the intensive care unit. Scientific reports Moore, A. R., Roque, J., Shaller, B. T., Asuni, T., Remmel, M., Rawling, D., Liesenfeld, O., Khatri, P., Wilson, J. G., Levitt, J. E., Sweeney, T. E., Rogers, A. J. 2021; 11 (1): 13062

  Abstract

  Several clinical calculators predict intensive care unit (ICU) mortality, however these are cumbersome and often require 24h of data to calculate. Retrospective studies have demonstrated the utility of whole blood transcriptomic analysis in predicting mortality. In this study, we tested prospective validation of an 11-gene messenger RNA (mRNA) score in an ICU population. Whole blood mRNA from 70 subjects in the Stanford ICU Biobank with samples collected within 24h of Emergency Department presentation were used to calculate an 11-gene mRNA score. We found that the 11-gene score was highly associated with 60-day mortality, with an area under the receiver operating characteristic curve of 0.68 in all patients, 0.77 in shock patients, and 0.98 in patients whose primary determinant of prognosis was acute illness. Subjects with the highest quartile of mRNA scores were more likely to die in hospital (40% vs 7%, p<0.01) and within 60days (40% vs 15%, p=0.06). The 11-gene score improved prognostication with a categorical Net Reclassification Improvement index of 0.37 (p=0.03) and an Integrated Discrimination Improvement index of 0.07 (p=0.02) when combined with Simplified Acute Physiology Score 3 or Acute Physiology and Chronic Health Evaluation II score. The test performed poorly in the 95 independent samples collected>24h after emergency department presentation. Tests will target a 30-min turnaround time, allowing for rapid results early in admission. Moving forward, this test may provide valuable real-time prognostic information to improve triage decisions and allow for enrichment of clinical trials.

  View details for DOI 10.1038/s41598-021-91201-7

  View details for PubMedID 34158514

• Integrated analysis of multimodal single-cell data. Cell Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zager, M., Hoffman, P., Stoeckius, M., Papalexi, E., Mimitou, E. P., Jain, J., Srivastava, A., Stuart, T., Fleming, L. M., Yeung, B., Rogers, A. J., McElrath, J. M., Blish, C. A., Gottardo, R., Smibert, P., Satija, R. 2021

  Abstract

  The simultaneous measurement of multiple modalities represents an exciting frontier for single-cell genomics and necessitates computational methods that can define cellular states based on multimodal data. Here, we introduce "weighted-nearest neighbor" analysis, an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities. We apply our procedure to a CITE-seq dataset of 211,000 human peripheral blood mononuclear cells (PBMCs) with panels extending to 228 antibodies to construct a multimodal reference atlas of the circulating immune system. Multimodal analysis substantially improves our ability to resolve cell states, allowing us to identify and validate previously unreported lymphoid subpopulations. Moreover, we demonstrate how to leverage this reference to rapidly map new datasets and to interpret immune responses to vaccination and coronavirus disease 2019 (COVID-19). Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets and to look beyond the transcriptome toward a unified and multimodal definition of cellular identity.

  View details for DOI 10.1016/j.cell.2021.04.048

  View details for PubMedID 34062119

• Effect of Simvastatin on Mortality in ARDS Patients with Low Cholesterol: A Secondary Analysis of the HARP-2 Trial Pienkos, S., Moore, A. R., Guan, J., Levitt, J. E., Matthay, M. A., Choi, A. M., Baron, R. M., McAuley, D. F., O'Kane, C. M., Rogers, A. J. AMER THORACIC SOC. 2021

  View details for Web of Science ID 000685468902225

• Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19 ACS CENTRAL SCIENCE Delaveris, C. S., Wilk, A. J., Riley, N. M., Stark, J. C., Yang, S. S., Rogers, A. J., Ranganath, T., Nadeau, K. C., Blish, C. A., Bertozzi, C. R., Stanford COVID-19 Biobank 2021; 7 (4): 650-657

  View details for DOI 10.1021/acscentsci.0c01669

  View details for Web of Science ID 000645561800015

• A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. The New England journal of medicine Lundgren, J. D., Grund, B., Barkauskas, C. E., Holland, T. L., Gottlieb, R. L., Sandkovsky, U., Brown, S. M., Knowlton, K. U., Self, W. H., Files, D. C., Jain, M. K., Benfield, T., Bowdish, M. E., Leshnower, B. G., Baker, J. V., Jensen, J. U., Gardner, E. M., Ginde, A. A., Harris, E. S., Johansen, I. S., Markowitz, N., Matthay, M. A., Østergaard, L., Chang, C. C., Davey, V. J., Goodman, A., Higgs, E. S., Murray, D. D., Murray, T. A., Paredes, R., Parmar, M. K., Phillips, A. N., Reilly, C., Sharma, S., Dewar, R. L., Teitelbaum, M., Wentworth, D., Cao, H., Klekotka, P., Babiker, A. G., Gelijns, A. C., Kan, V. L., Polizzotto, M. N., Thompson, B. T., Lane, H. C., Neaton, J. D. 2021; 384 (10): 905-914

  Abstract

  LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

  View details for DOI 10.1056/NEJMoa2033130

  View details for PubMedID 33356051

  View details for PubMedCentralID PMC7781100

• The ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) Trial: Rationale and Design. Annals of the American Thoracic Society Levitt, J. E., Festic, E., Desai, M., Hedlin, H., Mahaffey, K. W., Rogers, A. J., Gajic, O., Matthay, M. A., ARREST Pneumonia Clinical Trial Investigators 2021

  Abstract

  Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stay among patients hospitalized for pneumonia. Further, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure among patients hospitalized with pneumonia is unknown. Here we describe the Arrest Respiratory Failure due to Pneumonia (ARREST Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm randomized double-blinded placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure in hospitalized participants with severe pneumonia. The primary outcome is acute respiratory failure within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation, or need for high flow nasal cannula oxygen therapy or non-invasive ventilation for > 36 hours (each alone or combined), or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at ten academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the National Heart Lung and Blood Institute and is registered in clinicaltrials.gov (NCT04193878).

  View details for DOI 10.1513/AnnalsATS.202009-1115SD

  View details for PubMedID 33493423

• SARS-CoV-2 RNAemia predicts clinical deterioration and extrapulmonary complications from COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Ram-Mohan, N. n., Kim, D. n., Zudock, E. J., Hashemi, M. M., Tjandra, K. C., Rogers, A. J., Blish, C. A., Nadeau, K. C., Newberry, J. A., Quinn, J. V., O'Hara, R. n., Ashley, E. n., Nguyen, H. n., Jiang, L. n., Hung, P. n., Blomkalns, A. L., Yang, S. n. 2021

  Abstract

  The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between SARS-CoV-2 RNAemia and disease severity, clinical deterioration, and specific EPCs.We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression.23.0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1.4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAaemic patients were more likely to manifest severe disease (OR 6.72 [95% CI, 2.45 - 19.79]), worsening of disease severity (OR 2.43 [95% CI, 1.07 - 5.38]), and EPCs (OR 2.81 [95% CI, 1.26 - 6.36]). RNA load correlated with maximum severity (r = 0.47 [95% CI, 0.20 - 0.67]).dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

  View details for DOI 10.1093/cid/ciab394

  View details for PubMedID 33949665

• What Does "ARDS" Mean during the COVID-19 Pandemic? Annals of the American Thoracic Society Brown, S. M., Peltan, I. D., Barkauskas, C., Rogers, A. J., Kan, V., Gelijns, A., Thompson, B. T. 2021

  View details for DOI 10.1513/AnnalsATS.202105-534PS

  View details for PubMedID 34288834

• Active surveillance of serious adverse events following transfusion of COVID-19 convalescent plasma. Transfusion Swenson, E., Wong, L. K., Jhaveri, P., Weng, Y., Kappagoda, S., Pandey, S., Pritchard, A., Rogers, A., Ruoss, S., Subramanian, A., Shan, H., Hollenhorst, M. 2021

  Abstract

  The reported incidence of adverse reactions following Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) transfusion has generally been lower than expected based on the incidence of transfusion reactions that have been observed in studies of conventional plasma transfusion. This raises the concern for under-reporting of adverse events in studies of CCP that rely on passive surveillance strategies.Our institution implemented a protocol to actively identify possible adverse reactions to CCP transfusion. In addition, we retrospectively reviewed the charts of inpatients who received CCP at Stanford Hospital between May 13, 2020 and January 31, 2021. We determined the incidence of adverse events following CCP transfusion.A total of 49 patients received CCP. Seven patients (14%) had an increased supplemental oxygen requirement within 4 h of transfusion completion, including one patient who was intubated during the transfusion. An additional 11 patients (total of 18, 37%) had increased oxygen requirements within 24 h of transfusion, including 3 patients who were intubated. Six patients (12%) fulfilled criteria for transfusion-associated circulatory overload (TACO).Using an active surveillance strategy, we commonly observed adverse events following the transfusion of CCP to hospitalized patients. It was not possible to definitively determine whether or not these adverse events are related to CCP transfusion. TACO was likely over-diagnosed given overlap with the manifestations of COVID-19. Nevertheless, these results suggest that the potential adverse effects of CCP transfusion may be underestimated by reports from passive surveillance studies.

  View details for DOI 10.1111/trf.16711

  View details for PubMedID 34677830

• A Perspective on the Role of Point-of-Care "Immuno-Triaging" to Optimize COVID-19 Vaccination Distribution in a Time of Scarcity. Frontiers in public health Zhang, Y., Rogers, A., Nadeau, K., Gu, J., Yang, S. 2021; 9: 638316

  Abstract

  Vaccine bears hope to bring COVID-19 pandemic under control. With limited supply, vaccines must be utilized efficiently to provide protection to those who need it most. Currently, no practical framework has been proposed to ensure fair vaccine allocation at individual level, which is a recognized problem. We propose here an evidence-based decision-making framework for COVID-19 vaccine appropriation that prioritizes vaccine doses to individuals based on their immunological status, or immuno-triaging. To ensure successful implementation of the proposed framework, point-of-care (POC) immunodiagnostic testing is needed to quickly ramp up the testing capability. Considerations for deploying POC immunodiagnostic testing at such a large scale are discussed. We hope that the proposed immunological decision-making framework for evidence-based COVID-19 vaccine appropriation provides an objective approach to ensure fair and efficient utilization of the scarce vaccine resource at the individual level that also maximizes the collective societal benefit.

  View details for DOI 10.3389/fpubh.2021.638316

  View details for PubMedID 34414149

• Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA Self, W. H., Semler, M. W., Leither, L. M., Casey, J. D., Angus, D. C., Brower, R. G., Chang, S. Y., Collins, S. P., Eppensteiner, J. C., Filbin, M. R., Files, D. C., Gibbs, K. W., Ginde, A. A., Gong, M. N., Harrell, F. E., Hayden, D. L., Hough, C. L., Johnson, N. J., Khan, A., Lindsell, C. J., Matthay, M. A., Moss, M., Park, P. K., Rice, T. W., Robinson, B. R., Schoenfeld, D. A., Shapiro, N. I., Steingrub, J. S., Ulysse, C. A., Weissman, A., Yealy, D. M., Thompson, B. T., Brown, S. M., Steingrub, J., Smithline, H., Tiru, B., Tidswell, M., Kozikowski, L., Thornton-Thompson, S., De Souza, L., Hou, P., Baron, R., Massaro, A., Aisiku, I., Fredenburgh, L., Seethala, R., Johnsky, L., Riker, R., Seder, D., May, T., Baumann, M., Eldridge, A., Lord, C., Shapiro, N., Talmor, D., O’Mara, T., Kirk, C., Harrison, K., Kurt, L., Schermerhorn, M., Banner-Goodspeed, V., Boyle, K., Dubosh, N., Filbin, M., Hibbert, K., Parry, B., Lavin-Parsons, K., Pulido, N., Lilley, B., Lodenstein, C., Margolin, J., Brait, K., Jones, A., Galbraith, J., Peacock, R., Nandi, U., Wachs, T., Matthay, M., Liu, K., Kangelaris, K., Wang, R., Calfee, C., Yee, K., Hendey, G., Chang, S., Lim, G., Qadir, N., Tam, A., Beutler, R., Levitt, J., Wilson, J., Rogers, A., Vojnik, R., Roque, J., Albertson, T., Chenoweth, J., Adams, J., Pearson, S., Juarez, M., Almasri, E., Fayed, M., Hughes, A., Hillard, S., Huebinger, R., Wang, H., Vidales, E., Patel, B., Ginde, A., Moss, M., Baduashvili, A., McKeehan, J., Finck, L., Higgins, C., Howell, M., Douglas, I., Haukoos, J., Hiller, T., Lyle, C., Cupelo, A., Caruso, E., Camacho, C., Gravitz, S., Finigan, J., Griesmer, C., Park, P., Hyzy, R., Nelson, K., McDonough, K., Olbrich, N., Williams, M., Kapoor, R., Nash, J., Willig, M., Ford, H., Gardner-Gray, J., Ramesh, M., Moses, M., Ng Gong, M., Aboodi, M., Asghar, A., Amosu, O., Torres, M., Kaur, S., Chen, J. T., Hope, A., Lopez, B., Rosales, K., Young You, J., Mosier, J., Hypes, C., Natt, B., Borg, B., Salvagio Campbell, E., Hite, R. D., Hudock, K., Cresie, A., Alhasan, F., Gomez-Arroyo, J., Duggal, A., Mehkri, O., Hastings, A., Sahoo, D., Abi Fadel, F., Gole, S., Shaner, V., Wimer, A., Meli, Y., King, A., Terndrup, T., Exline, M., Pannu, S., Robart, E., Karow, S., Hough, C., Robinson, B., Johnson, N., Henning, D., Campo, M., Gundel, S., Seghal, S., Katsandres, S., Dean, S., Khan, A., Krol, O., Jouzestani, M., Huynh, P., Weissman, A., Yealy, D., Scholl, D., Adams, P., McVerry, B., Huang, D., Angus, D., Schooler, J., Moore, S., Files, C., Miller, C., Gibbs, K., LaRose, M., Flores, L., Koehler, L., Morse, C., Sanders, J., Langford, C., Nanney, K., MdalaGausi, M., Yeboah, P., Morris, P., Sturgill, J., Seif, S., Cassity, E., Dhar, S., de Wit, M., Mason, J., Goodwin, A., Hall, G., Grady, A., Chamberlain, A., Brown, S., Bledsoe, J., Leither, L., Peltan, I., Starr, N., Fergus, M., Aston, V., Montgomery, Q., Smith, R., Merrill, M., Brown, K., Armbruster, B., Harris, E., Middleton, E., Paine, R., Johnson, S., Barrios, M., Eppensteiner, J., Limkakeng, A., McGowan, L., Porter, T., Bouffler, A., Leahy, J. C., deBoisblanc, B., Lammi, M., Happel, K., Lauto, P., Self, W., Casey, J., Semler, M., Collins, S., Harrell, F., Lindsell, C., Rice, T., Stubblefield, W., Gray, C., Johnson, J., Roth, M., Hays, M., Torr, D., Zakaria, A., Schoenfeld, D., Thompson, T., Hayden, D., Ringwood, N., Oldmixon, C., Ulysse, C., Morse, R., Muzikansky, A., Fitzgerald, L., Whitaker, S., Lagakos, A., Brower, R., Reineck, L., Aggarwal, N., Bienstock, K., Freemer, M., Maclawiw, M., Weinmann, G., Morrison, L., Gillespie, M., Kryscio, R., Brodie, D., Zareba, W., Rompalo, A., Boeckh, M., Parsons, P., Christie, J., Hall, J., Horton, N., Zoloth, L., Dickert, N., Diercks, D. 2020; 324 (21): 2165-2176

  Abstract

  Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.ClinicalTrials.gov: NCT04332991.

  View details for DOI 10.1001/jama.2020.22240

  View details for PubMedID 33165621

  View details for PubMedCentralID PMC7653542

• Characteristics and Outcomes of Coronavirus Disease Patients under Nonsurge Conditions, Northern California, USA, March-April 2020. Emerging infectious diseases Ferguson, J., Rosser, J. I., Quintero, O., Scott, J., Subramanian, A., Gumma, M., Rogers, A., Kappagoda, S. 2020; 26 (8)

  Abstract

  Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.

  View details for DOI 10.3201/eid2608.201776

  View details for PubMedID 32407284

• A generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections. Nature communications Mayhew, M. B., Buturovic, L., Luethy, R., Midic, U., Moore, A. R., Roque, J. A., Shaller, B. D., Asuni, T., Rawling, D., Remmel, M., Choi, K., Wacker, J., Khatri, P., Rogers, A. J., Sweeney, T. E. 2020; 11 (1): 1177

  Abstract

  Improved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Here, we develop a generalizable host-gene-expression-based classifier for acute bacterial and viral infections. We use training data (N=1069) from 18 retrospective transcriptomic studies. Using only 29 preselected host mRNAs, we train a neural-network classifier with a bacterial-vs-other area under the receiver-operating characteristic curve (AUROC) 0.92 (95% CI 0.90-0.93) and a viral-vs-other AUROC 0.92 (95% CI 0.90-0.93). We then apply this classifier, inflammatix-bacterial-viral-noninfected-version 1(IMX-BVN-1), without retraining, to an independent cohort (N=163). In this cohort, IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.86 (95% CI 0.77-0.93), and viral-vs.-other 0.85 (95% CI 0.76-0.93). In patients enrolled within 36h of hospital admission (N=70), IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.92 (95% CI 0.83-0.99), and viral-vs.-other 0.91 (95% CI 0.82-0.98). With further study, IMX-BVN-1 could provide a tool for assessing patients with suspected infection and sepsis at hospital admission.

  View details for DOI 10.1038/s41467-020-14975-w

  View details for PubMedID 32132525

• Gender Differences in Authorship of Critical Care Literature. American journal of respiratory and critical care medicine Vranas, K. C., Ouyang, D., Lin, A. L., Slatore, C. G., Sullivan, D. R., Prasad Kerlin, M., Liu, K. D., Baron, R. M., Calfee, C. S., Ware, L. B., Halpern, S., Matthay, M. A., Herridge, M., Mehta, S., Rogers, A. J. 2020

  Abstract

  RATIONALE: Gender gaps exist in academic leadership positions in critical care. Peer-reviewed publications are crucial to career advancement, yet little is known regarding gender differences in authorship of critical care research.OBJECTIVES: To evaluate gender differences in authorship of critical care literature.METHODS: We used a validated database of author gender to analyze authorship of critical care articles indexed in PubMed between 2008-2018 in 40 frequently-cited journals. High-impact journals were defined as those in the top 5% of all journals. We used mixed-effects logistic regression to evaluate the association of senior author gender with first and middle author gender, and first author gender with journal impact factor.RESULTS: Among 18,483 studies, 30.8% had female first authors and 19.5% had female senior authors. Female authorship rose slightly over the last decade (average annual increase of 0.44% (p<0.01) and 0.51% (p<0.01) for female first and senior authors, respectively). When the senior author was female, the odds of female co-authorship rose substantially (first author aOR1.93, 95%CI:1.71-2.17; middle author aOR1.48, 95%CI:1.29-1.69). Female first authors had higher odds of publishing in lower-impact journals than men (aOR1.30, 95%CI:1.16-1.45).CONCLUSIONS: Women comprise less than one-third of first authors and one-quarter of senior authors of critical care research, with minimal increase over the past decade. When the senior author was female, the odds of female co-authorship rose substantially. However, female first authors tend to publish in lower-impact journals. These findings may help explain the underrepresentation of women in critical care academic leadership positions and identify targets for improvement.

  View details for DOI 10.1164/rccm.201910-1957OC

  View details for PubMedID 31968182

• Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Science immunology Röltgen, K. n., Powell, A. E., Wirz, O. F., Stevens, B. A., Hogan, C. A., Najeeb, J. n., Hunter, M. n., Wang, H. n., Sahoo, M. K., Huang, C. n., Yamamoto, F. n., Manohar, M. n., Manalac, J. n., Otrelo-Cardoso, A. R., Pham, T. D., Rustagi, A. n., Rogers, A. J., Shah, N. H., Blish, C. A., Cochran, J. R., Jardetzky, T. S., Zehnder, J. L., Wang, T. T., Narasimhan, B. n., Gombar, S. n., Tibshirani, R. n., Nadeau, K. C., Kim, P. S., Pinsky, B. A., Boyd, S. D. 2020; 5 (54)

  Abstract

  SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.

  View details for DOI 10.1126/sciimmunol.abe0240

  View details for PubMedID 33288645

• Association Between Peripheral Blood Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio Time at Risk and Hospital Mortality in Mechanically Ventilated Patients. The Permanente journal Adams, J. Y., Rogers, A. J., Schuler, A., Marelich, G. P., Fresco, J. M., Taylor, S. L., Riedl, A. W., Baker, J. M., Escobar, G. J., Liu, V. X. 2020; 24

  Abstract

  INTRODUCTION: Acute respiratory failure requiring mechanical ventilation is a leading cause of mortality in the intensive care unit. Although single peripheral blood oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratios of hypoxemia have been evaluated to risk-stratify patients with acute respiratory distress syndrome, the utility of longitudinal SpO2/FiO2 ratios is unknown.OBJECTIVE: To assess time-based SpO2/FiO2 ratios ≤ 150-SpO2/FiO2 time at risk (SF-TAR)-for predicting mortality in mechanically ventilated patients.METHODS: Retrospective, observational cohort study of mechanically ventilated patients at 21 community and 2 academic hospitals. Association between the SF-TAR in the first 24 hours of ventilation and mortality was examined using multivariable logistic regression and compared with the worst recorded isolated partial pressure of arterial oxygen/fraction of inspired oxygen (P/F) ratio.RESULTS: In 28,758 derivation cohort admissions, every 10% increase in SF-TAR was associated with a 24% increase in adjusted odds of hospital mortality (adjusted odds ratio = 1.24; 95% confidence interval [CI] = 1.23-1.26); a similar association was observed in validation cohorts. Discrimination for mortality modestly improved with SF-TAR (area under the receiver operating characteristic curve [AUROC] = 0.81; 95% CI = 0.81-0.82) vs the worst P/F ratio (AUROC = 0.78; 95% CI = 0.78-0.79) and worst SpO2/FiO2 ratio (AUROC = 0.79; 95% CI = 0.79-0.80). The SF-TAR in the first 6 hours offered comparable discrimination for hospital mortality (AUROC = 0.80; 95% CI = 0.79-0.80) to the 24-hour SF-TAR.CONCLUSION: The SF-TAR can identify ventilated patients at increased risk of death, offering modest improvements compared with single SpO2/FiO2 and P/F ratios. This longitudinal, noninvasive, and broadly generalizable tool may have particular utility for early phenotyping and risk stratification using electronic health record data in ventilated patients.

  View details for DOI 10.7812/TPP/19.113

  View details for PubMedID 32069205

• Delving beneath the surface of hyperinflammation in COVID-19. The Lancet Rheumatology Reddy, K. n., Rogers, A. J., McAuley, D. F. 2020

  View details for DOI 10.1016/S2665-9913(20)30304-0

  View details for PubMedID 32864626

  View details for PubMedCentralID PMC7442423

• Prolonged Hospitalization Following Acute Respiratory Failure. Chest Marmor, M. n., Liu, S. n., Long, J. n., Chertow, G. M., Rogers, A. J. 2020

  Abstract

  A better understanding of the clinical features associated with prolonged hospitalization in acute respiratory failure may allow for better informed care planning.To assess the incidence, mortality, cost and clinical determinants of prolonged hospitalization among patients with acute respiratory failure (ARF).Using the National Inpatient Sample (NIS) data from 2004 to 2014, we identified adults 18 years and older with International Classification of Disease, 9th Edition (ICD-9), codes for ARF requiring mechanical ventilation for at least two days (ICD-9 518.81 or 518.82, 96.7 or 96.04, and 96.05). Outcomes studied included incidence, in-hospital mortality, cost of hospitalization, and associated patient-level and hospital-level characteristics. Trends were assessed by logistic regression, linear regression and general linear modeling with Poisson distribution.Of the 5,539,567 patients with ARF, 77,665 (1.4%) had a prolonged length of stay, defined as ≥60 days (pLOS). Among pLOS, 52,776 (68%) survived to discharge. Over the study period, incidence of pLOS decreased by 48%, in-patient mortality decreased by 18%, per patient cost-of-care rose, but percent of the total cost of ARF care consumed by patients with pLOS did not significantly decrease (p=0.06). PLOS was more likely to occur in urban teaching hospitals (OR 6.8, CI 4.6-10.2, p<0.001), hospitals located in the Northeastern US (OR 3.6, CI 3.0-4.3, p<0.001), and among patients with Medicaid insurance coverage (OR 2.1, CI 1.9-2.4, p<0.001).From 2004-2014, incidence and mortality decreased among patients with ARF and pLOS, and while per patient costs rose, percent of total cost of care remained stable. There is substantial variation in length-of-stay for patients with ARF by US region, hospital teaching status and patient insurance coverage.

  View details for DOI 10.1016/j.chest.2020.11.023

  View details for PubMedID 33333057

• Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2. Cell host & microbe Nielsen, S. C., Yang, F. n., Jackson, K. J., Hoh, R. A., Röltgen, K. n., Jean, G. H., Stevens, B. A., Lee, J. Y., Rustagi, A. n., Rogers, A. J., Powell, A. E., Hunter, M. n., Najeeb, J. n., Otrelo-Cardoso, A. R., Yost, K. E., Daniel, B. n., Nadeau, K. C., Chang, H. Y., Satpathy, A. T., Jardetzky, T. S., Kim, P. S., Wang, T. T., Pinsky, B. A., Blish, C. A., Boyd, S. D. 2020

  Abstract

  B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.

  View details for DOI 10.1016/j.chom.2020.09.002

  View details for PubMedID 32941787

• Electrical Storm in COVID-19. JACC. Case reports O'Brien, C. n., Ning, N. n., McAvoy, J. n., Mitchell, J. E., Kalwani, N. n., Wang, P. n., Nguyen, D. n., Reejhsinghani, R. n., Rogers, A. n., Lorenzo, J. n. 2020; 2 (9): 1256–60

  Abstract

  COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae. (Level of Difficulty: Intermediate.).

  View details for DOI 10.1016/j.jaccas.2020.05.032

  View details for PubMedID 32835266

  View details for PubMedCentralID PMC7259914

• The authors reply. Critical care medicine Rogers, A. J., Desai, M., Matthay, M. A., Choi, A. M., Baron, R. M. 2020; 48 (1): e78

  View details for DOI 10.1097/CCM.0000000000004081

  View details for PubMedID 31833991

• Network study of nasal transcriptome profiles reveals master regulator genes of asthma. The Journal of allergy and clinical immunology Do, A. N., Chun, Y. n., Grishina, G. n., Grishin, A. n., Rogers, A. J., Raby, B. A., Weiss, S. T., Vicencio, A. n., Schadt, E. E., Bunyavanich, S. n. 2020

  Abstract

  Nasal transcriptomics can provide an accessible window into asthma pathobiology.Our goal was to move beyond gene signatures of asthma to identify master regulator genes that causally regulate genes associated with asthma phenotypes.We recruited 156 children with severe persistent asthma and controls for nasal transcriptome profiling and applied network-based and probabilistic causal methods to identify severe asthma genes and their master regulators. We then took the same approach in an independent cohort of 190 adults with mild/moderate asthma and controls to identify mild/moderate asthma genes and their master regulators. Comparative analysis of the master regulator genes followed by validation testing in independent children with severe asthma (n = 21) and mild/moderate asthma (n = 154) was then performed.Nasal gene signatures for severe persistent asthma and for mild/moderate persistent asthma were identified; both were found to be enriched in coexpression network modules for ciliary function and inflammatory response. By applying probabilistic causal methods to these gene signatures and validation testing in independent cohorts, we identified (1) a master regulator gene common to asthma across severity and ages (FOXJ1); (2) master regulator genes of severe persistent asthma in children (LRRC23, TMEM231, CAPS, PTPRC, and FYB); and (3) master regulator genes of mild/moderate persistent asthma in children and adults (C1orf38 and FMNL1). The identified master regulators were statistically inferred to causally regulate the expression of downstream genes that modulate ciliary function and inflammatory response to influence asthma.The identified master regulator genes of asthma provide a novel path forward to further uncovering asthma mechanisms and therapy.

  View details for DOI 10.1016/j.jaci.2020.07.006

  View details for PubMedID 32828590

• Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. The New England journal of medicine National Heart, L., Ginde, A. A., Brower, R. G., Caterino, J. M., Finck, L., Banner-Goodspeed, V. M., Grissom, C. K., Hayden, D., Hough, C. L., Hyzy, R. C., Khan, A., Levitt, J. E., Park, P. K., Ringwood, N., Rivers, E. P., Self, W. H., Shapiro, N. I., Thompson, B. T., Yealy, D. M., Talmor, D. 2019

  Abstract

  BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P=0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

  View details for DOI 10.1056/NEJMoa1911124

  View details for PubMedID 31826336

• Semi-quantitative visual assessment of chest radiography is associated with clinical outcomes in critically ill patients. Respiratory research Mason, S. E., Dieffenbach, P. B., Englert, J. A., Rogers, A. A., Massaro, A. F., Fredenburgh, L. E., Higuera, A., Pinilla-Vera, M., Vilas, M., San Jose Estepar, R., Washko, G. R., Baron, R. M., Ash, S. Y. 2019; 20 (1): 218

  Abstract

  BACKGROUND: Respiratory pathology is a major driver of mortality in the intensive care unit (ICU), even in the absence of a primary respiratory diagnosis. Prior work has demonstrated that a visual scoring system applied to chest radiographs (CXR) is associated with adverse outcomes in ICU patients with Acute Respiratory Distress Syndrome (ARDS). We hypothesized that a simple, semi-quantitative CXR score would be associated with clinical outcomes for the general ICU population, regardless of underlying diagnosis.METHODS: All individuals enrolled in the Registry of Critical Illness at Brigham and Women's Hospital between June 2008 and August 2018 who had a CXR within 24h of admission were included. Each patient's CXR was assigned an opacification score of 0-4 in each of four quadrants with the total score being the sum of all four quadrants. Multivariable negative binomial, logistic, and Cox regression, adjusted for age, sex, race, immunosuppression, a history of chronic obstructive pulmonary disease, a history of congestive heart failure, and APACHE II scores, were used to assess the total score's association with ICU length of stay (LOS), duration of mechanical ventilation, in-hospital mortality, 60-day mortality, and overall mortality, respectively.RESULTS: A total of 560 patients were included. Higher CXR scores were associated with increased mortality; for every one-point increase in score, in-hospital mortality increased 10% (OR 1.10, CI 1.05-1.16, p<0.001) and 60-day mortality increased by 12% (OR 1.12, CI 1.07-1.17, p<0.001). CXR scores were also independently associated with both ICU length of stay (rate ratio 1.06, CI 1.04-1.07, p<0.001) and duration of mechanical ventilation (rate ratio 1.05, CI 1.02-1.07, p<0.001).CONCLUSIONS: Higher values on a simple visual score of a patient's CXR on admission to the medical ICU are associated with increased in-hospital mortality, 60-day mortality, overall mortality, length of ICU stay, and duration of mechanical ventilation.

  View details for DOI 10.1186/s12931-019-1201-0

  View details for PubMedID 31606045

• Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial LANCET RESPIRATORY MEDICINE Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., Liu, K. D. 2019; 7 (2): 154–62

  View details for DOI 10.1016/S2213-2600(18)30418-1

  View details for Web of Science ID 000457172000025

• Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Critical care (London, England) Johansson, P. I., Nakahira, K., Rogers, A. J., McGeachie, M. J., Baron, R. M., Fredenburgh, L. E., Harrington, J., Choi, A. M., Christopher, K. B. 2018; 22 (1): 360

  Abstract

  BACKGROUND: Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA.METHODS: We performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels.RESULTS: Metabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥3200 copies/mul plasma relative to those with an ND1 mtDNA level <3200 copies/mul plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥3200 copies/mul plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines.CONCLUSIONS: Differential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively.

  View details for PubMedID 30594224

• Plasma mitochondrial DNA and metabolomic alterations in severe critical illness CRITICAL CARE Johansson, P. I., Nakahira, K., Rogers, A. J., McGeachie, M. J., Baron, R. M., Fredenburgh, L. E., Harrington, J., Choi, A. K., Christopher, K. B. 2018; 22

  View details for DOI 10.1186/s13054-018-2275-7

  View details for Web of Science ID 000454589100001

• Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Wu, A., Kiley, J. P., Noel, P. J., Amur, S., Burchard, E. G., Clancy, J. P., Galanter, J., Inada, M., Jones, T. K., Kropski, J. A., Loyd, J. E., Nogee, L. M., Raby, B. A., Rogers, A. J., Schwartz, D. A., Sin, D. D., Spira, A., Weiss, S. T., Young, L. R., Himes, B. E., Amer Thoracic Soc Assembly Behav, Sect Genetics Genomics 2018; 198 (12): 1479–89

  View details for Web of Science ID 000453253600011

• Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. The Lancet. Respiratory medicine Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B. T., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., Liu, K. D. 2018

  Abstract

  BACKGROUND: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.METHODS: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 * 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.FINDINGS: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.INTERPRETATION: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.FUNDING: National Heart, Lung, and Blood Institute.

  View details for PubMedID 30455077

• MUC5B Promoter Polymorphism and Development of Acute Respiratory Distress Syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rogers, A. J., Solus, J. F., Hunninghake, G. M., Baron, R. M., Meyer, N. J., Janz, D. R., Schwartz, D. A., May, A. K., Lawson, W. E., Blackwell, T. S., Ware, L. B. 2018; 198 (10): 1342-1345

  View details for DOI 10.1164/rccm.201801-0140LE

  View details for Web of Science ID 000450516500019

• MUC5B Promoter Polymorphism and Development of ARDS. American journal of respiratory and critical care medicine Rogers, A. J., Solus, J. F., Hunninghake, G. M., Baron, R. M., Meyer, N. J., Janz, D. R., Schwartz, D. A., May, A. K., Lawson, W. E., Blackwell, T. S., Ware, L. B. 2018

  View details for PubMedID 30025215

• A Nasal Brush-based Classifier of Asthma Identified by Machine Learning Analysis of Nasal RNA Sequence Data SCIENTIFIC REPORTS Pandey, G., Pandey, O. P., Rogers, A. J., Ahsen, M. E., Hoffman, G. E., Raby, B. A., Weiss, S. T., Schadt, E. E., Bunyavanich, S. 2018; 8: 8826

  Abstract

  Asthma is a common, under-diagnosed disease affecting all ages. We sought to identify a nasal brush-based classifier of mild/moderate asthma. 190 subjects with mild/moderate asthma and controls underwent nasal brushing and RNA sequencing of nasal samples. A machine learning-based pipeline identified an asthma classifier consisting of 90 genes interpreted via an L2-regularized logistic regression classification model. This classifier performed with strong predictive value and sensitivity across eight test sets, including (1) a test set of independent asthmatic and control subjects profiled by RNA sequencing (positive and negative predictive values of 1.00 and 0.96, respectively; AUC of 0.994), (2) two independent case-control cohorts of asthma profiled by microarray, and (3) five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibrosis, smoking), where the classifier had a low to zero misclassification rate. Following validation in large, prospective cohorts, this classifier could be developed into a nasal biomarker of asthma.

  View details for PubMedID 29891868

• Genome-Wide Association Study in Acute Respiratory Distress Syndrome Finding the Needle in the Haystack to Advance Our Understanding of Acute Respiratory Distress Syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rogers, A. J. 2018; 197 (11): 1373–74

  View details for DOI 10.1164/rccm.201801-0098ED

  View details for Web of Science ID 000433971100004

• Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome. Critical care medicine Sweeney, T. E., Thomas, N. J., Howrylak, J. A., Wong, H. R., Rogers, A. J., Khatri, P. n. 2018; 46 (2): 244–51

  Abstract

  To identify a novel, generalizable diagnostic for acute respiratory distress syndrome using whole-blood gene expression arrays from multiple acute respiratory distress syndrome cohorts of varying etiologies.We performed a systematic search for human whole-blood gene expression arrays of acute respiratory distress syndrome in National Institutes of Health Gene Expression Omnibus and ArrayExpress. We also included the Glue Grant gene expression cohorts.We included investigator-defined acute respiratory distress syndrome within 48 hours of diagnosis and compared these with relevant critically ill controls.We used multicohort analysis of gene expression to identify genes significantly associated with acute respiratory distress syndrome, both with and without adjustment for clinical severity score. We performed gene ontology enrichment using Database for Annotation, Visualization and Integrated Discovery and cell type enrichment tests for both immune cells and pneumocyte gene expression. Finally, we selected a gene set optimized for diagnostic power across the datasets and used leave-one-dataset-out cross validation to assess robustness of the model.We identified datasets from three adult cohorts with sepsis, one pediatric cohort with acute respiratory failure, and two datasets of adult patients with trauma and burns, for a total of 148 acute respiratory distress syndrome cases and 268 critically ill controls. We identified 30 genes that were significantly associated with acute respiratory distress syndrome (false discovery rate < 20% and effect size >1.3), many of which had been previously associated with sepsis. When metaregression was used to adjust for clinical severity scores, none of these genes remained significant. Cell type enrichment was notable for bands and neutrophils, suggesting that the gene expression signature is one of acute inflammation rather than lung injury per se. Finally, an attempt to develop a generalizable diagnostic gene set for acute respiratory distress syndrome showed a mean area under the receiver-operating characteristic curve of only 0.63 on leave-one-dataset-out cross validation.The whole-blood gene expression signature across a wide clinical spectrum of acute respiratory distress syndrome is likely confounded by systemic inflammation, limiting the utility of whole-blood gene expression studies for uncovering a generalizable diagnostic gene signature.

  View details for PubMedID 29337789

• VITAMIN C AND METABOLOME ALTERATIONS IN SEVERE CRITICAL ILLNESS Golmai, P., Rogers, A., Baron, R., Gazourian, L., Chary, S., Fredenburgh, L., Massaro, A., Choi, A., Christopher, K. LIPPINCOTT WILLIAMS & WILKINS. 2018: 712

  View details for DOI 10.1097/01.ccm.0000529458.76462.6e

  View details for Web of Science ID 000436796200620

• GWAS in ARDS: Finding the Needle in the Haystack to Advance our Understanding of ARDS. American journal of respiratory and critical care medicine Rogers, A. J. 2018

  View details for PubMedID 29438627

• New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society Bowler, R. P., Wendt, C. H., Fessler, M. B., Foster, M. W., Kelly, R. S., Lasky-Su, J., Rogers, A. J., Stringer, K. A., Winston, B. W. 2017; 14 (12): 1721-1743

  Abstract

  This document presents the proceedings from the workshop entitled, "New Strategies and Challenges in Lung Proteomics and Metabolomics" held February 4th-5th, 2016, in Denver, Colorado. It was sponsored by the National Heart Lung Blood Institute, the American Thoracic Society, the Colorado Biological Mass Spectrometry Society, and National Jewish Health. The goal of this workshop was to convene, for the first time, relevant experts in lung proteomics and metabolomics to discuss and overcome specific challenges in these fields that are unique to the lung. The main objectives of this workshop were to identify, review, and/or understand: (1) emerging technologies in metabolomics and proteomics as applied to the study of the lung; (2) the unique composition and challenges of lung-specific biological specimens for metabolomic and proteomic analysis; (3) the diverse informatics approaches and databases unique to metabolomics and proteomics, with special emphasis on the lung; (4) integrative platforms across genetic and genomic databases that can be applied to lung-related metabolomic and proteomic studies; and (5) the clinical applications of proteomics and metabolomics. The major findings and conclusions of this workshop are summarized at the end of the report, and outline the progress and challenges that face these rapidly advancing fields.

  View details for DOI 10.1513/AnnalsATS.201710-770WS

  View details for PubMedID 29192815

• Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury. American journal of respiratory cell and molecular biology Sweeney, T. E., Lofgren, S., Khatri, P., Rogers, A. J. 2017

  Abstract

  Rationale The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. Objectives Comprehensive integration of gene expression data in experimental ALI in rodents compared to humans. Methods We performed two separate gene expression multi-cohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. Main Results We identified 21 animal lung tissue datasets and 3 human lung injury BAL datasets. We show that the meta-signatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, VILI, LPS) are significantly correlated with human models of lung injury (Pearson r 0.33-0.45, P<1e-16). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Conclusions Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

  View details for DOI 10.1165/rcmb.2016-0395OC

  View details for PubMedID 28324666

• Metabolome alterations in severe critical illness and vitamin D status. Critical care (London, England) Lasky-Su, J. n., Dahlin, A. n., Litonjua, A. A., Rogers, A. J., McGeachie, M. J., Baron, R. M., Gazourian, L. n., Barragan-Bradford, D. n., Fredenburgh, L. E., Choi, A. M., Mogensen, K. M., Quraishi, S. A., Amrein, K. n., Christopher, K. B. 2017; 21 (1): 193

  Abstract

  Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status.We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status.Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71-0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status.Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.

  View details for PubMedID 28750641

  View details for PubMedCentralID PMC5532782

• Epidemiologic and Population Genetic Studies CLINICAL AND TRANSLATIONAL SCIENCE: PRINCIPLES OF HUMAN RESEARCH, 2ND EDITION Rogers, A. J., Weiss, S. T., Robertson, D., Williams, G. H. 2017: 313–26

  View details for DOI 10.1016/B978-0-12-802101-9.00017-X

  View details for Web of Science ID 000440395900017

• A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 2016; 11 (9): 646-649

  Abstract

  The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.

  View details for DOI 10.1002/jhm.2590

  View details for PubMedID 27079160

• A computational approach to mortality prediction of alcohol use disorder inpatients COMPUTERS IN BIOLOGY AND MEDICINE Calvert, J., Mao, Q., Rogers, A. J., Barton, C., Jay, M., Desautels, T., Mohamadlou, H., Jan, J., Das, R. 2016; 75: 74-79

  Abstract

  Health information technologies can assist clinicians in the Intensive Care Unit (ICU) by providing additional analysis of patient stability. However, because patient diagnoses can be confounded by chronic alcohol use, the predictive value of existing systems is suboptimal. Through the use of Electronic Health Records (EHR), we have developed computer software called AutoTriage to generate accurate predictions through multi-dimensional analysis of clinical variables. We analyze the performance of AutoTriage on the Alcohol Use Disorder (AUD) subpopulation in this study, and build on results we reported for AutoTriage performance on the general population in previous work.AUD-related ICD-9 codes were used to obtain a patient population from MIMIC III ICU dataset for a retrospective study. Patient mortality risk score is generated through analysis of eight EHR-based clinical variables. The score is determined by combining weighted subscores, each of which are obtained from singlets, doublets or triplets of one or more of the eight continuous-valued clinical variable inputs. A temporally updating risk score is computed with a continuously revised 12-hour mortality prediction.Among AUD patients, in a non-overlapping test set, AutoTriage outperforms existing systems with an Area Under Receiver Operating Characteristic (AUROC) value of 0.934 for 12-h mortality prediction. At a sensitivity of 90%, AutoTriage achieves a specificity of 80%, positive predictive value of 40%, negative predictive value of 89%, and an Odds Ratio of 36.For mortality prediction, AutoTriage demonstrates improvements in both the accuracy and the Odds Ratio over current systems among the AUD patient population.

  View details for DOI 10.1016/j.compbiomed.2016.05.015

  View details for Web of Science ID 000380623100009

  View details for PubMedID 27253619

• 16 Years and Counting? Time to Implement Noninvasive Screening for ARDS CHEST Rogers, A. J., Liu, V. X. 2016; 150 (2): 266–67

  View details for PubMedID 27502976

• Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis CLINICS IN CHEST MEDICINE Englert, J. A., Rogers, A. J. 2016; 37 (2): 321-?

  Abstract

  Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU.

  View details for DOI 10.1016/j.ccm.2016.01.011

  View details for Web of Science ID 000378582800015

  View details for PubMedID 27229648

• Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development EXPERT REVIEW OF PROTEOMICS Levitt, J. E., Rogers, A. J. 2016; 13 (5): 457-469

  Abstract

  The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.

  View details for DOI 10.1586/14789450.2016.1172481

  View details for PubMedID 27031735

• ATS Core Curriculum 2016: Part II. Adult Critical Care Medicine. Annals of the American Thoracic Society McSparron, J. I., Hayes, M. M., Poston, J. T., Thomson, C. C., Fessler, H. E., Stapleton, R. D., Carlos, W. G., Hinkle, L., Liu, K., Shieh, S., Ali, A., Rogers, A., Shah, N. G., Slack, D., Patel, B., Wolfe, K., Schweickert, W. D., Bakhru, R. N., Shin, S., Sell, R. E., Luks, A. M. 2016; 13 (5): 731-740

  View details for DOI 10.1513/AnnalsATS.201601-050CME

  View details for PubMedID 27144797

• Metabolites Associated With Malnutrition in the Intensive Care Unit Are Also Associated With 28-Day Mortality: A Prospective Cohort Study. JPEN. Journal of parenteral and enteral nutrition Mogensen, K. M., Lasky-Su, J. n., Rogers, A. J., Baron, R. M., Fredenburgh, L. E., Rawn, J. n., Robinson, M. K., Massarro, A. n., Choi, A. M., Christopher, K. B. 2016

  Abstract

  We hypothesized that metabolic profiles would differ in critically ill patients with malnutrition relative to those without.We performed a prospective cohort study on 85 adult patients with systemic inflammatory response syndrome or sepsis admitted to a 20-bed medical intensive care unit (ICU) in Boston. We generated metabolomic profiles using gas and liquid chromatography and mass spectroscopy. We followed this by logistic regression and partial least squares discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis and network model construction of chemical-protein target interactions to identify groups of metabolites and pathways that were differentiates in patients with and without malnutrition.Of the cohort, 38% were malnourished at admission to the ICU. Metabolomic profiles differed in critically ill patients with malnutrition relative to those without. Ten metabolites were significantly associated with malnutrition (P < .05). A parsimonious model of 5 metabolites effectively differentiated patients with malnutrition (AUC = 0.76), including pyroglutamine and hypoxanthine. Using pathway enrichment analysis, we identified a critical role of glutathione and purine metabolism in predicting nutrition. Nutrition status was associated with 28-day mortality, even after adjustment for known phenotypic variables associated with ICU mortality. Importantly, 7 metabolites associated with nutrition status were also associated with 28-day mortality.Malnutrition is associated with differential metabolic profiles early in critical illness. Common to all of our metabolome analyses, glutathione and purine metabolism, which play principal roles in cellular redox regulation and accelerated tissue adenosine triphosphate degradation, respectively, were significantly altered with malnutrition.

  View details for PubMedID 27406941

• Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Kangelaris, K. N., Prakash, A., Liu, K. D., Aouizerat, B., Woodruff, P. G., Erle, D. J., Rogers, A., Seeley, E. J., Chu, J., Liu, T., Osterberg-Deiss, T., Zhuo, H., Matthay, M. A., Calfee, C. S. 2015; 308 (11): L1102-L1113

  Abstract

  The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

  View details for DOI 10.1152/ajplung.00380.2014

  View details for Web of Science ID 000357509200002

  View details for PubMedID 25795726

  View details for PubMedCentralID PMC4451399

• Finding an early warning signal for acute respiratory distress syndrome: are we getting closer? Critical care medicine Rogers, A. J., Dhillon, G. S. 2015; 43 (3): 721-722

  View details for DOI 10.1097/CCM.0000000000000800

  View details for PubMedID 25700066

• Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet. Respiratory medicine Wilson, J. G., Liu, K. D., Zhuo, H., Caballero, L., McMillan, M., Fang, X., Cosgrove, K., Vojnik, R., Calfee, C. S., Lee, J., Rogers, A. J., Levitt, J., Wiener-Kronish, J., Bajwa, E. K., Leavitt, A., McKenna, D., Thompson, B. T., Matthay, M. A. 2015; 3 (1): 24-32

  Abstract

  No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.The National Heart, Lung, and Blood Institute.

  View details for DOI 10.1016/S2213-2600(14)70291-7

  View details for PubMedID 25529339

• Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation. PloS one Croteau-Chonka, D. C., Rogers, A. J., Raj, T., McGeachie, M. J., Qiu, W., Ziniti, J. P., Stubbs, B. J., Liang, L., Martinez, F. D., Strunk, R. C., Lemanske, R. F., Liu, A. H., Stranger, B. E., Carey, V. J., Raby, B. A. 2015; 10 (10)

  Abstract

  Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10-04), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2-2.0, P < 10-11) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5-2.3, P < 10-11). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3-10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization.

  View details for DOI 10.1371/journal.pone.0140758

  View details for PubMedID 26474488

  View details for PubMedCentralID PMC4608673

• METABOLOME ALTERATION IN CRITICAL ILLNESS ACCORDING TO VITAMIN D STATUS: A PROSPECTIVE COHORT STUDY Christopher, K., Rogers, A., Baron, R., Fredenburgh, L., Gazourian, L., Massaro, A., Choi, A., Litonjua, A. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000346211800310

• Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis. Human molecular genetics Qiu, W., Rogers, A. J., Damask, A., Raby, B. A., Klanderman, B. J., Duan, Q. L., Tyagi, S., Niu, S., Anderson, C., Cahir-McFarland, E., Mariani, T. J., Carey, V., Tantisira, K. G. 2014; 23 (18): 5017-5024

  Abstract

  Nearly one-half of asthmatic patients do not respond to the most commonly prescribed controller therapy, inhaled corticosteroids (ICS). We conducted an expression quantitative trait loci (eQTL) analysis using more than 300 expression microarrays (from 117 lymphoblastoid cell lines) in corticosteroid (dexamethasone) treated and untreated cells derived from asthmatic subjects in the Childhood Asthma Management Program (CAMP) clinical trial. We then tested the associations of eQTL with longitudinal change in airway responsiveness to methacholine (LnPC20) on ICS. We identified 2,484 cis-eQTL affecting 767 genes following dexamethasone treatment. A significant over-representation of lnPC20-associated cis-eQTL (190 SNPs) among differentially expressed genes (OR=1.76, 95% CI: 1.35-2.29) was noted in CAMP Caucasians. Forty-six of these 190 clinical associations were replicated in CAMP African Americans, including 7 SNPs near 6 genes meeting criteria for genome-wide significance (p<2x10(-7)). Notably, the majority of genome-wide findings would not have been uncovered via analysis of untreated samples. These results indicate that identifying eQTL after relevant environmental perturbation enables identification of true pharmacogenetic variants.

  View details for DOI 10.1093/hmg/ddu191

  View details for PubMedID 24770851

• Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes. American journal of respiratory and critical care medicine Langley, R. J., Tipper, J. L., Bruse, S., Baron, R. M., Tsalik, E. L., Huntley, J., Rogers, A. J., Jaramillo, R. J., O'Donnell, D., Mega, W. M., Keaton, M., Kensicki, E., Gazourian, L., Fredenburgh, L. E., Massaro, A. F., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S. F., Sopori, M. L., Perrella, M. A., Choi, A. M., Harrod, K. S. 2014; 190 (4): 445-455

  Abstract

  Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers.The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

  View details for DOI 10.1164/rccm.201404-0624OC

  View details for PubMedID 25054455

• Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome ANNALS OF INTENSIVE CARE Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 2014; 4

  View details for DOI 10.1186/s13613-014-0022-z

  View details for Web of Science ID 000345167000001

• Applying metabolomics to uncover novel biology in ARDS. American journal of physiology. Lung cellular and molecular physiology Rogers, A. J., Matthay, M. A. 2014; 306 (11): L957-61

  Abstract

  A better understanding of the pathogenesis and the resolution of the acute respiratory distress syndrome (ARDS) is needed. While some progress has been made with the use of protein biomarkers and candidate gene studies in understanding the pathobiology of ARDS, we propose that new studies that measure the chemical breakdown products of cellular metabolism (metabolomics) may provide new insights into ARDS, in part because the metabolomics targets a later point in the genomics cascade than is possible with studies of DNA, RNA and protein biomarkers. Technological advances have made large-scale metabolomic profiling increasingly feasible. Metabolomic approaches have already achieved novel insights in non-pulmonary diseases such as Diabetes Mellitus and malignancy, as well as in sepsis, a major risk factor for developing ARDS. Metabolomic profiling is a promising approach to identify novel pathways in both patients at risk for developing ARDS as well as in the early phase of established ARDS.

  View details for DOI 10.1152/ajplung.00376.2013

  View details for PubMedID 24727586

• Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation AMERICAN JOURNAL OF HEMATOLOGY Gazourian, L., Rogers, A. J., Ibanga, R., Weinhouse, G. L., Pinto-Plata, V., Ritz, J., Soiffer, R. J., Antin, J. H., Washko, G. R., Baron, R. M., Ho, V. T. 2014; 89 (4): 404-409

  Abstract

  Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t-test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48-2067) after HSCT. Eighty-six (97%) of our BOS cohort had extra-pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan-based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD.

  View details for DOI 10.1002/ajh.23656

  View details for Web of Science ID 000334645900011

  View details for PubMedID 24375545

• Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients PLOS ONE Rogers, A. J., McGeachie, M., Baron, R. M., Gazourian, L., Haspel, J. A., Nakahira, K., Fredenburgh, L. E., Hunninghake, G. M., Raby, B. A., Matthay, M. A., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S., Langley, R. J., Choi, A. M. 2014; 9 (1)

  Abstract

  To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.

  View details for DOI 10.1371/journal.pone.0087538

  View details for Web of Science ID 000330617100092

  View details for PubMedID 24498130

  View details for PubMedCentralID PMC3907548

• Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Annals of intensive care Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 2014; 4: 22-?

  Abstract

  Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.NCT01775774 and NCT02097641.

  View details for DOI 10.1186/s13613-014-0022-z

  View details for PubMedID 25593740

• Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation PLOS MEDICINE Nakahira, K., Kyung, S., Rogers, A. J., Gazourian, L., Youn, S., Massaro, A. F., Quintana, C., Osorio, J. C., Wang, Z., Zhao, Y., Lawler, L. A., Christie, J. D., Meyer, N. J., Mc Causland, F. R., Waikar, S. S., Waxman, A. B., Chung, R. T., Bueno, R., Rosas, I. O., Fredenburgh, L. E., Baron, R. M., Christiani, D. C., Hunninghake, G. M., Choi, A. M. 2013; 10 (12)

  Abstract

  Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.

  View details for DOI 10.1371/journal.pmed.1001577

  View details for Web of Science ID 000330534300016

  View details for PubMedID 24391478

  View details for PubMedCentralID PMC3876981

• An integrated clinico-metabolomic model improves prediction of death in sepsis. Science translational medicine Langley, R. J., Tsalik, E. L., Velkinburgh, J. C., Glickman, S. W., Rice, B. J., Wang, C., Chen, B., Carin, L., Suarez, A., Mohney, R. P., Freeman, D. H., Wang, M., You, J., Wulff, J., Thompson, J. W., Moseley, M. A., Reisinger, S., Edmonds, B. T., Grinnell, B., Nelson, D. R., Dinwiddie, D. L., Miller, N. A., Saunders, C. J., Soden, S. S., Rogers, A. J., Gazourian, L., Fredenburgh, L. E., Massaro, A. F., Baron, R. M., Choi, A. M., Corey, G. R., Ginsburg, G. S., Cairns, C. B., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S. F. 2013; 5 (195): 195ra95

  Abstract

  Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and β-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

  View details for DOI 10.1126/scitranslmed.3005893

  View details for PubMedID 23884467

• Copy number variation genotyping using family information BMC BIOINFORMATICS Chu, J., Rogers, A., Ionita-Laza, I., Darvishi, K., Mills, R. E., Lee, C., Raby, B. A. 2013; 14

  Abstract

  In recent years there has been a growing interest in the role of copy number variations (CNV) in genetic diseases. Though there has been rapid development of technologies and statistical methods devoted to detection in CNVs from array data, the inherent challenges in data quality associated with most hybridization techniques remains a challenging problem in CNV association studies.To help address these data quality issues in the context of family-based association studies, we introduce a statistical framework for the intensity-based array data that takes into account the family information for copy-number assignment. The method is an adaptation of traditional methods for modeling SNP genotype data that assume Gaussian mixture model, whereby CNV calling is performed for all family members simultaneously and leveraging within family-data to reduce CNV calls that are incompatible with Mendelian inheritance while still allowing de-novo CNVs. Applying this method to simulation studies and a genome-wide association study in asthma, we find that our approach significantly improves CNV calls accuracy, and reduces the Mendelian inconsistency rates and false positive genotype calls. The results were validated using qPCR experiments.In conclusion, we have demonstrated that the use of family information can improve the quality of CNV calling and hopefully give more powerful association test of CNVs.

  View details for DOI 10.1186/1471-2105-14-157

  View details for Web of Science ID 000319743600001

  View details for PubMedID 23656838

  View details for PubMedCentralID PMC3668900

• Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility CLINICAL AND EXPERIMENTAL ALLERGY Rogers, A. J., Chu, J., Darvishi, K., Ionita-Laza, I., Lehmann, H., Mills, R., Lee, C., Raby, B. A. 2013; 43 (4): 455-462

  Abstract

  Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci.We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV.Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma-candidate CNVs (range 1-29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.Although a substantial proportion of asthma-susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.

  View details for DOI 10.1111/cea.12060

  View details for Web of Science ID 000316623800010

  View details for PubMedID 23517041

  View details for PubMedCentralID PMC3609036

• Airway dilation in bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation RESPIRATORY MEDICINE Gazourian, L., Coronata, A. F., Rogers, A. J., Weinhouse, G. L., Soiffer, R. J., Antin, J. H., Ritz, J., Ho, V. T., Baron, R. M., Washko, G. R. 2013; 107 (2): 276-283

  Abstract

  Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). There is minimal data published on quantitative radiologic characterization of airway remodeling in these subjects.To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS.All adult patients who underwent allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n = 1854) between January 1st 2000 and June 30th 2010 were screened for the development of BOS. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. For each subjects discrete measures of airway wall area were performed and the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated.We identified 88 cases of BOS, and 37 of these patients had available HRCT. On CT scans obtained after BOS diagnosis, the Pi10 decreased (consistent with airway dilation) as compared with pre-BOS values (p < 0.001). After HSCT the Pi10 correlated with FEV(1)% predicted (r = 0.636, p < 0.0001), and RV/TLC% predicted (r = -0.736, p < 0.0001), even after adjusting for age, sex and total lung capacity (p < 0.0001 for both).On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. This is opposite of what has been previously demonstrated in COPD and asthma that quantitative measure of proximal airway wall thickening directly correlate with pulmonary function. Our data suggests that the pathologic process affecting the central airways is different from the pathology observed in the distal airways. Further work is needed to determine if such change can be used as a sensitive and specific tool for the future diagnosis and staging of BOS.

  View details for DOI 10.1016/j.rmed.2012.11.002

  View details for Web of Science ID 000314556000015

  View details for PubMedID 23195332

  View details for PubMedCentralID PMC3543517

• Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Dolinay, T., Kim, Y. S., Howrylak, J., Hunninghake, G. M., An, C. H., Fredenburgh, L., Massaro, A. F., Rogers, A., Gazourian, L., Nakahira, K., Haspel, J. A., Landazury, R., Eppanapally, S., Christie, J. D., Meyer, N. J., Ware, L. B., Christiani, D. C., Ryter, S. W., Baron, R. M., Choi, A. M. 2012; 185 (11): 1225-1234

  Abstract

  Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation.We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS.We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid.In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality.The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

  View details for DOI 10.1164/rccm.201201-0003OC

  View details for Web of Science ID 000304384600016

  View details for PubMedID 22461369

  View details for PubMedCentralID PMC3373064

• The CD4+ T-cell transcriptome and serum IgE in asthma: IL17RB and the role of sex. BMC pulmonary medicine Hunninghake, G. M., Chu, J., Sharma, S. S., Cho, M. H., Himes, B. E., Rogers, A. J., Murphy, A., Carey, V. J., Raby, B. A. 2011; 11: 17-?

  Abstract

  The relationships between total serum IgE levels and gene expression patterns in peripheral blood CD4+ T cells (in all subjects and within each sex specifically) are not known.Peripheral blood CD4+ T cells from 223 participants from the Childhood Asthma Management Program (CAMP) with simultaneous measurement of IgE. Total RNA was isolated, and expression profiles were generated with Illumina HumanRef8 v2 BeadChip arrays. Modeling of the relationship between genome-wide gene transcript levels and IgE levels was performed in all subjects, and stratified by sex.Among all subjects, significant evidence for association between gene transcript abundance and IgE was identified for a single gene, the interleukin 17 receptor B (IL17RB), explaining 12% of the variance (r2) in IgE measurement (p value = 7 × 10(-7), 9 × 10(-3) after adjustment for multiple testing). Sex stratified analyses revealed that the correlation between IL17RB and IgE was restricted to males only (r2 = 0.19, p value = 8 × 10(-8); test for sex-interaction p < 0.05). Significant correlation between gene transcript abundance and IgE level was not found in females. Additionally we demonstrated substantial sex-specific differences in IgE when considering multi-gene models, and in canonical pathway analyses of IgE level.Our results indicate that IL17RB may be the only gene expressed in CD4+ T cells whose transcript measurement is correlated with the variation in IgE level in asthmatics. These results provide further evidence sex may play a role in the genomic regulation of IgE.

  View details for DOI 10.1186/1471-2466-11-17

  View details for PubMedID 21473777

  View details for PubMedCentralID PMC3080837

• On the Genome-Wide Analysis of Copy Number Variants in Family-Based Designs: Methods for Combining Family-Based and Population-Based Information for Testing Dichotomous or Quantitative Traits, or Completely Ascertained Samples GENETIC EPIDEMIOLOGY Murphy, A., Won, S., Rogers, A., Chu, J., Raby, B. A., Lange, C. 2010; 34 (6): 582-590

  Abstract

  We propose a new approach for the analysis of copy number variants (CNVs)for genome-wide association studies in family-based designs. Our new overall association test combines the between-family component and the within-family component of the family-based data so that the new test statistic is fully efficient and, at the same time, maintains robustness against population-admixture and stratification, like classical family-based association tests that are based only on the within-family component. Although all data are incorporated into the test statistic, an adjustment for genetic confounding is not needed, even for the between-family component. The new test statistic is valid for testing either quantitative or dichotomous phenotypes. If external CNV data are available, the approach can also be applied to completely ascertained samples. Similar to the approach by Ionita-Laza et al. ([2008]. Genet Epidemiol 32:273-284), the proposed test statistic does not require a CNV-calling algorithm and is based directly on the CNV probe intensities. We show, via simulation studies, that our methodology increases the power of the FBAT statistic to levels comparable to those of population-based designs. The advantages of the approach in practice are demonstrated by an application to a genome-wide association study for body mass index.

  View details for DOI 10.1002/gepi.20515

  View details for Web of Science ID 000282038200008

  View details for PubMedID 20718041

  View details for PubMedCentralID PMC3349936

• A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Sharma, S., Tantisira, K., Carey, V., Murphy, A. J., Lasky-Su, J., Celedon, J. C., Lazarus, R., Klanderman, B., Rogers, A., Soto-Quiros, M., Avila, L., Mariani, T., Gaedigk, R., Leeders, S., Torday, J., Warburton, D., Raby, B., Weiss, S. T. 2010; 181 (4): 328-336

  Abstract

  Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003).Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.

  View details for DOI 10.1164/rccm.200907-1009OC

  View details for Web of Science ID 000274637100008

  View details for PubMedID 19926868

  View details for PubMedCentralID PMC2822972

• Stronger Evidence for Replication of NPPA Using Genome-wide Genotyping Data AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rogers, A. J., Raby, B. A., Lima, J., Lasky-Su, J. A., Murphy, A., Lazarus, R., Klanderman, B., Sylvia, J. S., Ziniti, J. P., Lange, C., Celedon, J. C., Silverman, E. K., Weiss, S. T. 2010; 181 (1): 96

  View details for DOI 10.1164/ajrccm.181.1.96

  View details for Web of Science ID 000273147100021

  View details for PubMedID 20026756

  View details for PubMedCentralID PMC6850781

• The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma CLINICAL AND EXPERIMENTAL ALLERGY Rogers, A. J., Brasch-Andersen, C., Ionita-Laza, I., Murphy, A., Sharma, S., Klanderman, B. J., Raby, B. A. 2009; 39 (11): 1721-1729

  Abstract

  The glutathione S-transferase M1 (GSTM1)-null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress.To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics.We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and post-natal, longitudinal smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes.Associations of GSTM1-null variants with asthma (P=0.03), younger age of asthma symptom onset (P=0.03), and greater airflow obstruction (reduced forced expiratory volume in 1 s / forced vital capacity, P=0.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1-null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection.These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.

  View details for DOI 10.1111/j.1365-2222.2009.03372.x

  View details for Web of Science ID 000271001600014

  View details for PubMedID 19860819

  View details for PubMedCentralID PMC2773694

• Predictors of poor response during asthma therapy differ with definition of outcome PHARMACOGENOMICS Rogers, A. J., Tantisira, K. G., Fuhlbrigge, A. L., Litonjua, A. A., Lasky-Su, J. A., Szefler, S. J., Strunk, R. C., Zeiger, R. S., Weiss, S. T. 2009; 10 (8): 1231-1242

  Abstract

  To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5-12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.

  View details for DOI 10.2217/PGS.09.86

  View details for Web of Science ID 000269408100011

  View details for PubMedID 19663668

  View details for PubMedCentralID PMC2746392

• Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rogers, A. J., Raby, B. A., Lasky-Su, J. A., Murphy, A., Lazarus, R., Klanderman, B. J., Sylvia, J. S., Ziniti, J. P., Lange, C., Celedon, J. C., Silverman, E. K., Weiss, S. T. 2009; 179 (12): 1084-1090

  Abstract

  Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin beta(3) [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true "asthma genes."

  View details for DOI 10.1164/rccm.200812-1860OC

  View details for Web of Science ID 000266787500006

  View details for PubMedID 19264973

  View details for PubMedCentralID PMC2695495

• Asthma genetics and genomics 2009 CURRENT OPINION IN GENETICS & DEVELOPMENT Weiss, S. T., Raby, B. A., Rogers, A. 2009; 19 (3): 279-282

  Abstract

  Asthma Genetic Association studies have been plagued by methodologic problems that are common in all studies of complex traits: small sample size, lack of replication, and lack of control of population stratification. Despite this, the field has identified 43 replicated genes from association studies. The most frequently replicated are: TNF alpha, IL4, FCERB, Adam 33, and GSTP1. Several genes have been identified by linkage and fine mapping (ADAM33, DPP10, GPR154, and PHF11) and one gene has been identified by GWAS (ORMD3). The major issue is that these genes have been looked at one at a time rather than in some more holistic manner where epistasis is considered. For asthma genetics to begin to have an impact on clinical medicine we need to consider epistatic interaction.

  View details for DOI 10.1016/j.gde.2009.05.001

  View details for Web of Science ID 000267585000012

  View details for PubMedID 19481925

• Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis GENOMICS Ionita-Laza, I., Rogers, A. J., Lange, C., Raby, B. A., Lee, C. 2009; 93 (1): 22-26

  Abstract

  Structural genetic variation, including copy-number variation (CNV), constitutes a substantial fraction of total genetic variability and the importance of structural genetic variants in modulating human disease is increasingly being recognized. Early successes in identifying disease-associated CNVs via a candidate gene approach mandate that future disease association studies need to include structural genetic variation. Such analyses should not rely on previously developed methodologies that were designed to evaluate single nucleotide polymorphisms (SNPs). Instead, development of novel technical, statistical, and epidemiologic methods will be necessary to optimally capture this newly-appreciated form of genetic variation in a meaningful manner.

  View details for DOI 10.1016/j.ygeno.2008.08.012

  View details for Web of Science ID 000262492000006

  View details for PubMedID 18822366

  View details for PubMedCentralID PMC2631358

• Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Rogers, A. J., Celedon, J. C., Lasky-Su, J. A., Weiss, S. T., Raby, B. A. 2007; 120 (6): 1332-1337

  Abstract

  Loss-of-function mutations in the filaggrin gene (FLG) have been strongly associated with atopic dermatitis and allergic phenotypes in multiple populations. The role of these mutations in the development of asthma is less clear, particularly in patients who do not have coincident atopic dermatitis.To determine whether FLG mutations are associated with asthma or asthma-related intermediate phenotypes.We genotyped 2 loss-of-function FLG mutations (R501X and 2282del4) in white children (age 5-12 years) with mild to moderate asthma in the Childhood Asthma Management Program. We assessed the relationship of these mutations to asthma and allergy-related phenotypes in children with and without atopic dermatitis using both population-based and family-based tests of association.Nearly 1/3 (185/646) of the participating children had atopic dermatitis. Although strong associations were observed between FLG mutations and atopic dermatitis (odds ratio, 2.4; P = 7.6 x 10(-5)) and between the mutations and total serum IgE level (P = .009 in the atopic dermatitis cohort), no association was noted with either asthma or asthma-related phenotypes, including FEV(1), FEV(1)/forced vital capacity, and methacholine PC(20) (P > .1 for all tests).Although FLG loss-of-function mutations are consistently associated with atopic dermatitis and other allergic phenotypes, these mutations do not appear to influence either susceptibility to asthma or asthma severity phenotypes.Filaggrin mutations that predispose to atopic dermatitis do not modulate the asthma phenotype.

  View details for DOI 10.1016/j.jaci.2007.09.037

  View details for Web of Science ID 000251653800013

  View details for PubMedID 18073125