Bio


Dr. Joseph Levitt specializes in the treatment of adult pulmonary diseases including COPD, asthma, bronchiectasis, chronic cough, sarcoidosis, and pulmonary infections. He has practiced pulmonary medicine for more than 10 years. In addition to outpatient pulmonary medicine, Dr. Levitt is a critical care intensivist with a specific research interest in the clinical management of the Acute Respiratory Distress Syndrome (ARDS).

Clinical Focus


  • Pulmonary Critical Care
  • Critical Care Medicine

Academic Appointments


Administrative Appointments


  • Program Director, Division of Pulmonary and Critical Care Medicine, Stanford University Department of Medicine (2015 - Present)

Professional Education


  • Residency: University of Chicago Hospitals Internal Medicine Residency (2001) IL
  • Medical Education: University of Minnesota School of Medicine (1998) MN
  • Board Certification: American Board of Internal Medicine, Critical Care Medicine (2017)
  • Fellowship: Stanford University Pulmonary and Critical Care Fellowship (2005) CA
  • Fellowship: University of Chicago Pulmonary Disease and Critical Care Medicine Fellowship (2004) IL
  • Internship: University of Arizona Internal Medicine Residency (1999) AZ
  • Residency: John H Stroger Jr Hospital of Cook County Internal Medicine Residency (2002) IL
  • Board Certification: American Board of Internal Medicine, Pulmonary Disease (2005)
  • M.D., University of Minnesota (1998)

Current Research and Scholarly Interests


My research focuses on the physiolgogic and biomarker characteristics of early acute lung injury (ALI) prior to need for mechanical ventilation. While, to date no pharmacologic treatment has improved survival in ALI, following the paradigm of early goal directed therapy for severe sepsis, clinical benefit may derive from identifying patients and initiating treatment prior to the need for positive pressure ventilation (and therefore prior to meeting current study entry criteria).

Clinical Trials


  • Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE Recruiting

    This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19 positive inpatients

    View full details

  • ARrest RESpiraTory Failure From PNEUMONIA Recruiting

    This research study seeks to establish the effectiveness of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure (ARF) in hospitalized patients with pneumonia and hypoxemia.

    View full details

  • EPVent 2- A Phase II Study of Mechanical Ventilation Directed by Transpulmonary Pressures Recruiting

    This phase II multi-centered, randomized controlled trial of mechanical ventilation directed by esophageal pressure measurement will test the primary hypothesis that using a strategy of maintaining a minimal but positive transpulmonary pressure (Ptp = airway pressure minus pleural pressure) throughout the ventilatory cycle will lead to an improvement in patient survival.

    View full details

  • Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome Recruiting

    This is a Phase 1, open label, dose escalation, multi-center clinical trial of Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) for the treatment of Acute Respiratory Distress Syndrome (ARDS). The purpose of this study is to assess the safety of hMSCs in patients with ARDS.

    View full details

  • Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START) Recruiting

    This was a Phase 2a, randomized, double-blind, placebo-controlled, multi-center trial to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS).

    View full details

  • I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients Recruiting

    The goal of this project is to rapidly screen promising agents, in the setting of an adaptive platform trial, for treatment of critically ill COVID-19 patients. In this phase 2 platform design, agents will be identified with a signal suggesting a big impact on reducing mortality and the need for, as well as duration, of mechanical ventilation.

    View full details

  • LIPS-A: Lung Injury Prevention Study With Aspirin Recruiting

    The primary hypothesis was that early aspirin administration will decrease the rate of developing acute lung injury during the first 7 days after presentation to the hospital.

    View full details

  • LIPS-B: Lung Injury Prevention Study With Budesonide and Beta Recruiting

    This study tested whether inhaled budesonide and formoterol were able to alleviate or prevent pulmonary injury when administered early in hospital course to the patients at risk for developing acute respiratory distress syndrome (ARDS). The FDA has approved many uses for budesonide and formoterol, including asthma and chronic obstructive pulmonary disease (COPD), but the use of these two drugs is experimental for ARDS.

    View full details

  • Novel Experimental COVID-19 Therapies Affecting Host Response Recruiting

    The overarching goal of the Master Protocol is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19.

    View full details

  • Statins for Acutely Injured Lungs From Sepsis Recruiting

    Objective: assess the efficacy and safety of oral rosuvastatin in patients with sepsis-induced Acute Lung Injury (ALI). Hypothesis: Rosuvastatin therapy will improve mortality in patients with sepsis-induced ALI.

    View full details

  • ACTIV-3: Therapeutics for Inpatients With COVID-19 Not Recruiting

    This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.

    Stanford is currently not accepting patients for this trial. For more information, please contact SPECTRUM, (650) 724 - 5282.

    View full details

  • Aspiration in Acute Respiratory Failure Survivors 2 Not Recruiting

    The purpose of this study is to learn more about problems with swallowing that could develop in patients who are very sick and need a machine to help them breathe.

    Stanford is currently not accepting patients for this trial.

    View full details

  • COVID-19 Outpatient Pragmatic Platform Study (COPPS) - Acebilustat Sub-Protocol Not Recruiting

    The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients. COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.

    Stanford is currently not accepting patients for this trial. For more information, please contact Study Team, 650-721-9316.

    View full details

  • COVID-19 Outpatient Pragmatic Platform Study (COPPS) - Master Protocol Not Recruiting

    The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients. COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.

    Stanford is currently not accepting patients for this trial. For more information, please contact Study Team, 650-721-9316.

    View full details

  • Reevaluation Of Systemic Early Neuromuscular Blockade Not Recruiting

    This study evaluates whether giving a neuromuscular blocker (skeletal muscle relaxant) to a patient with acute respiratory distress syndrome will improve survival. Half of the patients will receive a neuromuscular blocker for two days and in the other half the use of neuromuscular blockers will be discouraged.

    Stanford is currently not accepting patients for this trial. For more information, please contact SPECTRUM, (650) 723 - 6576.

    View full details

2023-24 Courses


Graduate and Fellowship Programs


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

  • 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

  • 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

  • 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

  • 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

  • Effectiveness of Monovalent mRNA Vaccines Against COVID-19-Associated Hospitalization Among Immunocompetent Adults During BA.1/BA.2 and BA.4/BA.5 Predominant Periods of SARS-CoV-2 Omicron Variant in the United States - IVY Network, 18 States, December 26, 2021-August 31, 2022. MMWR. Morbidity and mortality weekly report Surie, D., Bonnell, L., Adams, K., Gaglani, M., Ginde, A. A., Douin, D. J., Talbot, H. K., Casey, J. D., Mohr, N. M., Zepeski, A., McNeal, T., Ghamande, S., Gibbs, K. W., Files, D. C., Hager, D. N., Shehu, A., Frosch, A. P., Erickson, H. L., Gong, M. N., Mohamed, A., Johnson, N. J., Srinivasan, V., Steingrub, J. S., Peltan, I. D., Brown, S. M., Martin, E. T., Khan, A., Bender, W. S., Duggal, A., Wilson, J. G., Qadir, N., Chang, S. Y., Mallow, C., Rivas, C., Kwon, J. H., Exline, M. C., Lauring, A. S., Shapiro, N. I., Halasa, N., Chappell, J. D., Grijalva, C. G., Rice, T. W., Stubblefield, W. B., Baughman, A., Womack, K. N., Hart, K. W., Swan, S. A., Zhu, Y., DeCuir, J., Tenforde, M. W., Patel, M. M., McMorrow, M. L., Self, W. H. 2022; 71 (42): 1327-1334

    Abstract

    The SARS-CoV-2 Omicron variant (B.1.1.529 or BA.1) became predominant in the United States by late December 2021 (1). BA.1 has since been replaced by emerging lineages BA.2 (including BA.2.12.1) in March 2022, followed by BA.4 and BA.5, which have accounted for a majority of SARS-CoV-2 infections since late June 2022 (1). Data on the effectiveness of monovalent mRNA COVID-19 vaccines against BA.4/BA.5-associated hospitalizations are limited, and their interpretation is complicated by waning of vaccine-induced immunity (2-5). Further, infections with earlier Omicron lineages, including BA.1 and BA.2, reduce vaccine effectiveness (VE) estimates because certain persons in the referent unvaccinated group have protection from infection-induced immunity. The IVY Network† assessed effectiveness of 2, 3, and 4 doses of monovalent mRNA vaccines compared with no vaccination against COVID-19-associated hospitalization among immunocompetent adults aged ≥18 years during December 26, 2021-August 31, 2022. During the BA.1/BA.2 period, VE 14-150 days after a second dose was 63% and decreased to 34% after 150 days. Similarly, VE 7-120 days after a third dose was 79% and decreased to 41% after 120 days. VE 7-120 days after a fourth dose was 61%. During the BA.4/BA.5 period, similar trends were observed, although CIs for VE estimates between categories of time since the last dose overlapped. VE 14-150 days and >150 days after a second dose was 83% and 37%, respectively. VE 7-120 days and >120 days after a third dose was 60%and 29%, respectively. VE 7-120 days after the fourth dose was 61%. Protection against COVID-19-associated hospitalization waned even after a third dose. The newly authorized bivalent COVID-19 vaccines include mRNA from the ancestral SARS-CoV-2 strain and from shared mRNA components between BA.4 and BA.5 lineages and are expected to be more immunogenic against BA.4/BA.5 than monovalent mRNA COVID-19 vaccines (6-8). All eligible adults aged ≥18 years§ should receive a booster dose, which currently consists of a bivalent mRNA vaccine, to maximize protection against BA.4/BA.5 and prevent COVID-19-associated hospitalization.

    View details for DOI 10.15585/mmwr.mm7142a3

    View details for PubMedID 36264830

    View details for PubMedCentralID PMC9590291

  • Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study. BMJ (Clinical research ed.) Adams, K., Rhoads, J. P., Surie, D., Gaglani, M., Ginde, A. A., McNeal, T., Talbot, H. K., Casey, J. D., Zepeski, A., Shapiro, N. I., Gibbs, K. W., Files, D. C., Hager, D. N., Frosch, A. E., Exline, M. C., Mohamed, A., Johnson, N. J., Steingrub, J. S., Peltan, I. D., Brown, S. M., Martin, E. T., Lauring, A. S., Khan, A., Busse, L. W., Duggal, A., Wilson, J. G., Chang, S. Y., Mallow, C., Kwon, J. H., Chappell, J. D., Halasa, N., Grijalva, C. G., Lindsell, C. J., Lester, S. N., Thornburg, N. J., Park, S., McMorrow, M. L., Patel, M. M., Tenforde, M. W., Self, W. H., Influenza and other Viruses in the AcutelY ill (IVY) Network, Ghamande, S., Calhoun, N., Murthy, K., Herrick, J., McKillop, A., Hoffman, E., Zayed, M., Smith, M., Kozikowski, L., De Souza, L., Ouellette, S., Bolstad, M., Coviello, B., Ciottone, R., Devilla, A., Grafals, A., Higgins, C., Ottanelli, C., Redman, K., Scaffidi, D., Weingart, A., Lewis, N., Mehkri, O., Mitchell, M., Griffith, Z., Brennan, C., Ashok, K., Poynter, B., Ten Lohuis, C., Stanley, N., Zhang, S., Prekker, M., Erickson, H., Hendrickson, A., Caspers, S., Tordsen, W., Kaus, O., Scharber, T., Lumpkin, J., Smith, C., Marshall, H., Shehu, A., Ali, H., Rothman, R. E., Mohamed, A., Nair, R., Chen, J. T., Karow, S., Robart, E., Maldonado, P. N., Khan, M., So, P., So, M., Schwartz, E., Botros, M., Hough, C. L., Jung, H., Martinez, J., Luong, A., Huynh, B., Ibrahim, H., Villanueva-Vargas, C., Villanueva-Vargas, J., Quadri, S., Gordon, A. J., Levitt, J., Perez, C., Visweswaran, A., Roque, J., Qadir, N., Frankel, T., Garner, O., Chandrasekaran, S., Douin, D., Jensen, K., Huynh, D., Steinwand, A., Withers, C., Mohr, N., Nassar, P., Landers, S., Nielsen, K., Briggs, N., Fairfield, C., Gershengorn, H., Rivas, C., Monto, A., McSpadden, E. J., Truscon, R., Kaniclides, A., Thomas, L., Bielak, R., Valvano, W. D., Fong, R., Fitzsimmons, W. J., Blair, C., Gilbert, J., Baker, L., Srinivasan, V., Crider, C. D., Steinbock, K. A., Paulsen, T. C., Anderson, L. A., Jones, I., Womack, K., Baughman, A., Kampe, C., Johnson, J., Hart, K., Rice, T., Stubblefield, W. B., Zhu, Y., Short, L. L., Ezzell, L. J., Whitsett, M. E., McHenry, R. E., Hargrave, S. J., Blair, M., Luther, J. L., Pulido, C. G., Peterson, B. P., LaRose, M., Landreth, L., Hicks, M., Parks, L., Babcock, H., Bongu, J., McDonald, D., Cass, C., Seiler, S., Park, D., Hink, T., Wallace, M., Burnham, C., Arter, O. G. 2022; 379: e072065

    Abstract

    OBJECTIVE: To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States.DESIGN: Multicenter observational case-control study with a test negative design.SETTING: Hospitals in 18 US states.PARTICIPANTS: 4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls).MAIN OUTCOME MEASURES: The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products.RESULTS: Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P<0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P<0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04).CONCLUSION: During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19.READERS' NOTE: This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

    View details for DOI 10.1136/bmj-2022-072065

    View details for PubMedID 36220174

  • Opportunities for improved clinical trial designs in acute respiratory distress syndrome LANCET RESPIRATORY MEDICINE Wick, K. D., Aggarwal, N. R., Curley, M. Q., Fowler, A. A., Jaber, S., Kostrubiec, M., Lassau, N., Laterre, P., Lebreton, G., Levitt, J. E., Mebazaa, A., Rubin, E., Sinha, P., Ware, L. B., Matthay, M. A. 2022; 10 (9): 916-924
  • Opportunities for improved clinical trial designs in acute respiratory distress syndrome. The Lancet. Respiratory medicine Wick, K. D., Aggarwal, N. R., Curley, M. A., Fowler, A. A., Jaber, S., Kostrubiec, M., Lassau, N., Laterre, P. F., Lebreton, G., Levitt, J. E., Mebazaa, A., Rubin, E., Sinha, P., Ware, L. B., Matthay, M. A. 2022; 10 (9): 916-924

    Abstract

    The acute respiratory distress syndrome (ARDS) is a common critical illness syndrome with high morbidity and mortality. There are no proven pharmacological therapies for ARDS. The current definition of ARDS is based on shared clinical characteristics but does not capture the heterogeneity in clinical risk factors, imaging characteristics, physiology, timing of onset and trajectory, and biology of the syndrome. There is increasing interest within the ARDS clinical trialist community to design clinical trials that reduce heterogeneity in the trial population. This effort must be balanced with ongoing work to craft an inclusive, global definition of ARDS, with important implications for trial design. Ultimately, the two aims-to design trials that are applicable to the diverse global ARDS population while also advancing opportunities to identify targetable traits-should coexist. In this Personal View, we recommend two primary strategies to improve future ARDS trials: the development of new methods to target treatable traits in clinical trial populations, and improvements in the representativeness of ARDS trials, with the inclusion of global populations. We emphasise that these two strategies are complementary. We also discuss how a proposed expansion of the definition of ARDS could affect the future of clinical trials.

    View details for DOI 10.1016/S2213-2600(22)00294-6

    View details for PubMedID 36057279

  • I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ open Files, D. C., Matthay, M. A., Calfee, C. S., Aggarwal, N. R., Asare, A. L., Beitler, J. R., Berger, P. A., Burnham, E. L., Cimino, G., Coleman, M. H., Crippa, A., Discacciati, A., Gandotra, S., Gibbs, K. W., Henderson, P. T., Ittner, C. A., Jauregui, A., Khan, K. T., Koff, J. L., Lang, J., LaRose, M., Levitt, J., Lu, R., McKeehan, J. D., Meyer, N. J., Russell, D. W., Thomas, K. W., Eklund, M., Esserman, L. J., Liu, K. D., ISPY COVID Adaptive Platform Trial Network, undefined, Esserman, L. J., Calfee, C. S., Liu, K. D., Coleman, M. H., Matthay, M. A., Beitler, J. R., Mittel, A. M., Asare, A. L., Yen, A. F., Jauregui, A., Crippa, A., Suarez, A. E., Serra, A. L., Amin, A. N., Rosen, A., Dzierba, A. L., Discacciati, A., Haczku, A., Barker, A. D., Weisman, A. R., Daniel, B. M., Morrissey, B. M., Ittner, C. A., Jones, C., Creel-Bulos, C., Angelucci, C. M., Files, D. C., Russell, D. W., Ng, D., Burnham, E. L., Youssef, F. A., Chaparro-Rojas, F., Harris, G. H., Barot, H. V., Su, H., Garcia, I., Sutter, J. B., Dodin, J., McKeehan, J. D., Lee, J. S., Kazianis, J., Reilly, J. P., Koff, J. L., Detelich, J. F., Lang, J. E., Muir, J., Thomas, K. W., Khan, K. T., Gosek, K., Nugent, K. L., Gibbs, K. W., Yee, K., Rodrigues, L. G., Macias, L. R., Orr, L. A., Boerger, L. L., Rosario-Remigio, L., Kufa, L., Huerta, L. E., Tanios, M., Reyes, M. B., Eklund, M., LaRose, M., Adelman, M. W., Juarez, M. M., Jung, M., Meyers, M., Sternlieb, M. P., Cobb, N. K., Aggarwal, N., Mangalmurti, N. S., Meyer, N. J., Jones, P., Berger, P. A., Henderson, P., Saban, P. L., Marshall, P. S., Robinson, P. A., Yang, P., Madahar, P., Nair, R., Sonti, R., Lee, R. A., Wunderink, R. G., Wahab, R., Lupu, R. A., Lu, R., Kumar, S. I., Auld, S. C., Fields, S., Wong, S. F., Gandotra, S., Pearson, S. J., Whealon, S., Albertson, T. E., Obermiller, T. F., Oliver, T., Darmanian, A., Schicchi, J., Martinez, E., Sarafian, F., Nguyen, J., Weiler-Lisowski, B., Wyatt, J., Blevins, D., Melendrez, M., Lopez, B., Tzehaie, H., Amosu, O., Simonson, A., Patel, C., Levitt, J., Hardy, E., Lindgren, B., Peterfreund, G., Landreth, L., Parks, L., Aggarwal, N. 2022; 12 (6): e060664

    Abstract

    INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.TRIAL REGISTRATION NUMBER: NCT04488081.

    View details for DOI 10.1136/bmjopen-2021-060664

    View details for PubMedID 35667714

  • Effectiveness of a Third Dose of Pfizer-BioNTech and Moderna Vaccines in Preventing COVID-19 Hospitalization Among Immunocompetent and Immunocompromised Adults - United States, August-December 2021 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Tenforde, M. W., Patel, M. M., Gaglani, M., Ginde, A. A., Douin, D. J., Talbot, H., Casey, J. D., Mohr, N. M., Zepeski, A., McNeal, T., Ghamande, S., Gibbs, K. W., Files, D., Hager, D. N., Shehu, A., Prekker, M. E., Erickson, H. L., Gong, M. N., Mohamed, A., Johnson, N. J., Srinivasan, V., Steingrub, J. S., Peltan, I. D., Brown, S. M., Martin, E. T., Monto, A. S., Khan, A., Hough, C. L., Busse, L. W., Duggal, A., Wilson, J. G., Qadir, N., Chang, S. Y., Mallow, C., Rivas, C., Babcock, H. M., Kwon, J. H., Exline, M. C., Botros, M., Lauring, A. S., Shapiro, N., Halasa, N., Chappell, J. D., Grijalva, C. G., Rice, T. W., Jones, I. D., Stubblefield, W. B., Baughman, A., Womack, K. N., Rhoads, J. P., Lindsell, C. J., Hart, K. W., Zhu, Y., Naioti, E. A., Adams, K., Lewis, N. M., Surie, D., McMorrow, M. L., Self, W. H., IVY Network 2022; 71 (4): 118-124

    Abstract

    COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization.

    View details for Web of Science ID 000748639100001

    View details for PubMedID 35085218

  • Autoantibodies targeting cytokines and connective tissue disease autoantigens are common in acute non-SARS-CoV-2 infections. Research square Feng, A., Yang, E., Moore, A., Dhingra, S., Chang, S., Yin, X., Pi, R., Mack, E., Völkel, S., Geßner, R., Gundisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P., Asuni, A., Levitt, J., Wilson, J., Leong, M., Lumb, J., Mao, R., Pinedo, K., Roque, J., Richards, C., Stabile, M., Swaminathan, G., Salagianni, M., Triantafyllia, V., Bertrams, W., Blish, C., Carette, J., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T., Prak, E. L., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A., Utz, P. 2022

    Abstract

    The widespread presence of autoantibodies in acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is increasingly recognized, but the prevalence of autoantibodies in infections with organisms other than SARS-CoV-2 has not yet been reported. We used protein arrays to profile IgG autoantibodies from 317 samples from 268 patients across a spectrum of non-SARS-CoV-2 infections, many of whom were critically ill with pneumonia. Anti-cytokine antibodies (ACA) were identified in > 50% of patients infected with non-SARS-CoV-2 viruses and other pathogens, including patients with pneumonia attributed to bacterial causes. In cell-based functional assays, some ACA blocked binding to surface receptors for type I interferons (Type I IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6). Autoantibodies against traditional autoantigens associated with connective tissue diseases (CTDs) were also commonly observed in these cohorts, including newly-detected antibodies that emerged in longitudinal samples from patients infected with influenza. We conclude that autoantibodies, some of which are functionally active, may be much more prevalent than previously appreciated in patients who are symptomatically infected with diverse pathogens.

    View details for DOI 10.21203/rs.3.rs-1233038/v1

    View details for PubMedID 35075455

    View details for PubMedCentralID PMC8786233

  • Clinical trial design during and beyond the pandemic: the I-SPY COVID trial NATURE MEDICINE Calfee, C. S., Liu, K. D., Asare, A. L., Beitler, J. R., Berger, P. A., Coleman, M. H., Crippa, A., Discacciati, A., Eklund, M., Files, D. C., Gandotra, S., Gibbs, K. W., Henderson, P., Levitt, J. E., Lu, R., Matthay, M. A., Meyer, N. J., Russell, D. W., Thomas, K. W., Esserman, L. J., Mittel, A. M., Dzierba, A. L., Madahar, P., Serra, A. L., Rosen, A., Garcia, I., Muir, J., Schicchi, J., Darmanian, A., Wahab, R., Gosek, K., Auld, S. C., Adelman, M. W., Nugent, K. L., Harris, G. H., Creel-Bulos, C., Yang, P., Detelich, J. F., Spainhour, C., Cobb, N. K., Sonti, R., Orr, L. A., Robinson, P. A., Sarafian, F., Martinez, E., Jones, P., Nguyen, J., Obermiller, T. F., Weiler-Lisowski, B., Kufa, L., Saba, P. L., Wyatt, J., Youssef, F. A., Tanios, M., Blevins, D., Macias, L. R., Suarez, A. E., Reyes, M. B., Jung, M., Melendrez, M., Rosario-Remigio, L., Su, H., Friedman, E. B., Angelucci, C. M., Chaparro-Rojas, F., Sternlieb, M. P., Sutter, J. B., Whealon, S., Nair, R., Lopez, B., Amosu, O., Tzehaie, H., Wunderink, R. G., Patel, C., Simonson, A., Dodin, J., Oliver, T., Lupu, R. A., Meyers, M., Albertson, T. E., Haczku, A., Hardy, E., Morrissey, B. M., Juarez, M. M., Pearson, S. J., Lee, R., Amin, A. N., Jauregui, A., Fields, S., Ng, D., Daniel, B. M., Yee, K., Jones, C., Burnham, E. L., McKeehan, J. D., Ittner, C. G., Reilly, J. P., Mangalmurti, N. S., Rodrigues, L. G., Weisman, A. R., Khan, K. T., Wong, S., Yen, A. F., Peterfreund, G., Kumar, S. I., Marshall, P. S., Huerta, L. E., Lindgren, B., Lee, J. S., Barker, A. D., Lang, J. E., LaRose, M., Landreth, L., Parks, L., Barot, H. V., Koff, J. L., Kazianis, J., Boerger, L. L., Consortium Contributors 2022; 28 (1): 9-11

    View details for DOI 10.1038/s41591-021-01617-x

    View details for Web of Science ID 000759051400005

    View details for PubMedID 35058620

  • Effectiveness of mRNA vaccines in preventing COVID-19 hospitalization by age and burden of chronic medical conditions among immunocompetent US adults, March-August 2021. The Journal of infectious diseases Lewis, N. M., Naioti, E. A., Self, W. H., Ginde, A. A., Douin, D. J., Talbot, H. K., Casey, J. D., Mohr, N. M., Zepeski, A., Gaglani, M., Ghamande, S. A., McNeal, T. A., Shapiro, N. I., Gibbs, K. W., Files, D. C., Hager, D. N., Shehu, A., Prekker, M. E., Erickson, H. L., Gong, M. N., Mohamed, A., Henning, D. J., Steingrub, J. S., Peltan, I. D., Brown, S. M., Martin, E. T., Hubel, K., Hough, C. L., Busse, L. W., Ten Lohuis, C. C., Duggal, A., Wilson, J. G., Gordon, A. J., Qadir, N., Chang, S. Y., Mallow, C., Rivas, C., Babcock, H. M., Kwon, J. H., Exline, M. C., Halasa, N., Chappell, J. D., Lauring, A. S., Grijalva, C. G., Rice, T. W., Rhoads, J. P., Stubblefield, W. B., Baughman, A., Womack, K. N., Lindsell, C. J., Hart, K. W., Zhu, Y., Schrag, S. J., Kobayashi, M., Verani, J. R., Patel, M. M., Tenforde, M. W. 1800

    Abstract

    In a multi-state network, vaccine effectiveness (VE) against COVID-19 hospitalizations was evaluated among immunocompetent adults (≥18-years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was higher at 96% (95% CI: 93-98%) among patients with no chronic medical conditions than patients with ≥3 categories of conditions (83% [95% CI: 76-88%]). VE was similar between those aged 18-64 years vs ≥65 years (p>0.05). Vaccine effectiveness against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing burden of comorbidities.

    View details for DOI 10.1093/infdis/jiab619

    View details for PubMedID 34932114

  • Promises and challenges of personalized medicine to guide ARDS therapy CRITICAL CARE Wick, K. D., McAuley, D. F., Levitt, J. E., Beitler, J. R., Annane, D., Riviello, E. D., Calfee, C. S., Matthay, M. A. 2021; 25 (1): 404

    Abstract

    Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

    View details for DOI 10.1186/s13054-021-03822-z

    View details for Web of Science ID 000721875300001

    View details for PubMedID 34814925

    View details for PubMedCentralID PMC8609268

  • Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions - United States, March-August 2021 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Self, W. H., Tenforde, M. W., Rhoads, J. P., Gaglani, M., Ginde, A. A., Douin, D. J., Olson, S. M., Talbot, K., Casey, J. D., Mohr, N. M., Zepeski, A., McNeal, T., Ghamande, S., Gibbs, K. W., Files, D., Hager, D. N., Shchu, A., Prekker, M. E., Erickson, H. L., Gong, M. N., Mohamed, A., Henning, D. J., Steingrub, J. S., Peltan, I. D., ten Lohuis, C. C., Duggal, A., Wilson, J. G., Gordon, A., Qadir, N., Chang, S. Y., Mallow, C., Rivas, C., Babcock, H. M., Kwon, J. H., Exline, M. C., Halasa, N., Chappell, J. D., Lauring, A. S., Grijalva, C. G., Rice, T. W., Jones, I. D., Stubblefield, W. B., Baughman, A., Womack, K. N., Lindsell, C. J., Hart, K. W., Zhu, Y., Mills, L., Lester, S. N., Stumpf, M. M., Naioti, E. A., Kobayashi, M., Verani, J. R., Thornburg, N. J., Patel, M. M., Brown, S. M., Martin, E. T., Monto, A. S., Khan, A., Hough, C. L., Busse, L. W., IVY Network 2021; 70 (38): 1337-1343

    Abstract

    Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization.

    View details for Web of Science ID 000701940200005

    View details for PubMedID 34555004

    View details for PubMedCentralID PMC8459899

  • Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults - United States, March-July 2021 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Tenforde, M. W., Self, W. H., Naioti, E. A., Ginde, A. A., Douin, D. J., Olson, S. M., Talbot, H., Casey, J. D., Mohr, N. M., Zepeski, A., Gaglani, M., McNeal, T., Ghamande, S., Shapiro, N. I., Gibbs, K. W., Files, D., Hager, D. N., Shehu, A., Prekker, M. E., Erickson, H. L., Gong, M. N., Mohamed, A., Henning, D. J., Steingrub, J. S., Peltan, I. D., Brown, S. M., Martin, E. T., Monto, A. S., Khan, A., Hough, C. L., Busse, L. W., ten Lohuis, C. C., Duggal, A., Wilson, J. G., Gordon, A., Qadir, N., Chang, S. Y., Mallow, C., Rivas, C., Babcock, H. M., Kwon, J. H., Exline, M. C., Halasa, N., Chappell, J. D., Lauring, A. S., Grijalva, C. G., Rice, T. W., Jones, I. D., Stubblefield, W. B., Baughman, A., Womack, K. N., Lindsell, C. J., Hart, K. W., Zhu, Y., Stephenson, M., Schrag, S. J., Kobayashi, M., Verani, J. R., Patel, M. M., IVY Network Investigators 2021; 70 (34): 1156-1162

    Abstract

    Real-world evaluations have demonstrated high effectiveness of vaccines against COVID-19-associated hospitalizations (1-4) measured shortly after vaccination; longer follow-up is needed to assess durability of protection. In an evaluation at 21 hospitals in 18 states, the duration of mRNA vaccine (Pfizer-BioNTech or Moderna) effectiveness (VE) against COVID-19-associated hospitalizations was assessed among adults aged ≥18 years. Among 3,089 hospitalized adults (including 1,194 COVID-19 case-patients and 1,895 non-COVID-19 control-patients), the median age was 59 years, 48.7% were female, and 21.1% had an immunocompromising condition. Overall, 141 (11.8%) case-patients and 988 (52.1%) controls were fully vaccinated (defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines ≥14 days before illness onset), with a median interval of 65 days (range = 14-166 days) after receipt of second dose. VE against COVID-19-associated hospitalization during the full surveillance period was 86% (95% confidence interval [CI] = 82%-88%) overall and 90% (95% CI = 87%-92%) among adults without immunocompromising conditions. VE against COVID-19- associated hospitalization was 86% (95% CI = 82%-90%) 2-12 weeks and 84% (95% CI = 77%-90%) 13-24 weeks from receipt of the second vaccine dose, with no significant change between these periods (p = 0.854). Whole genome sequencing of 454 case-patient specimens found that 242 (53.3%) belonged to the B.1.1.7 (Alpha) lineage and 74 (16.3%) to the B.1.617.2 (Delta) lineage. Effectiveness of mRNA vaccines against COVID-19-associated hospitalization was sustained over a 24-week period, including among groups at higher risk for severe COVID-19; ongoing monitoring is needed as new SARS-CoV-2 variants emerge. To reduce their risk for hospitalization, all eligible persons should be offered COVID-19 vaccination.

    View details for Web of Science ID 000691315200005

    View details for PubMedID 34437524

  • 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. J., Harward, M., Venz, E., Brady, K., Vale, C., Shekar, K., Lavana, J., Parmar, D., Williams, P., Kurenda, C., Miles, H., Attokaran, A., Gluck, S., O'Connor, S., Chapman, M., Glasby, K., Smyth, K., Phillips, M., Barge, D., Byrne, K., Driscoll, A., Fortune, L., Janin, P., Yarad, E., Bass, F., Hammond, N., O'Connor, A., Waterson, S., McNamara, R., Buhr, H., Coles, J., Schweikert, S., Wibrow, B., Rauniyar, R., Deshpande, K., Konecny, P., Miller, J., Kintono, A., Tung, R., Fysh, E., Dawda, A., Mevavala, B., De Keulenaer, A. R., Litton, E., Ferrier, J., Nair, P., Buscher, H., Reynolds, C., Newman, S., Santamaria, J., Barbazza, L., Homes, J., Smith, R., Garrett, P., Murray, L., Brailsford, J., Forbes, L., Maguire, T., Fennessy, G., Mulder, J., Morgan, R., McEldrew, R., Naeem, A., Fagan, L., Ryan, E., Mariappa, V., Smith, J., Simpson, S., Maiden, M., Bone, A., Horton, M., Salerno, T., Sterba, M., Geng, W., Depuydt, P., De Waele, J., De Bus, L., Fierens, J., Bracke, S., Vermassen, J., Vermeiren, D., Reeve, B., Dechert, W., Lellouche, F., Lizotte, P., Chasse, M., Carrier, F. M., Boumahni, D., Benettaib, F., Ghamraoui, A., Bellemare, D., Cloutier, E., Daher, R., Costerousse, O., Boulanger, M., Couillard-Chenard, E., Lauzier, F., Francoeur, C., Lamontagne, F., D'Aragon, F., Carbonneau, E., Leblond, J., Vazquez-Grande, G., Marten, N., Liu, T., Siddiqui, A., Wilson, M., Albert, M., Serri, K., Cavayas, A., Duplaix, M., Williams, V., Rochwerg, B., Karachi, T., Oczkowski, S., Centofanti, J., Millen, T., Khwaja, K., Campisi, J., Duan, E., Tsang, J., Patterson, L., Sy, E., Gupta, C., Kassir, S. S., Kutsogiannis, D., Thompson, P., Kamra, M., Marinoff, N., Cook, D., Clarke, F., Kruisselbrink, R., Brochard, L., Burns, K., Sandhu, G., Khalid, I., English, S., Watpool, I., Porteous, R., Miezitis, S., McIntyre, L., Wilcox, E., Del Sorbo, L., Abdelhady, H., Romagnuolo, T., Baig, N., Rewa, O., Bagshaw, S., Binnie, A., Powell, E., McMillan, A., Luk, T., Aref, N., Pratheema, R., Babu, S., Vignesh, C., Kumar, B., Ramakrishnan, N., James, A., Elvira, E., Ebenezer, R., Krishnaoorthy, S., Ranganathan, L., Shree, M. M., Mani, A. K., Mathew, M., Revathi, R., Khanal, S., Amatya, S., Paneru, H. R., Koirala, S., Paudel, P., Koirala, K., Rai, N., Luitel, S., Bhattarai, B., Panjwani, A., Umrani, Z. A., Siddiq, S., Shaikh, M., Salahuddin, N., Masood, S., Andric, Z., Cviljevic, S., Dimoti, R., Zapalac, M., Gordan, G., Barsic, B., Kutlesa, M., Kotarski, V., Vujaklija Brajkovic, A., Babel, J., Sever, H., Dragija, L., Kusan, I., Vaara, S., Pettila, L., Heinonen, J., Kuitunen, A., Karlsson, S., Vahtera, A., Kiiski, H., Ristimaki, S., Azaiz, A., Charron, C., Godement, M., Geri, G., Vieillard-Baron, A., Pourcine, F., Monchi, M., Luis, D., Mercier, R., Sagnier, A., Verrier, N., Caplin, C., Richecoeu, J., Combaux, D., Siami, S., Aparicio, C., Vautier, S., Jeblaoui, A., Lemaire-Brunel, D., Fartoukh, M., Courtin, L., Labbe, V., Voiriot, G., Nesrine Salhi, S., Plantefeve, G., Leparco, C., Contou, D., Muller, G., Nay, M., Kamel, T., Benzekri, D., Jacquier, S., Runge, I., Mathonnet, A., Barbier, F., Bretagnol, A., Mercier, E., Chartier, D., Salmon, C., Dequin, P., Garot, D., Schneider, F., Castelain, V., Morel, G., L'Hotellier, S., Badie, J., Berdaguer, F. D., Malfroy, S., Mezher, C., Bourgoin, C., Moneger, G., Bouvier, E., Megarbane, B., Voicu, S., Deye, N., Malissin, I., Sutterlin, L., Mrad, A., Pepin Lehalleur, A., Naim, G., Nguyen, P., Ekherian, J., Boue, Y., Sideris, G., Vodovar, D., Guerin, E., Grant, C., Guitton, C., Darreau, C., Landais, M., Chudeau, N., Robert, A., Tirot, P., Callahan, J. C., Saint Martin, M., Le Moal, C., Marnai, R., Leroyer, M. H., Moine, P., Heming, N., Maxime, V., Bossard, I., Nicholier, T. B., Clair, B., Orlikowski, D., Bounab, R., Abdeladim, L., Colin, G., Zinzoni, V., Maquigneau, N., Henri-Lagarrigue, M., Pouplet, C., Soukup, J., Wetzold, R., Lobel, M., Ing, D., Starke, L., Grimm, P., Finn, A., KreSS, G., Hoff, U., Hinrichs, C. F., Nee, J., Pletz, M. W., Hagel, S., Ankert, J., Kolanos, S., Bloos, F., Nickoleit-Bitzenberger, D., Schaaf, B., Meermeier, W., Prebeg, K., Azzaui, H. S., Hower, M., Brieger, K., Elender, C., Sabelhaus, T., Riepe, A., Akamp, C., Kremling, J., Klein, D., Landsiedel-Mechenbier, E., Petros, S., Kunz, K., Schutze, B., Kluge, S., Nierhaus, A., Jarczak, D., Roedl, K., Gerhard, G., Rohde, U., Grunewaldt, A., Bojunga, J., Weismann, D., Frey, A., Drayss, M., Goebeler, M. E., Flor, T., Fragner, G., Wahl, N., Totzke, J., Sayehli, C., Reill, L., Distler, M., Maselli, A., Belteczki, J., Magyar, I., Fazekas, A., Kovacs, S., Szoke, V., Szigligeti, G., Leszkoven, J., Collins, D., Reid, L., Smyth, M., Breen, P., Spain, S., Curley, G., McEvoy, N., Geoghegan, P., Clarke, J., Laffeyirbre McNicholas, J., Scully, M., Casey, S., Kernan, M., Brennan, A., Rangan, R., Tully, R., Corbett, S., McCarthy, A., Duffy, O., Burke, D., Hayes, L., Murphy, L., Neill, A., Reidy, B., O'Dwyer, M., Ryan, D., Hoiting, O., Peters, M., Rengers, E., Evers, M., Prinssen, A., van den Oever, H. L., Kruisdijk-Gerritsen, A., Simons, K., van Zuylen, T., Bouman, A., van Gulik, L., Schouten, J., Pickkers, P., Roovers, N., Klop-Riehl, M., van der Eng, H., de Jonge, E., Wigbers, J., Del Prado, M., Mulier, J. H., Peters, A. L., Romberg, B., van Bree, S., Bouw-Ruiterrbara Festen, M., van Gelder, F., van Iperen, M., Osinga, M., Schellaars, R., Tjan, D., van der Wekken, R., Melchers, M., van Zanten, A., van Nieuwkoop, K., Ottens, T., Visser, Y., Juffermans, N., Koopmans, M., Guilder, E., Butler, M., Cowdrey, K., Woollett, M., Newby, L., Chen, Y., Simmonds, C., McConnochie, R., O'Connor, C., Ritzema Carter, J., 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., MClinIm, M., 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., Angharad, A., Williams, W., 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., Govern, C. M., 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., Novellas, N. G., 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., Prabakaran, R. O., 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., Arun Sathe, S., 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., Blakemore, H., 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., Stavor, D., Burbee, D., McNamara, A., Bensen, N., Richardson, A., Adams, P., Vita, T., Buhay, M., Scholl, D., Gilliam, M., Winters, J., Doherty, K., Berryman, E., Ghaffari, M., Fitzpatrick, M., Bagavathy, K., Drapola, D., Hussain, M., Donadee, C., Bryan-Morris, K., Arnold, J., Reynolds, B., Beard, G., McAdams, D., Walker, G., Dunsavage, J., 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., McCreary, E., 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., Fesz, J., Carpio, L., Malakouti, S., Clermont, G., Bart, R., Yealy, D., Barton, D., Talia, N., Schoenling, A., Andreae, M., Shetty, V., Malley, B., Bain, W., Barbash, I., Franz, C., Kitsios, G., Moghbeli, K., Rosborough, B., Shah, F., Suber, T., Roberts, T., Becker, R. C., Del Zoppo, G., Henke, P., Holubkov, R., Kerr, K., Lee, A., Lurie, F., Vesely, S. K., Hochman, J. S., Neal, M. D., Berger, J. S., Cushman, M., Baumann Kreuziger, L., Farkouh, M., Gong, M. N., Hudock, K., Mstr, M., Kim, K. S., Kornblith, L. Z., Lawler, P. R., Leifer, E., McVerry, B. J., Reynolds, H. R., Wilson, J. G., Hochman, J., Berger, J., Reynolds, H., Contreras, A., Mavromichalis, S., Gilsenan, M., Naumova, A., Roberts, A., Wisniewski, S., Leeper, C., Eng, H., Brooks, M., Martinez, M., Schreiber, J., Froess, J., Fu, Z., Zhong, Y., Vadlamudi, A., Sciurba, F., Morris, A., Kirwan, B., de Brouwer, S., Perrin, E., Gombault, C., Bula, S., Nelson, M., Daelemans, C., Wegmuller, R., La Framboise, D., Hoots, W. K., Kindzelski, A., Mondoro, T., Punturieri, A., Weinmann, G., Troendle, J. F., Kendrick, A. S., Nolen, T. L., Thomas, S., Sin, D., Diene, E., Gwiszcz, E., Hogan, I., Holden, A., Gong, M., Ringwood, N., Fitzgerald, L., Sharer, J., Ceusters, D., Hintlian, C., Kornblith, L., Nunez-Garcia, B., Uribe, V., Hendrickson, C., Barua, C., Knudson, M. M., Park, J., Gonzalez, A., Lopez-Sendon, J., Moraga Alapont, P., Prieto, P., Hernandez, V., Broaddrick, S., Kim, K., Quigley, S., Kamel, H., Khatri, P., Frasure, J., Silken, A., Lopez-Sendon Moreno, J. L., Morillo Guerrero, R., Garcia Madrona, S., Molinera, A., Navarro Carrion, O., Besse Diaz, R., Diz Farina, S., Hidalgo Salinas, F., Gonzalez Ferrandiz, P., Zhilina, S., Alpanes Buesa, M., Gonzalez Garcia, A., Marcos Martin, M., Sanchez, M., Hernandez, J., Alvarez Navid, F., Garcia, M. B., Carbonell Munoz, C., Hernandez Perez, G., Lopez Bernus, A., Oterino, J. A., Keller, N., Yuriditsky, E., Ahuja, T., Horowitz, J., Hindenburg, A., Chkhikvadze, T., Parnia, S., Moran, Z., Fadzan, M., Levine, J., Cobos, S., Roberts, A., Mamistvalova, L., Garabedian, M., Ahmed, F., Zapata, G., Robinson, M., Quigley, J., Jacobson, J., Atal, N., Amosu, O., Tzehaie, H., Nair, R., Lopez, B., Hache Marliere, M., Fein, D., Offor, O., Kiyatkin, M., Chekuri, S., Galen, B., Hambardzumyan, A., Desai, A., Akhter, M., Aleem, H., Virdi, S., Shah, R., Hope, A., Chen, J., Mohamed, A., Kornblith, A., Shelley, I., Ambachew, B., Abaye, M., Yang, A., Amin, S. S., King, A. J., Franz, C. A., Kitsios, G. D., Mayr, F. B., Shah, F. A., Shetty, V. U., Schaefer, C., Muir, M., Urbanek, K. L., Greenstein, Y., Teeter, R., Plump, M., Kovalenko, O., Obando, E., Taveras, Y., Fanka, B., Suri, N., Patel, S., Kaur, M., Hite, R., Roads, T., Gebremedhen, A., Kiran, S., More, H., Costantini, T., Curry, T., Trinidad, E., Tyler, M., Berndtson, A., Allison, M., Bhatia, H., Denenberg, J., Marsh-Armstrong, B., Verzhbinsky, I., Morris, T., Fernandes, T., Elliott, A., Eastman, A., Lim, G., Hendey, G., Chang, S., Qadir, N., Beutler, R., Agarwal, T., Vargas, J., Singer, J., Haase, D., Murphy, J., Brzezinski, A., Yap, A., Yao, D. H., Bolduc, C., Antonuk, C., Spungen, H., Vuong, A., Wilson, J., Rogers, A., Levitt, J., Vojnik, R., Roque, J., Perez, C., Khan, A., Krol, O., Mistry, K., Nguyen, K., Lu, Z., Jouzestani, M. K., Singh, A., Mcdougal, M., Salar, A., Florea, S., Adi, R., Anadkat, C., Mills, E., Zouyed, Z., Deshmukh, R., Hough, C., Widmer, R., Fikes, W., Kiesle, E., Hyzy, R., Park, P., Jia, S., McSparron, J., Wang, B., Hanna, S., McDonough, K., Melvin, A., Nelson, K., Olbrich, N., Goodman, A., Hank, H. E., Quillen, D., Shamsuddin, A., Michl, L., Harper, M., Phipps, M., Braker, C., Wahid, L., Mohammed, O., Gazda, S., Craven, J., Jackson, R., Abuchowski, K., Dolor, R., Ortel, T., Manson, M., Vergara, L., Pinero, G., Freel, S., Krishnan, V., Newman, C., Leo, P., Greenwood, C., Wright, A., Warren, E. L., Thornton, J. D., Frolkis, C., Matthay, M., Kangelaris, K., Liu, K., Zhuo, H., Daniel, B., Yee, K., Jauregui, A., Ghale, R., Chak, S., Wick, K., Siegel, E., Jones, C., Ashktorab, K., Satterwhite, L., Harris, P., Lovell, K., Mourad, M., Bengtson, C., Atieh, T., Brownback, K., Aguiar, C., White, M., Deculus, K., Scott, L., English, L., Greer, S., Murry, S., Woodring, L., Nazir, U., Truong, A., Mallett, N., Williams, S., Hellwig, H., Burton, M., Pandey, A., Bates, C., Lewis, B., Tarbutton, J., Kondamudi, N., Huet, R. G., Xu, X., Berger-Nagele, M., Molina, E., Duggal, A., Mucha, S., Mehkri, O., King, A., Poynter, B., Ashok, K., Thiruchelvam, N., Sahoo, D., Goyanes, A., Siuba, M., Sunderkrishnan, R., Minear, S., Hernandez-Montfort, J., Mehta, J., McWilliams, C., Anekwe, C., Van, A., Calderon, A., Arazo, L., Sohaib Nasim, S., De Carvalho Teixeira, C., Zelaya, D., Malhotra, S., Nedeltcheva, A., Rezai, K., Hoffman, M., Hernandez Acosta, R., Sarmiento, J., Uday, S., Hanna, N., Malik, A., Merritt, S., Davenport, J., Mears, K., Bryce, J., Arnold, M., Norwood, J., Urias, C., Kutcher, M., Galbraith, J., Jones, A., Nandi, U., Garla, V., Peacock, R., Davis, J., Grenn, E., Shaw, T., Moore, M., Prekker, M., Puskarich, M., Driver, B., Baker, J., Frosch, A., Kolb, A., Hubbard, L., Dunn, A., Hendrickson, A., Maruggi, E., Andersen, T., Miller, W., Raiter, A., Edpuganti, R., Ehlen, Q., Leland, G., Roth, M., Scharber, T., Tordsen, W., Reing, M., Isaksen, A., Erickson, H., Sheehan, J., Stewart, S., Kumfer, K., Veintimilla, R., Roginski, C., Bonk, N., Ensminger, S., Shahzeb Munir, M., Octain, J., Sheehy, A., Waters, A., Wilson, S., Hamburg, N., Minetti, E. T., Damus, K., Eberhardt, R., Klings, E., Zheng, R., Behrooz, L., Gao, A., Cohen, M., Robinson, C., Byars, A., Fitzpatrik-Wilson, M., Ling, K., Bendelow, T., Wallace, J., Douglas, I., Gandotra, S., Dransfield, M., Westfall, E., Whitson, M., Harris, D., Russell, D., Patel, S., Shah, B., Maranan, L., Choy-Shan, A., Smilowitz, N., Donnino, R., Lorin, J., Keary, M., Moore, S., Karamchandani, K., Go, P., Bonavia, A., Fender, L., Campbell, N., Howrylak, J., Gardner, K., Fox, L., Trump, P., Loffredo, K., Snyder, M., O Brien, S., Schultz, L., Kinard, S., Bochicchio, G., Bochicchio, K., Reese, S., Fonseca, R., Sato, B., Ferguson, K., Machica, C., McCarthy, J., Aldana, J., Rasane, R., Canas, M., Afzal, H., Osborn, T., Hoofnagle, M., Leonard, J., Snyder, J., Schuerer, D., Stewart, M., Kopar, P., Vallar, K., Kramer, J., Turnbull, I., Douketis, J., Scales, D., Nickerson, P., Rosenson, R., Nicolau, J., Escobedo, J., Turgeon, A. F., Dzavik, V., Gibson McDonald, E., Gross, P., Houston, B., Hussain, M., Kahn, S., Slutsky, A., Tritschler, T., Ostrowski, M., Dubois, S., Bond, L., Amaral, J., Wareham, V., Trafford, K., Khanna, M., Solvason, D., Hayes, K., Hiebert, L., Musto, H., Kannu, M., Martinez, A., Ohara, P., Bacca, J., de Jesus, N., Zier, S., Assis, D., Huemer, N., Martins, N., Nakajima, F., Everett, B., van Diepen, S., Le Gal, G., Siegal, D., Galanaud, J., Hegde, S., Kim, Y., Rost, N., Singhal, A., Selby, R., Alias, S., Silva, R., Dao, V., Hutmacher, M., Rigaux, L., Tays, Q., Kashani, H., Drobot, G., Choi, N., Dunbar-Yaffe, R., Shafiee, M., Wong, J., Zondag, M., Castellucci, L., Philips, P., Meteb, M., Couillard-Chenrd, E., Duceppe, E., Carling, R., Durand, M., Tagalakis, V., Shulikovsky, E., Florencio, S., McDonald, E., Elsayed, S., Moran, K., Lavoie, A., Townsend, K., Ovakim, D., Parfett, D., Gross, F. A., Michele, M., Carrier, Z. M., Carrier, M., Paul, J., Arevalo, C., Molignoni, K., Effron, M. B., Cohen, S., McDaniel, H., Nair, G. B., Osentoski, T., Schoen, M., Courtright, K., Reno, K., Meyer, D., Gerry, T., Aday, A., Shardelow, E., Burton, M., Kaatz, S., Ellsworth, S., Wells, B., Merlin, C., Fieback, A., Iyer, V., Johnson, M., Mistry, N., Turner, A., Puri, N., Schorr, C., Go, R., Canino, P., Billett, H., Mazniku, E., Gallego Lima, F., Vieira, A., Maia, R., Mostachio, A., Braga, W., Lima, S., Santos, F., Siciliano, R., Furtado, R., Ferraz Assir, F., Moraes, B., Santos, M., Barros, L., Herdy, A., Pereira, V., Hernandes, M., Amorim, R., Bandeira, M., Kormann, A., Spricigo, J., Zimmerman, S., Tumelero, R., Giordani, A., Ghizzoni, F., Manenti, E., Ruschel, K., Borba, A., Saraiva, J., Vicente, C., Silva Joao Moraes, M. J., Ribeiro, S., Barros Delcio Silva, T. J., Serafin, P., Dutra, J. X., Brum, A., Procopio, A., Alves, M., Grumach, A., Bertolini, L., Porto, C., Oliveira, S., Burihan, M., Santos Delcio Silva, M. 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. C., Chkhikvadze, T., Coiffard, B., Costantini, T. W., de Brouwer, S., Derde, L. P., Detry, M. A., Duggal, A., Dzavik, V., Effron, M. B., Estcourt, L. J., Everett, B. M., Fergusson, D. A., Fitzgerald, M., Fowler, R. A., Galanaud, J. P., Galen, B. T., Gandotra, S., Garcia-Madrona, S., Girard, T. D., Godoy, L. C., Goodman, A. L., Goossens, H., Green, C., Greenstein, Y. Y., Gross, P. L., Hamburg, N. M., Haniffa, R., Hanna, G., Hanna, N., Hegde, S. M., Hendrickson, C. M., Hite, R. D., Hindenburg, A. A., Hope, A. A., Horowitz, J. M., Horvat, C. M., Hudock, K., Hunt, B. J., Husain, M., Hyzy, R. C., Iyer, V. N., Jacobson, J. R., Jayakumar, D., Keller, N. M., Khan, A., Kim, Y., Kindzelski, A. L., King, A. J., Knudson, M. M., Kornblith, A. E., Krishnan, V., Kutcher, M. E., Laffan, M. A., Lamontagne, F., Le Gal, G., Leeper, C. M., Leifer, E. S., Lim, G., Lima, F. G., Linstrum, K., Litton, E., Lopez-Sendon, J., Lopez-Sendon Moreno, J. L., Lother, S. A., Malhotra, S., Marcos, M., Saud Marinez, A., Marshall, J. C., Marten, N., Matthay, M. A., McAuley, D. F., McDonald, E. G., McGlothlin, A., McGuinness, S. P., Middeldorp, S., Montgomery, S. K., Moore, S. C., Morillo Guerrero, R., Mouncey, P. R., Murthy, S., Nair, G. B., Nair, R., Nichol, A. D., Nunez-Garcia, B., Pandey, A., Park, P. K., Parke, R. L., Parker, J. C., Parnia, S., Paul, J. D., Perez Gonzalez, Y. S., Pompilio, M., Prekker, M. E., Quigley, J. G., Rost, N. S., Rowan, K., Santos, F. O., Santos, M., Olombrada Santos, M., Satterwhite, L., Saunders, C. T., Schutgens, R. E., Seymour, C. W., Siegal, D. M., Silva, D. G., Shankar-Hari, M., Sheehan, J. P., Singhal, A. B., Solvason, D., Stanworth, S. J., Tritschler, T., Turner, A. M., van Bentum-Puijk, W., van de Veerdonk, F. L., van Diepen, S., Vazquez-Grande, G., Wahid, L., Wareham, V., Wells, B. J., Widmer, R. J., Wilson, J. G., Yuriditsky, E., Zampieri, F. G., Connor, J., Manax, V., Bion, J., Gates, S., Reynolds, J., Douketis, J., Scales, D., Zarychanski, R., Lawler, P., Goligher, E., Rosenson, R., Nicolau, J., Escobedo, J., Farkouh, M., Fergusson, D., Kumar, A., Marten, N., Marshall, J., Turgeon, A. F., Bradbury, C., Carrier, M., Dzavik, V., Fowler, R., Gibson McDonals, E., Gross, P., Houston, B., Hussain, M., Kahn, S., Murthy, S., Slutsky, A., Tritschler, T., Ostrowski, M., Dubois, S., Bond, L., Amaral, J., Wareham, V., Trafford, K., Khanna, M., Solvason, D., Hayes, K., Hiebert, L., Musto, H., Kannu, M., Kirwan, B., de Brouwer, S., Perrin, E., Martinez, A., Ohara, P., Bacca, J., de Jesus, N., Zier, S., Assis, D., Huemer, N., Martins, N., Nakajima, F., Everett, B., Diepen, S. v., Le Gal, G., Siegal, D., Galanaud, J., Hegde, S., Kim, Y., Rost, N., Singhal, A., Lewis, R., Detry, M., McGlothlin, A., Fitzgerald, M., Saunders, C., Brooks, M., Selby, R., Alias, S., Silva, R., Dao, V., Hutmacher, M., Rigaux, L., Tays, Q., Kashani, H., Drobot, G., Marten, N., Hutmacher, M., Choi, N., Dunbar-Yaffe, R., Shafiee, M., Wong, J., Zondag, M., Castellucci, L., Philips, P., Meteb, M., Watpool, I., Porteous, R., Bellemare, D., Costerousse, O., Cloutier, E., Daher, R., Boulanger, M., Couillard-Chenrd, E., Lauzier, F., Francoeur, C., Duceppe, E., Carling, R., Durand, M., Tagalakis, V., Shulikovsky, E., Florencio, S., McDonald, E., Elsayed, S., Moran, K., Lellouche, F., Lizotte, P., Lavoie, A., Townsend, K., Ovakim, D., Parfett, D., Auld, F., Michele, M., Carrier, Z. M., Potvin, M., Lamontagne, F., Carbonneau, E., Bouchard, M., Paul, J., Arevalo, C., Molignoni, K., Effron, M. B., Cohen, S., McDaniel, H., Nair, G. B., Osentoski, T., Schoen, M., Courtright, K., Reno, K., Meyer, D., Gerry, T., Levesque, A., Aday, A., Shardelow, E., Burton, M., Kaatz, S., Ellsworth, S., Wells, B., Merlin, C., Fieback, A., Iyer, V., Johnson, M., Mistry, N., Turner, A., Puri, N., Schorr, C., Go, R., Canino, P., Billett, H., Mazniku, E., Lima, F. G., Vieira, A., Maia, R., Mostachio, A., Braga, W., Lima, S., Santos, F., Siciliano, R., Furtado, R., Ferraz Assir, F., Moraes, B., Santos, M., Barros, L., Herdy, A., Pereira, V., Hernandes, M., Amorim, R., Bandeira, M., Kormann, A., Spricigo, J., Zimmerman, S., Tumelero, R., Giordani, A., Ghizzoni, F., Manenti, E., Ruschel, K., Borba, A., Saraiva, J., Vicente, C., Silva Joao Moraes, M. J., Ribeiro, S., Barros Delcio Silva, T. J., Serafin, P., Dutra, J. X., Brum, A., Procopio, A., Alves, M., Grumach, A., Bertolini, L., Porto, C., Oliveira, S., Burihan, M., Santos Delcio Silva, M. J., Nery, E., Saporito, W., Pereira, T., Mancini, B., Kowalski Neto, E., Andrade, B., Santos, J., Pompilio, M., Pompilio, R., Agostinho, T., Grava, S., Koga, K., Silva, M., Lemos, D., Villegas, B., Medina, O., Gudino, H., Borja, P., Mateos Garcia, E., Cortes Vazquez, M. A., Perez Gonzalez, Y. S., Carreno Perez, P., Santillan, J. A., Becker, R. C., Del Zoppo, G., Henke, P., Holubkov, R., Kerr, K., Lee, A., Lurie, F., Vesely, S. K., Hochman, J. S., Neal, M. D., Berger, J. S., Cushman, M., Baumann Kreuziger, L., Berry, S., Gong, M. N., Hudock, K., Kim, K. S., Kornblith, L. Z., Lawler, P. R., Leifer, E., McVerry, B. J., Reynolds, H. R., Wilson, J. G., Hochman, J., Berger, J., Reynolds, H., Bragat, A., Goldfeld, K., Hade, E., Contreras, A., Mavromichalis, S., Iturrate, E., Gilsenan, M., Naumova, A., Roberts, A., Neal, M., Wisniewski, S., Leeper, C., Angus, D., Eng, H., Linstrum, K., Seymour, C., Girard, T., Montgomery, S., Martinez, M., Schreiber, J., Froess, J., Fu, Z., Zhong, Y., Vadlamudi, A., Sciurba, F., Morris, A., Gombault, C., Bula, S., Nelson, M., Daelemans, C., Wegmuller, R., La Framboise, D., Hoots, W. K., Kindzelski, A., Mondoro, T., Punturieri, A., Weinmann, G., Troendle, J. F., Kendrick, A. S., Nolen, T. L., Thomas, S., Sin, D., Diene, E., Gwiszcz, E., Hogan, I., Holden, A., Gong, M., Ringwood, N., Fitzgerald, L., Sharer, J., Ceusters, D., Hintlian, C., Kornblith, L., Nunez-Garcia, B., Uribe, V., Hendrickson, C., Barua, C., Knudson, M. M., Park, J., Gonzalez, A., Lopez-Sendon, J., Moraga Alapont, P., Prieto, P., Hernandez, V., Broaddrick, S., Kim, K., Quigley, S., McVerry, B., Huang, D., Buxton, M., Roberts, T., Kamel, H., Khatri, P., Frasure, J., Silken, A., Lopez-Sendon Moreno, J. L., Morillo Guerrero, R., Garcia Madrona, S., Molinera, A., Navarro Carrion, O., Besse Diaz, R., Diz Farina, S., Hidalgo Salinas, F., Gonzalez Ferrandiz, P., Zhilina, S., Alpanes Buesa, M., Gonzalez Garcia, A., Marcos Martin, M., Sanchez, M., Hernandez, J., Alvarez Navid, F., Belhassen Garcia, M., Carbonell Munoz, C., Hernandez Perez, G., Lopez Bernus, A., Martin Oterino, J. A., Sanchez Fernandez, P. L., de Tapia Majado, B., Gonzalez Juanatey, J. R., Seijas, J., Dominguez Santallas, M. J., Pose Reino, A., Valdes Cuadrado, L., Rodriguez Nunez, N., Keller, N., Yuriditsky, E., Ahuja, T., Horowitz, J., Hindenburg, A., Chkhikvadze, T., Parnia, S., Moran, Z., Fadzan, M., Levine, J., Cobos, S., Roberts, A., Mamistvalova, L., Garabedian, M., Ahmed, F., Zapata, G., Robinson, M., Quigley, J., Jacobson, J., Atal, N., Amosu, O., Tzehaie, H., Nair, R., Lopez, B., Hache Marliere, M., Fein, D., Offor, O., Kiyatkin, M., Chekuri, S., Galen, B., Hambardzumyan, A., Desai, A., Akhter, M., Aleem, H., Virdi, S., Shah, R., Hope, A., Chen, J., Mohamed, A., Kornblith, A., Shelley, I., Ambachew, B., Bensen, N., Burbee, D., Richardson, A., McNamara, A., Stavor, D., Abaye, M., Scholl, D., Wunderley, R., Yang, A., Amin, S. S., Berryman, E., Gilliam, M., Basile, K., Clermont, G., Garrard, W., Horvat, C., Kalchthaler, K., King, A. J., Ricketts, D., Malakouti, S., Marroquin, O., Music, E., Quinn, K., Andreae, M., Bain, W., Barbash, I., Brant, E., Barton, D., Fitzpatrick, M., Franz, C. A., Haidar, G., Hussain, M., Kitsios, G. D., Mayr, F. B., Malley, B., McCreary, E., Moghbeli, K., Rosborough, B., Schoenling, A., Shah, F. A., Shetty, V. U., Suber, T., Talia, N., Weissman, A., Schaefer, C., Muir, M., Urbanek, K. L., Greenstein, Y., Teeter, R., Plump, M., Kovalenko, O., Obando, E., Taveras, Y., Fanka, B., Suri, N., Patel, S., Kaur, M., Hite, R., Roads, T., Gebremedhen, A., Kiran, S., More, H., Costantini, T., Curry, T., Trinidad, E., Tyler, M., Berndtson, A., Allison, M., Bhatia, H., Denenberg, J., Marsh-Armstrong, B., Verzhbinsky, I., Morris, T., Fernandes, T., Elliott, A., Eastman, A., Lim, G., Hendey, G., Chang, S., Qadir, N., Beutler, R., Agarwal, T., Vargas, J., Singer, J., Haase, D., Murphy, J., Brzezinski, A., Yap, A., Yao, D. H., Bolduc, C., Antonuk, C., Spungen, H., Vuong, A., Wilson, J., Rogers, A., Levitt, J., Vojnik, R., Roque, J., Perez, C., Khan, A., Krol, O., Mistry, K., Nguyen, K., Lu, Z., Jouzestani, M. K., Singh, A., Mcdougal, M., Salar, A., Florea, S., Adi, R., Anadkat, C., Mills, E., Zouyed, Z., Deshmukh, R., Hough, C., Widmer, R., Fikes, W., Kiesle, E., Hyzy, R., Park, P., Jia, S., McSparron, J., Wang, B., Hanna, S., McDonough, K., Melvin, A., Nelson, K., Olbrich, N., Goodman, A., Hank, H. E., Quillen, D., Shamsuddin, A., Michl, L., Harper, M., Phipps, M., Braker, C., Wahid, L., Mohammed, O., Gazda, S., Craven, J., Jackson, R., Abuchowski, K., Dolor, R., Ortel, T., Manson, M., Vergara, L., Pinero, G., Freel, S., Krishnan, V., Newman, C., Leo, P., Greenwood, C., Wright, A., Warren, E. L., Thornton, J. D., Frolkis, C., Matthay, M., Kirsten, K., Kangelaris, K., Liu, K., Calfee, C., Zhuo, H., Daniel, B., Yee, K., Jauregui, A., Ghale, R., Chak, S., Wick, K., Siegel, E., Jones, C., Ashktorab, K., Satterwhite, L., Harris, P., Lovell, K., Mourad, M., Bengtson, C., Atieh, T., Brownback, K., Aguiar, C., White, M., Deculus, K., Scott, L., English, L., Greer, S., Murry, S., Woodring, L., Nazir, U., Truong, A., Mallett, N., Williams, S., Hellwig, H., Burton, M., Pandey, A., Bates, C., Lewis, B., Tarbutton, J., Kondamudi, N., Huet, R. G., Xu, X., Berger-Nagele, M., Molina, E., Duggal, A., Mucha, S., Mehkri, O., King, A., Poynter, B., Ashok, K., Thiruchelvam, N., Sahoo, D., Goyanes, A., Siuba, M., Sunderkrishnan, R., Minear, S., Hernandez-Montfort, J., Mehta, J., McWilliams, C., Anekwe, C., Van, A., Calderon, A., Arazo, L., Nasim, S. S., De Carvalho Teixeira, C., Zelaya, D., Malhotra, S., Nedeltcheva, A., Rezai, K., Hoffman, M., Hernandez Acosta, R., Sarmiento, J., Uday, S., Hanna, N., Malik, A., Merritt, S., Davenport, J., Mears, K., Bryce, J., Arnold, M., Norwood, J., Urias, C., Kutcher, M., Galbraith, J., Jones, A., Nandi, U., Garla, V., Peacock, R., Davis, J., Grenn, E., Shaw, T., Moore, M., Prekker, M., Puskarich, M., Driver, B., Baker, J., Frosch, A., Kolb, A., Hubbard, L., Dunn, A., Hendrickson, A., Maruggi, E., Andersen, T., Miller, W., Raiter, A., Edpuganti, R., Ehlen, Q., Leland, G., Roth, M., Scharber, T., Tordsen, W., Reing, M., Isaksen, A., Erickson, H., Sheehan, J., Stewart, S., Kumfer, K., Veintimilla, R., Roginski, C., Bonk, N., Ensminger, S., Munir, M. S., Octain, J., Sheehy, A., Waters, A., Wilson, S., Hamburg, N., Minetti, E. T., Damus, K., Eberhardt, R., Klings, E., Zheng, R., Behrooz, L., Gao, A., Cohen, M., Robinson, C., Byars, A., Fitzpatrik-Wilson, M., Ling, K., Bendelow, T., Wallace, J., Douglas, I., Gandotra, S., Dransfield, M., Westfall, E., Whitson, M., Harris, D., Russell, D., Patel, S., Shah, B., Maranan, L., Choy-Shan, A., Smilowitz, N., Donnino, R., Lorin, J., Keary, M., Moore, S., Karamchandani, K., Go, P., Bonavia, A., Fender, L., Campbell, N., Howrylak, J., Gardner, K., Fox, L., Trump, P., Loffredo, K., Snyder, M., O Brien, S., Schultz, L., Kinard, S., Bochicchio, G., Bochicchio, K., Reese, S., Fonseca, R., Sato, B., Ferguson, K., Machica, C., McCarthy, J., Aldana, J., Rasane, R., Canas, M., Afzal, H., Osborn, T., Hoofnagle, M., Leonard, J., Snyder, J., Schuerer, D., Stewart, M., Kopar, P., Vallar, K., Kramer, J., Turnbull, I., van der Poll, T., Al-Beidh, F., Annane, D., Arabi, Y., Beane, A., van Bentum-Puijk, W., Bhimani, Z., Bonten, M., Brunkhorst, F., Cheng, A., Derde, L., Estcourt, L., Goossens, H., Gordon, A., Green, C., Haniffa, R., Litton, E., McArthur, C., McAuley, D., McGuinness, S., Mouncey, P., Nichol, A., Parke, R., Parker, J., Rowan, K., Santos, M., Shankar-Hari, M., Turgeon, A., Turner, A., van de Veerdonk, F., Webb, S., Campbell, L., Forbes, A., Gattas, D., Heritier, S., Kruger, P., Peake, S., Presneill, J., Seppelt, I., Trapani, T., Young, P., Cuthbertson, B., Manoharan, V., Aryal, D., Beane, A., 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., Mayr, F., Beasley, R., Daneman, N., Fowler, R., McGloughlin, S., Morpeth, S., Paterson, D., Venkatesh, B., 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., Bihari, S., Hunt, B., Jayakumar, D., Laffan, M., Lother, S., Middeldorp, S., McQuilten, Z., Schutgens, R., Stanworth, S., Adhikari, N., Anstey, M., 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., Thomas, H., Tinmouth, A., Triulzi, D., Walsh, T., Wood, E., O'Kane, C., Shyamsundar, M., Sinha, P., Thompson, T., Young, I., Lawless, P., 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., Sanil, A., Berry, L., Lorenzi, E., Buzgau, A., Higgins, A., 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., van Beurden, M., Effelaar, E., Schotsman, J., Boyd, C., Harland, C., Shearer, A., Wren, J., 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., Debigare, S., Devine, D. V., Germain, M., Arnold, D. M., Begin, P., Callum, J. L., Chasse, M., Cook, D. J., English, S. W., Fergusson, D. A., Fowler, R. A., Goligher, E. C., Houston, B. L., Lawler, P. R., Marshall, J. C., Moore, L., Paunovic, B., Robitaille, N., Tinmouth, A. T., 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, J., Harward, M., Venz, E., Brady, K., Vale, C., Shekar, K., Lavana, J., Parmar, D., Williams, P., Kurenda, C., Miles, H., Attokaran, A., Gluck, S., O'Connor, S., Chapman, M., Glasby, K., Smyth, K., Phillips, M., Barge, D., Byrne, K., Driscoll, A., Fortune, L., Janin, P., Yarad, E., Bass, F., Hammond, N., O'Connor, A., Waterson, S., McNamara, R., Buhr, H., Coles, J., Schweikert, S., Wibrow, B., Rauniyar, R., Deshpande, K., Konecny, P., Miller, J., Kintono, A., Tung, R., Fysh, E., Dawda, A., Mevavala, B., De Keulenaer, A. R., Litton, E., Ferrier, J., Nair, P., Buscher, H., Reynolds, C., Newman, S., Santamaria, J., Barbazza, L., Homes, J., Smith, R., Garrett, P., Murray, L., Brailsford, J., Forbes, L., Maguire, T., Fennessy, G., Mulder, J., Morgan, R., McEldrew, R., Naeem M, A., Fagan, L., Ryan, E., Mariappa, V., Smith, J., Simpson, S., Maiden, M., Bone, A., Horton, M., Salerno, T., Sterba, M., Geng, W., Depuydt, P., Waele, J. D., De Bus, L., Fierens, J., Bracke, S., Vermassen, J., Vermeiren, D., Reeve, B., Dechert, W., Chasse, M., Carrier, F. M., Boumahni, D., Benettaib, F., Ghamraoui, A., Couillard-Chenard, E., Lauzier, F., Francoeur, C., Lamontagne, F., D'Aragon, F., Carbonneau, E., Leblond, J., Vazquez-Grande, G., Liu, T., Siddiqui, A., Wilson, M., Albert, M., Serri, K., Cavayas, A., Duplaix, M., Williams, V., Rochwerg, B., Karachi, T., Oczkowski, S., Centofanti, J., Millen, T., Khwaja, K., Campisi, J., Duan, E., Tsang, J., Patterson, L., Sy, E., Gupta, C., Kassir, S. S., Kutsogiannis, D., Thompson, P., Kamra, M., Marinoff, N., Cook, D., Clarke, F., Kruisselbrink, R., Brochard, L., Burns, K., Sandhu, G., Khalid, I., English, S., Miezitis, S., McIntyre, L., Wilcox, E., Del Sorbo, L., Abdelhady, H., Romagnuolo, T., Baig, N., Rewa, O., Bagshaw, S., Binnie, A., Powell, E., McMillan, A., Luk, T., Aref, N., Pratheema, R., Babu, S., Vignesh, C., Kumar, B., Ramakrishnan, N., James, A., Elvira, E., Ebenezer, R., Krishnaoorthy, S., Ranganathan, L., Shree, M. M., Mani, A. K., Mathew, M., Khanal, R. S., Amatya, S., Paneru, H. R., Koirala, S., Paudel, P., Koirala, K., Rai, N., Luitel, S., Bhattarai, B., Hashmi, M., Panjwani, A., Umrani, Z. A., Siddiq, S., Shaikh, M., Salahuddin, N., Masood, S., Andric, Z., Cviljevic, S., Dimoti, R., Zapalac, M., Mirkovic, G., Barsic, B., Kutlesa, M., Kotarski, V., Vujaklija Brajkovic, A., Babel, J., Sever, H., Dragija, L., Kusan, I., Vaara, S., Pettila, L., Heinonen, J., Kuitunen, A., Karlsson, S., Vahtera, A., Kiiski, H., Ristimaki, S., Azaiz, A., Charron, C., Godement, M., Geri, G., Vieillard-Baron, A., Pourcine, F., Monchi, M., Luis, D., Mercier, R., Sagnier, A., Verrier, N., Caplin, C., Richecoeu, J., Combaux, D., Siami, S., Aparicio, C., Vautier, S., Jeblaoui, A., Lemaire-Brunel, D., Fartoukh, M., Courtin, L., Labbe, V., Voiriot, G., Salhi, S. N., Plantefeve, G., Leparco, C., Contou, D., Muller, G., Nay, M., Kamel, T., Benzekri, D., Jacquier, S., Runge, I., Mathonnet, A., Barbier, F., Bretagnol, A., Mercier, E., Chartier, D., Salmon, C., Dequin, P. F., Garot, D., Schneider, F., Castelain, V., Morel, G., L'Hotellier, S., Badie, J., Berdaguer, F. D., Malfroy, S., Mezher, C., Bourgoin, C., Moneger, G., Bouvier, E., Megarbane, B., Voicu, S., Deye, N., Malissin, I., Sutterlin, L., Mrad, A., Pepin Lehalleur, A., Naim, G., Nguyen, P., Ekherian, J., Boue, Y., Sideris, G., Vodovar, D., Guerin, E., Grant, C., Guitton, C., Darreau, C., Landais, M., Chudeau, N., Robert, A., Tirot, P., Callahan, J. C., Saint Martin, M., Le Moal, C., Marnai, R., Leroyer, M. H., Moine, P., Heming, N., Maxime, V., Bossard, I., Nicholier, T. B., Clair, B., Orlikowski, D., Bounab, R., Abdeladim, L., Colin, G., Zinzoni, V., Maquigneau, N., Henri-Lagarrigue, M., Pouplet, C., Soukup, J., Wetzold, R., Lobel, M., Ing, D., Starke, L., Grimm, P., Finn, A., KreSS, G., Hoff, U., Hinrichs, C. F., Nee, J., Pletz, M. W., Hagel, S., Ankert, J., Kolanos, S., Bloos, F., Nickoleit-Bitzenberger, D., Schaaf, B., Meermeier, W., Prebeg, K., Azzaui, H. S., Hower, M., Brieger, K., Elender, C., Sabelhaus, T., Riepe, A., Akamp, C., Kremling, J., Klein, D., Landsiedel-Mechenbier, E., Petros, S., Kunz, K., Schutze, B., Kluge, S., Nierhaus, A., Jarczak, D., Roedl, K., Ulrich Rohde, G. G., Grunewaldt, A., Bojunga, J., Weismann, D., Frey, A., Drayss, M., Goebeler, M. E., Flor, T., Fragner, G., Wahl, N., Totzke, J., Sayehli, C., Reill, L., Distler, M., Maselli, A., Belteczki, J., Magyar, I., Fazekas, A., Kovacs, S., Szoke, V., Szigligeti, G., Leszkoven, J., Collins, D., Reid, L., Smyth, M., Breen, P., Spain, S., Curley, G., McEvoy, N., Geoghegan, P., Clarke, J., Laffeyirbre McNicholas, J., Scully, M., Casey, S., Kernan, M., Brennan, A., Rangan, R., Tully, R., Corbett, S., McCarthy, A., Duffy, O., Burke, D., Hayes, L., Murphy, L., Neill, A., Reidy, B., O'Dwyer, M., Ryan, D., Hoiting, O., Peters, M., Rengers, E., Evers, M., Prinssen, A., van den Oever, H. L., Kruisdijk-Gerritsen, A., Simons, K., van Zuylen, T., Bouman, A., van Gulik, L., Schouten, J., Pickkers, P., Roovers, N., Klop-Riehl, M., van der Eng, H., Jonge, E. d., Wigbers, J., Del Prado, M., Haitsma Mulier, J., Peters, A. L., Romberg, B., van Bree, S., Bouw-Ruiterrbara Festen, M., van Gelder, F., van Iperen, M., Osinga, M., Schellaars, R., Tjan, D., van der Wekken, R., Melchers, M., van Zanten, A., van Nieuwkoop, K., Ottens, T., Visser, Y., Juffermans, N., Koopmans, M., Guilder, E., Butler, M., Cowdrey, K., Woollett, M., Newby, L., Chen, Y., Simmonds, C., McConnochie, R., O'Connor, C., Carter, J. 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

  • 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

  • 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

  • Correction to: Abnormalities of Aspiration and Swallowing Function in Survivors of Acute Respiratory Failure. Dysphagia Langmore, S. E., Krisciunas, G. P., Warner, H. n., White, S. D., Dvorkin, D. n., Fink, D. n., McNally, E. n., Scheel, R. n., Higgins, C. n., Levitt, J. E., McKeehan, J. n., Deane, S. n., Siner, J. M., Vojnik, R. n., Moss, M. n. 2021

    View details for DOI 10.1007/s00455-020-10226-8

    View details for PubMedID 33635374

  • Phenotypes and personalized medicine in the acute respiratory distress syndrome INTENSIVE CARE MEDICINE Matthay, M. A., Arabi, Y. M., Siegel, E. R., Ware, L. B., Bos, L. J., Sinha, P., Beitler, J. R., Wick, K. D., Curley, M. Q., Constantin, J., Levitt, J. E., Calfee, C. S. 2020: 2136–52

    Abstract

    Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.

    View details for DOI 10.1007/s00134-020-06296-9

    View details for Web of Science ID 000590531800001

    View details for PubMedID 33206201

    View details for PubMedCentralID PMC7673253

  • 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

  • Systemic and Inhaled Corticosteroids, with or without Beta Agonists, as Adjuvant Therapy in Community Acquired Pneumonia. Acta medica academica Helgeson, S. A., Levitt, J. E., Festic, E. 2020; 49 (1): 9–20

    Abstract

    The aim is to provide a narrative review of the role of corticosteroids, with and without inhaled beta agonist, in communityacquired pneumonia. Community and health-care associated pneumonia remain leading causes of morbidity and mortality despite appropriate antibiotic therapy. The pneumonia-associated adverse outcomes are not only related to the infectious organism, but also to a dysfunctional host-immune response resulting in overwhelming inflammation. Use of systemic corticosteroids as adjuvant therapy in pneumonia remains controversial. Multiple randomized clinical trials evaluating corticosteroids in patients with community acquired pneumonia have found discrepant results in terms of benefits and adverse effects. Inhaled delivery of corticosteroids offer the potential advantage of providing therapeutic benefits directly to the lung, with minimal to no adverse systemic effects. CONCLUSION: Although meta-analyses suggest potential benefits in a select group of patients with more severe pneumonia, the ideal timing, dose, route of delivery, duration, and patient selection remain to be established. A smaller body of literature suggests benefit of inhaled corticosteroids, with or without inhaled beta agonists, but future large scale clinical trials are needed to establish clinical benefit with inhaled delivery.

    View details for DOI 10.5644/ama2006-124.279

    View details for PubMedID 32738113

  • Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States. American journal of kidney diseases : the official journal of the National Kidney Foundation Flythe, J. E., Assimon, M. M., Tugman, M. J., Chang, E. H., Gupta, S. n., Shah, J. n., Sosa, M. A., DeMauro Renaghan, A. n., Melamed, M. L., Wilson, F. P., Neyra, J. A., Rashidi, A. n., Boyle, S. M., Anand, S. n., Christov, M. n., Thomas, L. F., Edmonston, D. n., Leaf, D. E. 2020

    Abstract

    Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes.Retrospective cohort study SETTINGS & PARTICIPANTS: 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States.Presence (versus absence) of pre-existing kidney disease OUTCOME(S): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) ANALYTICAL APPROACH: We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations.Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44).Potential residual confounding CONCLUSIONS: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population.

    View details for DOI 10.1053/j.ajkd.2020.09.003

    View details for PubMedID 32961244

  • The Association Between Endotracheal Tube Size and Aspiration (During Flexible Endoscopic Evaluation of Swallowing) in Acute Respiratory Failure Survivors. Critical care medicine Krisciunas, G. P., Langmore, S. E., Gomez-Taborda, S. n., Fink, D. n., Levitt, J. E., McKeehan, J. n., McNally, E. n., Scheel, R. n., Rubio, A. C., Siner, J. M., Vojnik, R. n., Warner, H. n., White, S. D., Moss, M. n. 2020

    Abstract

    To determine whether a modifiable risk factor, endotracheal tube size, is associated with the diagnosis of postextubation aspiration in survivors of acute respiratory failure.Prospective cohort study.ICUs at four academic tertiary care medical centers.Two hundred ten patients who were at least 18 years old, admitted to an ICU, and mechanically ventilated with an endotracheal tube for longer than 48 hours were enrolled.Within 72 hours of extubation, all patients received a flexible endoscopic evaluation of swallowing examination that entailed administration of ice, thin liquid, thick liquid, puree, and cracker boluses. Patient demographics, treatment variables, and hospital outcomes were abstracted from the patient's medical records. Endotracheal tube size was independently selected by the patient's treating physicians.For each flexible endoscopic evaluation of swallowing examination, laryngeal pathology was evaluated, and for each bolus, a Penetration Aspiration Scale score was assigned. Aspiration (Penetration Aspiration Scale score ≥ 6) was further categorized into nonsilent aspiration (Penetration Aspiration Scale score = 6 or 7) and silent aspiration (Penetration Aspiration Scale score = 8). One third of patients (n = 68) aspirated (Penetration Aspiration Scale score ≥ 6) on at least one bolus, 13.6% (n = 29) exhibited silent aspiration, and 23.8% (n = 50) exhibited nonsilent aspiration. In a multivariable analysis, endotracheal tube size (≤ 7.5 vs ≥ 8.0) was significantly associated with patients exhibiting any aspiration (Penetration Aspiration Scale score ≥ 6) (p = 0.016; odds ratio = 2.17; 95% CI 1.14-4.13) and with risk of developing laryngeal granulation tissue (p = 0.02).Larger endotracheal tube size was associated with increased risk of aspiration and laryngeal granulation tissue. Using smaller endotracheal tubes may reduce the risk of postextubation aspiration.

    View details for DOI 10.1097/CCM.0000000000004554

    View details for PubMedID 32804785

  • Development of an accurate bedside swallowing evaluation decision tree algorithm for detecting aspiration in acute respiratory failure survivors. Chest Moss, M. n., White, S. D., Warner, H. n., Dvorkin, D. n., Fink, D. n., Gomez-Taborda, S. n., Higgins, C. n., Krisciunas, G. P., Levitt, J. E., McKeehan, J. n., McNally, E. n., Rubio, A. n., Scheel, R. n., Siner, J. M., Vojnik, R. n., Langmore, S. E. 2020

    Abstract

    The bedside swallowing evaluation (BSE) is an assessment of swallowing function and airway safety during swallowing. After extubation, the BSE is often used to identify the risk of aspiration in acute respiratory failure (ARF) survivors.We conducted a multi-center prospective study of ARF survivors to determine the accuracy of the BSE and to develop a decision tree algorithm to identify aspiration risk.and Methods: Patients extubated after ≥48 hours of mechanical ventilation were eligible. Study procedures included the BSE followed by a gold-standard evaluation, the flexible endoscopic evaluation of swallowing (FEES).Overall, 213 patients were included in the final analysis. Median time from extubation to BSE was 25 hours (interquartile range=21-45 hours). FEES was completed 1 hour after the BSE (interquartile range=0.5-2 hours). A total of 33% (70/213, 95%CI=26.6-39.2%) of patients aspirated on at least one FEES bolus consistency test. Thin liquids were the most commonly aspirated consistency; 27% (54/197, 95%CI =21-34%). The BSE detected any aspiration with an accuracy of 52% (95%CI =45-58%), a sensitivity of 83% (95%CI =74-92%), and negative predictive value of 81% (95%CI=72-91%). Using recursive partitioning analyses, a five variable BSE-based decision tree algorithm was developed that improved the detection of aspiration with an accuracy of 81% (95%CI=75-87%), sensitivity of 95% (95%CI =90-98%), and negative predictive value of 97% (95%CI =95-99%).The BSE demonstrates variable accuracy to identify patients at high risk for aspiration. Our decision tree algorithm may enhance the BSE and be used to identify patients at high risk for aspiration yet requires further validation.

    View details for DOI 10.1016/j.chest.2020.07.051

    View details for PubMedID 32721404

  • Abnormalities of Aspiration and Swallowing Function in Survivors of Acute Respiratory Failure. Dysphagia Langmore, S. E., Krisciunas, G. P., Warner, H. n., White, S. D., Dvorkin, D. n., Fink, D. n., McNally, E. n., Scheel, R. n., Higgins, C. n., Levitt, J. E., McKeehan, J. n., Deane, S. n., Siner, J. M., Vojnik, R. n., Moss, M. n. 2020

    Abstract

    The mechanisms responsible for aspiration are relatively unknown in patients recovering from acute respiratory failure (ARF) who required mechanical ventilation. Though many conditions may contribute to swallowing dysfunction, alterations in laryngeal structure and swallowing function likely play a role in the development of aspiration. At four university-based tertiary medical centers, we conducted a prospective cohort study of ARF patients who required intensive care and mechanical ventilation for at least 48 h. Within 72 h after extubation, a Fiberoptic Flexible Endoscopic Evaluation of Swallowing (FEES) examination was performed. Univariate and multivariable analyses examined the relationship between laryngeal structure and swallowing function abnormalities. Aspiration was the primary outcome, defined as a Penetration- Aspiration Scale (PAS) score of 6 or greater. Two other salient signs of dysphagia-spillage and residue-were secondary outcomes. A total of 213 patients were included in the final analysis. Aspiration was detected in 70 patients (33%) on at least one bolus. The most commonly aspirated consistency was thin liquids (27%). In univariate analyses, several abnormalities in laryngeal anatomy and structural movement were significantly associated with aspiration, spillage, and residue. In a multivariable analysis, the only variables that remained significant with aspiration were pharyngeal weakness (Odds ratio = 2.57, 95%CI = 1.16-5.84, p = 0.019) and upper airway edema (Odds ratio = 3.24, 95%CI = 1.44-7.66, p = 0.004). These results demonstrated that dysphagia in ARF survivors is multifactorial and characterized by both anatomic and physiologic abnormalities. These findings may have important implications for the development of novel interventions to treat dysphagia in ARF survivors.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT02363686, Aspiration in Acute Respiratory Failure Survivors.

    View details for DOI 10.1007/s00455-020-10199-8

    View details for PubMedID 33156398

  • Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source. BioMed research international Levitt, D. G., Levitt, J. E., Levitt, M. D. 2020; 2020: 2608318

    Abstract

    Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05mmol/min/70kg and 1.5L/min/70kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

    View details for DOI 10.1155/2020/2608318

    View details for PubMedID 33150168

  • 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

  • Relationship Between Laryngeal Sensation, Length of Intubation, and Aspiration in Patients with Acute Respiratory Failure DYSPHAGIA Borders, J. C., Fink, D., Levitt, J. E., McKeehan, J., McNally, E., Rubio, A., Scheel, R., Siner, J. M., Taborda, S., Vojnik, R., Warner, H., White, S., Langmore, S. E., Moss, M., Krisciunas, G. P. 2019; 34 (4): 521–28
  • Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-FIO2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome A Randomized Clinical Trial Beitler, J. R., Sarge, T., Banner-Goodspeed, V. M., Gong, M. N., Cook, D., Novack, V., Loring, S. H., Talmor, D., Loring, S., Banner-Goodspeed, V., Fish, E., Jinadasa, S., Ritz, R., Previtera, J., Lee, L., Clarke, F., Piraino, T., Levitt, J., Vojnik, R., Park, P., Brierley, K., Haas, C., Weirauch, A., Fan, E., Matte, A., Harris, R., Kone, M., Heard, S., Longtine, K., Lellouche, F., Bouchard, P., Rubinson, L., McGrain, J., Griesdale, D. G., Foster, D., Oeckler, R., Amsbaugh, A., Jimenez, E., Danesh, V., Slutsky, A. S., Hall, J., Hubmayr, R. D., Rubenfeld, G., Schoenfeld, D., EPVent-2 Study Grp AMER MEDICAL ASSOC. 2019: 846–57

    Abstract

    Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS).To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS.Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018.Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes.The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy.Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2.Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS.ClinicalTrials.gov Identifier NCT01681225.

    View details for DOI 10.1001/jama.2019.0555

    View details for Web of Science ID 000460351600015

    View details for PubMedID 30776290

  • 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
  • Relationship Between Laryngeal Sensation, Length of Intubation, and Aspiration in Patients with Acute Respiratory Failure. Dysphagia Borders, J. C., Fink, D., Levitt, J. E., McKeehan, J., McNally, E., Rubio, A., Scheel, R., Siner, J. M., Taborda, S. G., Vojnik, R., Warner, H., White, S. D., Langmore, S. E., Moss, M., Krisciunas, G. P. 2019

    Abstract

    Dysphagia is common in hospitalized patients post-extubation and associated with poor outcomes. Laryngeal sensation is critical for airway protection and safe swallowing. However, current understanding of the relationship between laryngeal sensation and aspiration in post-extubation populations is limited. Acute respiratory failure patients requiring intensive care unit admission and mechanical ventilation received a Flexible Endoscopic Evaluation of Swallowing (FEES) within 72h of extubation. Univariate and multivariable analyses were performed to examine the relationship between laryngeal sensation, length of intubation, and aspiration. Secondary outcomes included pharyngolaryngeal secretions, pneumonia, and diet recommendations. One-hundred and three patients met inclusion criteria. Fifty-one patients demonstrated an absent laryngeal adductor reflex (LAR). Altered laryngeal sensation correlated with the presence of secretions (p=0.004). There was a significant interaction between the LAR, aspiration, and duration of mechanical ventilation. Altered laryngeal sensation was significantly associated with aspiration on FEES only in patients with a shorter length of intubation (p=0.008). Patients with altered laryngeal sensation were prescribed significantly more restricted liquid (p=0.03) and solid (p=0.001) diets. No relationship was found between laryngeal sensation and pneumonia. There is a high prevalence of laryngeal sensory deficits in mechanically ventilated patients post-extubation. Altered laryngeal sensation was associated with secretions, aspiration, and modified diet recommendations especially in those patients with a shorter length of mechanical ventilation. These results demonstrate that laryngeal sensory abnormalities impact the development of post-extubation dysphagia.

    View details for PubMedID 30694412

  • 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

  • Effect of Rosuvastatin on Acute Kidney Injury in Sepsis-Associated Acute Respiratory Distress Syndrome. Canadian journal of kidney health and disease Hsu, R. K., Truwit, J. D., Matthay, M. A., Levitt, J. E., Thompson, B. T., Liu, K. D. 2018; 5: 2054358118789158

    Abstract

    Background: Acute kidney injury (AKI) commonly occurs in patients with sepsis and acute respiratory distress syndrome (ARDS).Objective: To investigate whether statin treatment is protective against AKI in sepsis-associated ARDS.Design: Secondary analysis of data from Statins for Acutely Injured Lungs in Sepsis (SAILS), a randomized controlled trial that tested the impact of rosuvastatin therapy on mortality in patients with sepsis-associated ARDS.Setting: 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network.Patients: 644 of 745 participants in SAILS who had available baseline serum creatinine data and who were not on chronic dialysis.Measurements: Our primary outcome was AKI defined using the Kidney Disease Improving Global Outcomes creatinine criteria. Randomization to rosuvastatin vs placebo was the primary predictor. Additional covariates include demographics, ARDS etiology, and severity of illness.Methods: We used multivariable logistic regression to analyze AKI outcomes in 511 individuals without AKI at randomization, and 93 with stage 1 AKI at randomization.Results: Among individuals without AKI at randomization, rosuvastatin treatment did not change the risk of AKI (adjusted odds ratio: 0.99, 95% confidence interval [CI]: 0.67-1.44). Among those with preexisting stage 1 AKI, rosuvastatin treatment was associated with an increased risk of worsening AKI (adjusted odds ratio: 3.06, 95% CI: 1.14-8.22). When serum creatinine was adjusted for cumulative fluid balance among those with preexisting stage 1 AKI, rosuvastatin was no longer associated worsening AKI (adjusted odds ratio: 1.85, 95% CI: 0.70-4.84).Limitations: Sample size, lack of urine output data, and prehospitalization baseline creatinine.Conclusion: Treatment with rosuvastatin in patients with sepsis-associated ARDS did not protect against de novo AKI or worsening of preexisting AKI.

    View details for PubMedID 30116543

  • Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome CRITICAL CARE MEDICINE Festic, E., Carr, G. E., Cartin-Ceba, R., Hinds, R. F., Banner-Goodspeed, V., Bansal, V., Asuni, A. T., Talmor, D., Rajagopalan, G., Frank, R. D., Gajic, O., Matthay, M. A., Levitt, J. E. 2017; 45 (5): 798-805

    Abstract

    Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance.Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome.Five academic centers in the United States.Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome.Aerosolized budesonide/formoterol versus placebo bid for up to 5 days.Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%).Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

    View details for DOI 10.1097/CCM.0000000000002284

    View details for Web of Science ID 000399522200007

    View details for PubMedID 28240689

  • 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

  • Increased Resource Use in Lung Transplant Admissions in the Lung Allocation Score Era AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Maxwelll, B. G., Mooney, J. J., Lee, P. H., Levitt, J. E., Chhatwani, L., Nicolls, M. R., Zamora, M. R., Valentine, V., Weill, D., Dhillon, G. S. 2015; 191 (3): 302-308

    Abstract

    Rationale: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize one-year survival. It resulted in transplantation of older and sicker patients without changing one-year survival. Its effect on resource utilization is unknown. Objective: To determine changes in resource utilization over time in lung transplant admissions Methods: Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges amongst lung transplant and other solid organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource utilization, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation (ECMO). Measurements and Main Results: A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, that was not seen in other solid organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort [$569,942 ($53,229) vs. $407,489 ($28,360)] along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant utilization of ECMO (OR 2.35, 95% CI 1.56, 3.55) and higher incidence of tracheostomy (OR 1.52, 95% CI 1.22, 1.89). Conclusions: LAS implementation is associated with a significant increase in resource utilization during index hospitalization for lung transplant.

    View details for DOI 10.1164/rccm.201408-1562OC

    View details for Web of Science ID 000348827000014

    View details for PubMedID 25517213

  • 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

  • Evolving Epidemiology and Definitions of the Acute Respiratory Distress Syndrome and Early Acute Lung Injury CLINICS IN CHEST MEDICINE Sweatt, A. J., Levitt, J. E. 2014; 35 (4): 609-?

    Abstract

    This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury.

    View details for DOI 10.1016/j.ccm.2014.08.002

    View details for Web of Science ID 000346214200002

  • Evolving epidemiology and definitions of the acute respiratory distress syndrome and early acute lung injury. Clinics in chest medicine Sweatt, A. J., Levitt, J. E. 2014; 35 (4): 609-624

    Abstract

    This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury.

    View details for DOI 10.1016/j.ccm.2014.08.002

    View details for PubMedID 25453413

  • 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
  • Designing a better "nest": applicable to preventing hospital exposures to risk factors for acute respiratory distress syndrome or just retrospective study design? Critical care medicine Levitt, J. 2014; 42 (1): 197-198

    View details for DOI 10.1097/CCM.0b013e3182a11eab

    View details for PubMedID 24346523

    View details for PubMedCentralID PMC3869104

  • 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

  • Prehospital use of inhaled steroids and incidence of acute lung injury among patients at risk JOURNAL OF CRITICAL CARE Festic, E., Ortiz-Diaz, E., Lee, A., Li, G., Kor, D. J., Adebola, A., Akca, O., Hoth, J., Levitt, J. E., Carter, R., Gajic, O. 2013; 28 (6): 985-991

    Abstract

    Inhaled corticosteroids (ICSs) attenuated lung injury in animal studies. We investigated the association between prehospital ICS and incidence of acute lung injury (ALI) among patients at risk.In this ancillary analysis of the large multicenter Lung Injury Prediction Study cohort, we developed a propensity score for prehospital ICS use followed by matching, for all patients and for a subgroup of patients with at least 1 risk factor for direct pulmonary injury. The primary outcome was ALI; secondary outcomes included acute respiratory distress syndrome, need for invasive mechanical ventilation, and hospital mortality.Of the 5126 patients, 401 (8%) were using ICS. Acute lung injury developed in 343 (7%). The unadjusted incidence of ALI was 4.7% vs 6.9% (P = .12) among those in ICS compared with non-ICS group. In the "direct" lung injury subgroup, the unadjusted incidence of ALI was 4.1% vs 10.6% (P = 0.006). After propensity matching, the estimated effect for ALI in the whole cohort was 0.69 (95% confidence interval, 0.39-1.2; P = .18), and that in the direct subgroup was 0.56 (95% confidence interval, 0.22-1.46; P = .24).Preadmission use of ICS in a hospitalized population of patients at risk for ALI was not significantly associated with a lower incidence of ALI once controlled by comprehensive propensity-matched analysis.

    View details for DOI 10.1016/j.jcrc.2013.08.011

    View details for Web of Science ID 000326945100020

    View details for PubMedID 24075297

    View details for PubMedCentralID PMC4219561

  • Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation*. Critical care medicine Levitt, J. E., Calfee, C. S., Goldstein, B. A., Vojnik, R., Matthay, M. A. 2013; 41 (8): 1929-1937

    Abstract

    Mortality associated with acute lung injury remains high. Early identification of acute lung injury prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score identifies patients at risk for acute lung injury but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of early acute lung injury to identify patients with lung injury prior to the need for positive pressure ventilation.Prospective observational cohort study.Stanford University Hospital.We prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.None.Of the 256 patients enrolled, 62 patients (25%) progressed to acute lung injury requiring positive pressure ventilation. Clinical variables (through first 72 hr or up to 6 hr prior to acute lung injury) associated with progression to acute lung injury were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to acute lung injury. A simple three-component early acute lung injury score (1 point for oxygen requirement > 2-6 L/min or 2 points for > 6 L/min; 1 point each for a respiratory rate ≥ 30 and immune suppression) accurately identified patients who progressed to acute lung injury requiring positive pressure ventilation (area under the receiver-operator characteristic curve, 0.86) and performed similarly to the Lung Injury Prediction Score. An early acute lung injury score greater than or equal to 2 identified patients who progressed to acute lung injury with 89% sensitivity and 75% specificity. Median time of progression from early acute lung injury criteria to acute lung injury requiring positive pressure ventilation was 20 hours.This pragmatic definition of early acute lung injury accurately identified patients who progressed to acute lung injury prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of acute lung injury.

    View details for DOI 10.1097/CCM.0b013e31828a3d99

    View details for PubMedID 23782966

  • Emerging Pharmacological Therapies for Prevention and Early Treatment of Acute Lung Injury SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Ortiz-Diaz, E., Festic, E., Gajic, O., Levitt, J. E. 2013; 34 (4): 448-458

    Abstract

    Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are serious complications of acute illness and injury, associated with an inpatient mortality of up to 40%. Despite considerable basic science and clinical research, therapeutic options for established ALI are limited. Survivors of ARDS are often faced with poor health-related quality of life, depressive-anxiety disorders, cognitive deficits, and financial strain. An attractive approach toward managing ALI lies in its prevention and early treatment. In addition to improving recognition of at-risk patients, it is necessary to identify novel treatments targeting the pathways that may prevent or ameliorate lung injury. The rationale and animal and clinical evidence for aspirin, systemic and inhaled steroids, β-agonists, renin-angiotensin axis blockers, statins, peroxisome proliferator agonist receptor ligands, curcumin, and inhaled heparin are included in this narrative review. Randomized, controlled trials are currently being designed and implemented to address their efficacy in populations at risk for ALI.

    View details for DOI 10.1055/s-0033-1351118

    View details for Web of Science ID 000322911200003

    View details for PubMedID 23934714

  • OXYGEN SATURATION TO FRACTION OF INSPIRED OXYGEN RATIO ON ADMISSION IS A PREDICTOR OF ARDS DEVELOPMENT AMONG PATIENTS AT RISK Festic, E., Levitt, J., Kor, D., Gajic, O. LIPPINCOTT WILLIAMS & WILKINS. 2012: U176
  • Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Agrawal, A., Zhuo, H., Brady, S., Levitt, J., Steingrub, J., Siegel, M. D., Soto, G., Peterson, M. W., Chesnutt, M. S., Matthay, M. A., Liu, K. D. 2012; 303 (8): L634-L639

    Abstract

    Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

    View details for DOI 10.1152/ajplung.00195.2012

    View details for Web of Science ID 000309996300002

    View details for PubMedID 22865551

    View details for PubMedCentralID PMC3469636

  • Clinical review: Early treatment of acute lung injury - paradigm shift toward prevention and treatment prior to respiratory failure CRITICAL CARE Levitt, J. E., Matthay, M. A. 2012; 16 (3)

    Abstract

    ABSTRACT: Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.

    View details for DOI 10.1186/cc11144

    View details for Web of Science ID 000313197500058

    View details for PubMedID 22713281

    View details for PubMedCentralID PMC3580596

  • Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients CLINICAL TRANSPLANTATION Dhillon, G. S., Valentine, V. G., Levitt, J., Patel, P., Gupta, M. R., Duncan, S. R., Seoane, L., Weill, D. 2012; 26 (1): 105-110

    Abstract

    Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined.Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database.When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24).Routine use of clarithromycin does not delay development of BOS or improve survival.

    View details for DOI 10.1111/j.1399-0012.2011.01420.x

    View details for PubMedID 21352378

  • PATIENT-RELATED FACTORS ASSOCIATED WITH HOSPITAL DISCHARGE TO A CARE FACILITY AFTER CRITICAL ILLNESS AMERICAN JOURNAL OF CRITICAL CARE Gehlbach, B. K., Salamanca, V. R., Levitt, J. E., Sachs, G. A., Sweeney, M. K., Pohlman, A. S., Charbeneau, J., Krishnan, J. A., Hall, J. B. 2011; 20 (5): 378-386

    Abstract

    Many critically ill patients are transferred to other care facilities instead of to home at hospital discharge.To identify patient-related factors associated with hospital discharge to a care facility after critical illness and to estimate the magnitude of risk associated with each factor.Retrospective cohort study of 548 survivors of critical illness in a medical intensive care unit. Multivariable logistic regression was used to identify independent risk factors for discharge to a care facility. Only the first 72 hours of intensive care were analyzed.Approximately one-quarter of the survivors of critical illness were discharged to a care facility instead of to home. This event occurred more commonly in older patients, even after adjustment for severity of illness and comorbid conditions (odds ratio [OR] 1.8 for patients ≥ 65 years of age vs patients < 65 years; 95% confidence interval [CI], 1.1-3.1; P = .02). The risk was greatest for patients who received mechanical ventilation (OR, 3.4; 95% CI, 2.0-5.8; P < .001) or had hospitalizations characterized by severe cognitive dysfunction (OR, 8.1; 95% CI, 1.3-50.6; P = .02) or poor strength and/or mobility (OR, 31.7; 95% CI, 6.4-157.3; P < .001). The model showed good discrimination (area under the curve, 0.82; 95% CI, 0.77-0.86).The model, which did not include baseline function or social variables, provided good discrimination between patients discharged to a care facility after critical illness and patients discharged to home. These results suggest that future research should focus on the debilitating effects of respiratory failure and on conditions with cognitive and neuromuscular sequelae.

    View details for DOI 10.4037/ajcc2011827

    View details for Web of Science ID 000294460500006

    View details for PubMedID 21885459

  • The utility of clinical predictors of acute lung injury: towards prevention and earlier recognition. Expert review of respiratory medicine Levitt, J. E., Matthay, M. A. 2010; 4 (6): 785-797

    Abstract

    Despite significant advances in our understanding of the pathophysiology of acute lung injury, a lung-protective strategy of mechanical ventilation remains the only therapy with a proven survival advantage. Numerous pharmacologic therapies have failed to show benefit in multicenter clinical trials. The paradigm of early, goal-directed therapy of sepsis suggests greater clinical benefit may derive from initiating therapy prior to the onset of respiratory failure that requires mechanical ventilation. Thus, there is heightened interest in more accurate and complete characterization of high-risk patient populations and identification of patients in the early stage of acute lung injury, prior to the need for mechanical ventilation. This article discusses the growing literature on clinical predictors of acute lung injury (including risk factors for specific subgroups) with an emphasis on transfusion-related risk factors and recent research targeting the early identification of high-risk patients and those with early acute lung injury prior to the onset of respiratory failure.

    View details for DOI 10.1586/ers.10.78

    View details for PubMedID 21128753

    View details for PubMedCentralID PMC3044497

  • Impact of Hepatitis B Core Antibody Positive Donors in Lung and Heart-Lung Transplantation: An Analysis of the United Network for Organ Sharing Database TRANSPLANTATION Dhillon, G. S., Levitt, J., Mallidi, H., Valentine, V. G., Gupta, M. R., Sista, R., Weill, D. 2009; 88 (6): 842-846

    Abstract

    The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients.Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs.We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant.Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.

    View details for DOI 10.1097/TP.0b013e3181b4e1fd

    View details for PubMedID 19920785

  • Does Itraconazole Improve Quality of Life in Severe Asthma with Fungal Sensitization? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Khazeni, N., Levitt, J. E. 2009; 180 (2): 191-192

    View details for Web of Science ID 000268112500021

    View details for PubMedID 19578143

  • The pathogenetic and prognostic value of biologic markers in acute lung injury. Journal of intensive care medicine Levitt, J. E., Gould, M. K., Ware, L. B., Matthay, M. A. 2009; 24 (3): 151-167

    Abstract

    Over the past 2 decades, measurement of biomarkers in both the airspaces and plasma early in the course of acute lung injury has provided new insights into the mechanisms of lung injury. In addition, biologic markers of cell-specific injury, acute inflammation, and altered coagulation correlate with mortality from acute lung injury in several single center studies as well as in multicenter clinical trials. To date, biomarkers have been measured largely for research purposes. However, with improved understanding of their role in the pathogenesis of acute lung injury, biomarkers may play an important role in early detection of lung injury, risk stratification for clinical trials, and, ultimately, tailoring specific therapies to individual patients. This article provides a review of biologic markers in acute lung injury, with an emphasis on recent analysis of results from multicenter clinical trials.

    View details for DOI 10.1177/0885066609332603

    View details for PubMedID 19282296

  • Identification of Early Acute Lung Injury at Initial Evaluation in an Acute Care Setting Prior to the Onset of Respiratory Failure CHEST Levitt, J. E., Bedi, H., Calfee, C. S., Gould, M. K., Matthay, M. A. 2009; 135 (4): 936-943

    Abstract

    Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality. However, the current consensus definition impedes identification of patients with ALI before they require mechanical ventilation. To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of progression to ALI.Potential cases of EALI were identified by daily screening of chest radiographs (CXRs) for all adult emergency department and new medicine service admissions at Stanford University Hospital.Of 1,935 screened patients with abnormal CXRs, we enrolled 100 patients admitted with bilateral opacities present < 7 days and not due exclusively to left atrial hypertension. A total of 33 of these 100 patients progressed to ALI requiring mechanical ventilation during their hospitalization. Progression to ALI was associated with immunosuppression, the modified Rapid Emergency Medicine Score, airspace opacities beyond the bases, systemic inflammatory response syndrome, and the initial oxygen requirement (> 2 L/min). On multivariate analysis, only an initial oxygen requirement > 2 L/min predicted progression to ALI (odds ratio, 8.1; 95% confidence interval, 2.7 to 24.5). A clinical diagnosis of EALI, defined by hospital admission with bilateral opacities on CXR not exclusively due to left atrial hypertension and an initial oxygen requirement of > 2 L/min, was 73% sensitive and 79% specific for progression to ALI.A new clinical definition of EALI may have value in identifying patients with ALI early in their disease course.

    View details for DOI 10.1378/chest.08-2346

    View details for Web of Science ID 000265113800012

    View details for PubMedID 19188549

    View details for PubMedCentralID PMC2758305

  • Randomized clinical trial of activated protein C for the treatment of acute lung injury AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Liu, K. D., Levitt, J., Zhuo, H., Kallet, R. H., Brady, S., Steingrub, J., Tidswell, M., Siegel, M. D., Soto, G., Peterson, M. W., Chesnutt, M. S., Phillips, C., Weinacker, A., Thompson, B. T., Eisner, M. D., Matthay, M. A. 2008; 178 (6): 618-623

    Abstract

    Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

    View details for DOI 10.1164/rccm.200803-419OC

    View details for Web of Science ID 000259158600011

    View details for PubMedID 18565951

    View details for PubMedCentralID PMC2542435

  • Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study CRITICAL CARE Levitt, J. E., Vinayak, A. G., Gehlbach, B. K., Pohlman, A., Van Cleve, W., Hall, J. B., Kress, J. P. 2008; 12 (1)

    Abstract

    Distinguishing pulmonary edema due to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) from hydrostatic or cardiogenic edema is challenging in critically ill patients. B-type natriuretic peptide (BNP) can effectively identify congestive heart failure in the emergency room setting but, despite increasing use, its diagnostic utility has not been validated in the intensive care unit (ICU).We performed a prospective, blinded cohort study in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible if they were admitted to the ICU with respiratory distress, bilateral pulmonary edema and a central venous catheter suggesting either high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema. BNP levels were measured within 48 hours of ICU admission and development of pulmonary edema and onward up to three consecutive days. All levels were drawn simultaneously with the measurement of right atrial or pulmonary artery wedge pressure. The etiology of pulmonary edema--cardiogenic or ALI/ARDS--was determined by three intensivists blinded to BNP levels.We enrolled a total of 54 patients (33 with ALI/ARDS and 21 with cardiogenic edema). BNP levels were lower in patients with ALI/ARDS than in those with cardiogenic edema (496 +/- 439 versus 747 +/- 476 pg/ml, P = 0.05). At an accepted cutoff of 100 pg/ml, specificity for the diagnosis of ALI/ARDS was high (95.2%) but sensitivity was poor (27.3%). Cutoffs at higher BNP levels improved sensitivity at considerable cost to specificity. Invasive measures of filling pressures correlated poorly with initial BNP levels and subsequent day BNP values fluctuated unpredictably and without correlation with hemodynamic changes and net fluid balance.BNP levels drawn within 48 hours of admission to the ICU do not reliably distinguish ALI/ARDS from cardiogenic edema, do not correlate with invasive hemodynamic measurements, and do not track predictably with changes in volume status on consecutive daily measurements.

    View details for DOI 10.1186/cc6764

    View details for Web of Science ID 000254812500043

    View details for PubMedID 18194554

    View details for PubMedCentralID PMC2374600

  • Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease CRITICAL CARE MEDICINE Kress, J. P., Vinayak, A. G., Levitt, J., Schweickert, W. D., Gehlbach, B. K., Zimmerman, F., Pohlman, A. S., Hall, J. B. 2007; 35 (2): 365-371

    Abstract

    To determine the prevalence of myocardial ischemia in mechanically ventilated patients with coronary risk factors and compare periods of sedative interruption vs. sedative infusion.Prospective, blinded observational study.Medical intensive care unit of tertiary care medical center.Intubated, mechanically ventilated patients with established coronary artery disease risk factors.Continuous three-lead Holter monitors with ST-segment analysis by a blinded cardiologist were used to detect myocardial ischemia. Ischemia was defined as ST-segment elevation or depression of >0.1 mV from baseline.Comparisons between periods of awakening from sedation vs. sedative infusion were made. Vital signs, catecholamine levels, and time with ischemia detected by Holter monitor during the two periods were compared. Heart rate, mean arterial pressure, rate-pressure product, respiratory rate, and catecholamine levels were all significantly higher during sedative interruption. Eighteen of 74 patients (24%) demonstrated ischemic changes. Patients with myocardial ischemia had a longer intensive care unit length of stay (17.4+/-17.5 vs. 9.6+/-6.7 days, p=.04). Despite changes in vital signs and catecholamine levels during sedative interruption, fraction of ischemic time did not differ between the time awake vs. time sedated [median [interquartile range] of 0% [0, 0] compared with 0% [0, 0] while they were sedated [p=.17]). The finding of similar fractions of ischemic time between awake and sedated states persisted with analysis of the subgroup of 18 patients with ischemia.Myocardial ischemia is common in critically ill mechanically ventilated patients with coronary artery disease risk factors. Daily sedative interruption is not associated with an increased occurrence of myocardial ischemia in these patients.

    View details for DOI 10.1097/01.CCM.0000254334.46406.B3

    View details for Web of Science ID 000243739100004

    View details for PubMedID 17205005

  • Usefulness of the external jugular vein examination in detecting abnormal central venous pressure in critically ill patients ARCHIVES OF INTERNAL MEDICINE Vinayak, A. G., Levitt, J., Gehlbach, B., Pohlman, A. S., Hall, J. B., Kress, J. P. 2006; 166 (19): 2132-2137

    Abstract

    Central venous pressure (CVP) provides important information for the management of critically ill patients. The external jugular vein (EJV) is easier to visualize than the internal jugular vein and may give a reliable estimate of CVP.To determine the usefulness of the EJV examination in detecting abnormal CVP values, we performed a prospective blinded evaluation comparing it with CVP measured using an indwelling catheter in critically ill patients with central venous catheters. Blinded EJV examinations were performed by clinicians with 3 experience levels (attending physicians, residents and fellows, and interns and fourth-year medical students) to estimate CVP (categorized as low [/=10 cm of water]). The usefulness of the EJV examination in discriminating low vs high CVP was measured using receiver operating characteristic curve analysis.One hundred eighteen observations were recorded among 35 patients. The range of CVP values was 2 to 20 cm of water. The EJV was easier to visualize than the internal jugular vein (mean visual analog scale score, 8 vs 5; P<.001). The reliability for determining low and high CVP was excellent, with areas under the curve of 0.95 (95% confidence interval [CI], 0.88-1.00) and 0.97 (95% CI, 0.92-1.00), respectively, for attending physicians and 0.86 (95% CI, 0.78-0.95) and 0.90 (95% CI, 0.84-0.96), respectively, for all examiners.The EJV examination correlates well with catheter-measured CVP and is a reliable means of identifying low and high CVP values.

    View details for Web of Science ID 000241467500010

    View details for PubMedID 17060544

  • Treatment of acute lung injury: Historical perspective and potential future therapies SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Levitt, J. E., Matthay, M. A. 2006; 27 (4): 426-437

    Abstract

    The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.

    View details for DOI 10.1055/s-2006-948296

    View details for Web of Science ID 000239897800011

    View details for PubMedID 16909376

  • Poor choice of primary outcome in a clinical trial of pirfenidone in patients with IPF AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LEVITT, J., Gould, M. K. 2005; 172 (9): 1228-1229

    View details for Web of Science ID 000232971400019

    View details for PubMedID 16249322