47 results on '"Paul W. Blair"'
Search Results
2. Sepsis endotypes identified by host gene expression across global cohorts
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Josh G. Chenoweth, Joost Brandsma, Deborah A. Striegel, Pavol Genzor, Elizabeth Chiyka, Paul W. Blair, Subramaniam Krishnan, Elliot Dogbe, Isaac Boakye, Gary B. Fogel, Ephraim L. Tsalik, Christopher W. Woods, Alex Owusu-Ofori, Chris Oppong, George Oduro, Te Vantha, Andrew G. Letizia, Charmagne G. Beckett, Kevin L. Schully, and Danielle V. Clark
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Medicine - Abstract
Abstract Background Sepsis from infection is a global health priority and clinical trials have failed to deliver effective therapeutic interventions. To address complicating heterogeneity in sepsis pathobiology, and improve outcomes, promising precision medicine approaches are helping identify disease endotypes, however, they require a more complete definition of sepsis subgroups. Methods Here, we use RNA sequencing from peripheral blood to interrogate the host response to sepsis from participants in a global observational study carried out in West Africa, Southeast Asia, and North America (N = 494). Results We identify four sepsis subtypes differentiated by 28-day mortality. A low mortality immunocompetent group is specified by features that describe the adaptive immune system. In contrast, the three high mortality groups show elevated clinical severity consistent with multiple organ dysfunction. The immunosuppressed group members show signs of a dysfunctional immune response, the acute-inflammation group is set apart by molecular features of the innate immune response, while the immunometabolic group is characterized by metabolic pathways such as heme biosynthesis. Conclusions Our analysis reveals details of molecular endotypes in sepsis that support immunotherapeutic interventions and identifies biomarkers that predict outcomes in these groups.
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- 2024
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3. Gene expression signatures in blood from a West African sepsis cohort define host response phenotypes
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Josh G. Chenoweth, Carlo Colantuoni, Deborah A. Striegel, Pavol Genzor, Joost Brandsma, Paul W. Blair, Subramaniam Krishnan, Elizabeth Chiyka, Mehran Fazli, Rittal Mehta, Michael Considine, Leslie Cope, Audrey C. Knight, Anissa Elayadi, Anne Fox, Ronna Hertzano, Andrew G. Letizia, Alex Owusu-Ofori, Isaac Boakye, Albert A. Aduboffour, Daniel Ansong, Eno Biney, George Oduro, Kevin L. Schully, and Danielle V. Clark
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Science - Abstract
Abstract Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a critical lack of data from low- and middle-income countries where the sepsis burden is increased which inhibits generalized strategies for therapeutic intervention. Here we perform RNA sequencing of whole blood to investigate longitudinal host response to sepsis in a Ghanaian cohort. Data dimensional reduction reveals dynamic gene expression patterns that describe cell type-specific molecular phenotypes including a dysregulated myeloid compartment shared between sepsis and COVID-19. The gene expression signatures reported here define a landscape of host response to sepsis that supports interventions via targeting immunophenotypes to improve outcomes.
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- 2024
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4. A proof of concept for a targeted enrichment approach to the simultaneous detection and characterization of rickettsial pathogens from clinical specimens
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Adrian C. Paskey, Kevin L. Schully, Logan J. Voegtly, Catherine E. Arnold, Regina Z. Cer, Kenneth G. Frey, Paul W. Blair, Danielle V. Clark, Hong Ge, Allen L. Richards, Christina M. Farris, and Kimberly A. Bishop-Lilly
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rickettsial pathogens ,targeted enrichment ,detection ,characterization ,qPCR ,high throughput sequencing ,Microbiology ,QR1-502 - Abstract
Infection with either Rickettsia prowazekii or Orientia tsutsugamushi is common, yet diagnostic capabilities are limited due to the short window for positive identification. Until now, although targeted enrichment had been applied to increase sensitivity of sequencing-based detection for various microorganisms, it had not been applied to sequencing of R. prowazekii in clinical samples. Additionally, hybridization-based targeted enrichment strategies had only scarcely been applied to qPCR of any pathogens in clinical samples. Therefore, we tested a targeted enrichment technique as a proof of concept and found that it dramatically reduced the limits of detection of these organisms by both qPCR and high throughput sequencing. The enrichment methodology was first tested in contrived clinical samples with known spiked-in concentrations of R. prowazekii and O. tsutsugamushi DNA. This method was also evaluated using clinical samples, resulting in the simultaneous identification and characterization of O. tsutsugamushi directly from clinical specimens taken from sepsis patients. We demonstrated that the targeted enrichment technique is helpful by lowering the limit of detection, not only when applied to sequencing, but also when applied to qPCR, suggesting the technique could be applied more broadly to include other assays and/or microbes for which there are limited diagnostic or detection modalities.
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- 2024
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5. Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19
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Paul W. Blair, Joost Brandsma, Josh Chenoweth, Stephanie A. Richard, Nusrat J. Epsi, Rittal Mehta, Deborah Striegel, Emily G. Clemens, Sultanah Alharthi, David A. Lindholm, Ryan C. Maves, Derek T. Larson, Katrin Mende, Rhonda E. Colombo, Anuradha Ganesan, Tahaniyat Lalani, Christopher J. Colombo, Allison A. Malloy, Andrew L. Snow, Kevin L. Schully, Charlotte Lanteri, Mark P. Simons, John S. Dumler, David Tribble, Timothy Burgess, Simon Pollett, Brian K. Agan, Danielle V. Clark, and the EPICC COVID-19 Cohort Study Group
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Medicine ,Science - Abstract
Abstract The associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p
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- 2022
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6. Aetiology of hospitalized fever and risk of death at Arua and Mubende tertiary care hospitals in Uganda from August 2019 to August 2020
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Paul W. Blair, Kenneth Kobba, Francis Kakooza, Matthew L. Robinson, Emmanuel Candia, Jonathan Mayito, Edgar C. Ndawula, Abraham J. Kandathil, Alphonsus Matovu, Gilbert Aniku, Yukari C. Manabe, and Mohammed Lamorde
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Acute febrile illness ,Uganda ,Epidemiology ,Mubende ,Emerging communicable diseases ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Epidemiology of febrile illness in Uganda is shifting due to increased HIV treatment access, emerging viruses, and increased surveillance. We investigated the aetiology and outcomes of acute febrile illness in adults presenting to hospital using a standardized testing algorithm of available assays in at Arua and Mubende tertiary care hospitals in Uganda. Methods We recruited adults with a ≥ 38.0 °C temperature or history of fever within 48 h of presentation from August 2019 to August 2020. Medical history, demographics, and vital signs were recorded. Testing performed included a complete blood count, renal and liver function, malaria smears, blood culture, and human immunodeficiency virus (HIV). When HIV positive, testing included cryptococcal antigen, CD4 count, and urine lateral flow lipoarabinomannan assay for tuberculosis. Participants were followed during hospitalization and at a 1-month visit. A Cox proportional hazard regression was performed to evaluate for baseline clinical features and risk of death. Results Of 132 participants, the median age was 33.5 years (IQR 24 to 46) and 58.3% (n = 77) were female. Overall, 73 (55.3%) of 132 had a positive microbiologic result. Among those living with HIV, 31 (68.9%) of 45 had at least one positive assay; 16 (35.6%) had malaria, 14 (31.1%) tuberculosis, and 4 (8.9%) cryptococcal antigenemia. The majority (65.9%) were HIV-negative; 42 (48.3%) of 87 had at least one diagnostic assay positive; 24 (27.6%) had positive malaria smears and 1 was Xpert MTB/RIF Ultra positive. Overall, 16 (12.1%) of 132 died; 9 (56.3%) of 16 were HIV-negative, 6 died after discharge. High respiratory rate (≥ 22 breaths per minute) (hazard ratio [HR] 8.05; 95% CI 1.81 to 35.69) and low (i.e.,
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- 2022
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7. Additive value of lung ultrasound to clinical parameters for prognosticating COVID-19
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Trishul Siddharthan, Paul W. Blair, Erjia Cui, Jackson Pearce, Phabiola Herrera, Gigi Liu, Joshua East, Ciprian Crainiceanu, Danielle V. Clark, the CCPSEI Research Team, and Katherine Fenstermacher
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Medicine - Published
- 2023
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8. Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection
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Annukka A. R. Antar, Tong Yu, Zoe O Demko, Chen Hu, Jeffrey A. Tornheim, Paul W. Blair, David L. Thomas, and Yukari C. Manabe
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COVID-19 ,long COVID ,post-acute COVID-19 syndrome ,post-acute sequelae of SARS-CoV-2 infection ,brain fog ,cognitive dysfunction ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionThe incidence of long COVID is substantial, even in people with mild to moderate acute COVID-19. The role of early viral kinetics in the subsequent development of long COVID is largely unknown, especially in individuals who were not hospitalized for acute COVID-19.MethodsSeventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional SARS-CoV-2 test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1-, 3-, 6-, 12-, and 18-months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90+ days from acute COVID-19 symptom onset.ResultsSelf-reported brain fog and muscle pain at 90+ days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI ≥ 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22-0.95; muscle pain: aRR 0.28, 95% CI 0.08-0.94). Participants reporting higher severity brain fog or muscle pain at 90+ days after acute COVID-19 onset were less likely to have cleared SARS-CoV-2 RNA within 28 days. The acute viral RNA decay trajectories of participants who did and did not later go on to experience brain fog 90+ days after acute COVID-19 onset were distinct.DiscussionThis work indicates that at least two long COVID symptoms - brain fog and muscle pain – at 90+ days from acute COVID-19 onset are specifically associated with prolonged time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute COVID-19. This finding provides evidence that delayed immune clearance of SARS-CoV-2 antigen or greater amount or duration of viral antigen burden in the upper respiratory tract during acute COVID-19 are directly linked to long COVID. This work suggests that host-pathogen interactions during the first few weeks after acute COVID-19 onset have an impact on long COVID risk months later.
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- 2023
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9. A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms
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Nusrat J. Epsi, John H. Powers, David A. Lindholm, Katrin Mende, Allison Malloy, Anuradha Ganesan, Nikhil Huprikar, Tahaniyat Lalani, Alfred Smith, Rupal M. Mody, Milissa U. Jones, Samantha E. Bazan, Rhonda E. Colombo, Christopher J. Colombo, Evan C. Ewers, Derek T. Larson, Catherine M. Berjohn, Carlos J. Maldonado, Paul W. Blair, Josh Chenoweth, David L. Saunders, Jeffrey Livezey, Ryan C. Maves, Margaret Sanchez Edwards, Julia S. Rozman, Mark P. Simons, David R. Tribble, Brian K. Agan, Timothy H. Burgess, Simon D. Pollett, and for the EPICC COVID-19 Cohort Study Group
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Medicine ,Science - Abstract
Background Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. Methods 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. Results We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 (“Nasal cluster”) is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 (“Sensory cluster”) is highly correlated with loss of smell or taste, and cluster 3 (“Respiratory/Systemic cluster”) is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). Conclusions We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.
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- 2023
10. Do worsening lung ultrasound scans identify severe COVID-19 trajectories?
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Paul W. Blair, Jimin Hwang, Jackson Pearce, Tiffany C. Fong, Erjia Cui, Phabiola Herrera, Gigi Liu, Ciprian Crainiceanu, Trishul Siddharthan, Danielle V. Clark, The CCPSEI Research Team, Katherine Fenstermacher, Sophia Shea, Stefanie Seo, Josh Lawrence, Lauren Sauer, Bhakti Hansoti, and Richard Rothman
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lung ultrasound ,point-of-care lung ultrasound ,COVID-19 ,severe COVID-19 ,cohort study ,Medicine (General) ,R5-920 - Abstract
BackgroundWhile point-of-care ultrasound (POCUS) has been used to track worsening COVID-19 disease it is unclear if there are dynamic differences between severity trajectories.MethodsWe studied 12-lung zone protocol scans from 244 participants [with repeat scans obtained in 3 days (N = 114), 7 days (N = 53), and weekly (N = 9)] ≥ 18 years of age hospitalized for COVID-19 pneumonia. Differences in mean lung ultrasound (LUS) scores and percent of lung fields with A-lines over time were compared between peak severity levels (as defined by the WHO clinical progression scale) using linear mixed-effects models.ResultsMean LUS scores were elevated by 0.19 (p = 0.035) and A-lines were present in 14.7% fewer lung fields (p = 0.02) among those with ICU-level or fatal peak illness compared to less severe hospitalized illness, regardless of duration of illness. There were no differences between severity groups in the trajectories of mean LUS score 0.19 (p = 0.66) or percent A-lines (p = 0.40).DiscussionOur results do not support the use of serial LUS scans to monitor COVID-19 disease progression among hospitalized adults.
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- 2022
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11. Point-of-Care Lung Ultrasound Predicts Severe Disease and Death Due to COVID-19: A Prospective Cohort Study
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Paul W. Blair, MD, Trishul Siddharthan, MD, Gigi Liu, MD, Jiawei Bai, PhD, Erja Cui, BSc, Joshua East, RPSGT, Phabiola Herrera, MD, Lalaine Anova, MS, Varun Mahadevan, BA, Jimin Hwang, MD, Shakir Hossen, MBBS, Stefanie Seo, BS, Olamide Sonuga, BS, Joshua Lawrence, BS, Jillian Peters, MD, Andrea L. Cox, MD, PhD, Yukari C. Manabe, MD, Katherine Fenstermacher, PhD, Sophia Shea, MPH, Richard E. Rothman, MD, PhD, Bhakti Hansoti, MD, Lauren Sauer, MS, Ciprian Crainiceanu, PhD, and Danielle V. Clark, PhD
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Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
OBJECTIVES:. The clinical utility of point-of-care lung ultrasound (LUS) among hospitalized patients with COVID-19 is unclear. DESIGN:. Prospective cohort study. SETTING:. A large tertiary care center in Maryland, between April 2020 and September 2021. PATIENTS:. Hospitalized adults (≥ 18 yr old) with positive severe acute respiratory syndrome coronavirus 2 reverse transcriptase-polymerase chain reaction results. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. All patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28 days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean LUS Score (mLUSS) (ranging from 0 to 3) across lung zones was determined. The primary outcome was time to ICU-level care, defined as high-flow oxygen, noninvasive, or invasive mechanical ventilation, within 28 days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 61 years and 114 participants (43.2%) were female. The median mLUSS was 1.0 (interquartile range, 0.5–1.3). Following enrollment, 27 participants (10.0%) went on to require ICU-level care, and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (adjusted hazard ratio [aHR], 3.61; 95% CI, 1.27–10.2) and 28-day mortality (aHR, 3.10; 95% CI, 1.29–7.50). Pleural line abnormalities were independently associated with disease progression to death (aHR, 20.93; CI, 3.33–131.30). CONCLUSIONS:. Participants with a mLUSS greater than or equal to 1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high-flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.
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- 2022
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12. Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis
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Paul W. Blair, Maryam Keshtkar-Jahromi, Kevin J. Psoter, Ronald B. Reisler, Travis K. Warren, Sara C. Johnston, Arthur J. Goff, Lydia G. Downey, Sina Bavari, and Anthony P. Cardile
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Marburg virus disease ,hemorrhagic fevers ,viral ,models ,animal ,filoviridae ,mononegavirales ,marburgvirus ,Angola ,Musoke ,Microbiology ,QR1-502 - Abstract
Angola variant (MARV/Ang) has replaced Mt. Elgon variant Musoke isolate (MARV/MtE-Mus) as the consensus standard variant for Marburg virus research and is regarded as causing a more aggressive phenotype of disease in animal models; however, there is a dearth of published evidence supporting the higher virulence of MARV/Ang. In this retrospective study, we used data pooled from eight separate studies in nonhuman primates experimentally exposed with either 1000 pfu intramuscular (IM) MARV/Ang or MARV/MtE-Mus between 2012 and 2017 at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Multivariable Cox proportional hazards regression was used to evaluate the association of variant type with time to death, the development of anorexia, rash, viremia, and 10 select clinical laboratory values. A total of 47 cynomolgus monkeys were included, of which 18 were exposed to MARV/Ang in three separate studies and 29 to MARV/MtE-Mus in five studies. Following universally fatal Marburg virus exposure, compared to MARV/MtE-Mus, MARV/Ang was associated with an increased risk of death (HR = 22.10; 95% CI: 7.08, 68.93), rash (HR = 5.87; 95% CI: 2.76, 12.51) and loss of appetite (HR = 35.10; 95% CI: 7.60, 162.18). Our data demonstrate an increased virulence of MARV/Ang compared to MARV/MtE-Mus variant in the 1000 pfu IM cynomolgus macaque model.
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- 2018
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13. Clinical evaluation of the BioFire Global Fever Panel for the identification of malaria, leptospirosis, chikungunya, and dengue from whole blood: a prospective, multicentre, cross-sectional diagnostic accuracy study
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Yukari C Manabe, Joshua Betz, Olivia Jackson, Victor Asoala, Isabel Bazan, Paul W Blair, Aileen Chang, Sarunyou Chusri, John A Crump, Kimberly A Edgel, Dennis J Faix, Stefan Fernandez, Anne T Fox, Jose A Garcia, Max Grogl, Erin A Hansen, Vireak Heang, Stacey L House, Krisada Jongsakul, Michael B Kaburise, Chonticha Klungthong, Mohammed Lamorde, Andrew G Letizia, Ivette Lorenzana, Malen Luy, Vanance P Maro, Christopher N Mores, Christopher A Myers, Abraham R Oduro, Leda Parham, Abigail J Porzucek, Michael Prouty, David S Rabiger, Matthew P Rubach, Crystyan Siles, Maria Silva, Chinaka Ukachu, John N Waitumbi, Cynthia L Phillips, and Brian W Jones
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Adult ,Aged, 80 and over ,Male ,Plasmodium ,Adolescent ,Fever ,Infant, Newborn ,Infant ,Middle Aged ,Malaria ,Dengue ,Young Adult ,Cross-Sectional Studies ,Infectious Diseases ,Child, Preschool ,Chikungunya Fever ,Humans ,Female ,Leptospirosis ,Prospective Studies ,Child ,Chikungunya virus ,Aged - Abstract
Acute febrile illness is a common presentation for patients at hospitals globally. Assays that can diagnose a variety of common pathogens in blood could help to establish a diagnosis for targeted disease management. We aimed to evaluate the performance of the BioFire Global Fever Panel (GF Panel), a multiplex nucleic acid amplification test performed on whole blood specimens run on the BioFire FilmArray System, in the diagnosis of several pathogens that cause acute febrile illness.We did a prospective, multicentre, cross-sectional diagnostic accuracy study to evaluate the GF Panel. Consenting adults and children older than 6 months presenting with fever in the previous 2 days were enrolled consecutively in sub-Saharan Africa (Ghana, Kenya, Tanzania, Uganda), southeast Asia (Cambodia, Thailand), central and South America (Honduras, Peru), and the USA (Washington, DC; St Louis, MO). We assessed the performance of six analytes (chikungunya virus, dengue virus [serotypes 1-4], Leptospira spp, Plasmodium spp, Plasmodium falciparum, and Plasmodium vivax or Plasmodium ovale) on the GF Panel. The performance of the GF Panel was assessed using comparator PCR assays with different primers followed by bidirectional sequencing on nucleic acid extracts from the same specimen. We calculated the positive percent agreement and negative percent agreement of the GF Panel with respect to the comparator assays. This study is registered with ClinicalTrials.gov, NCT02968355.From March 26, 2018, to Sept 30, 2019, 1965 participants were enrolled at ten sites worldwide. Of the 1875 participants with analysable results, 980 (52·3%) were female and the median age was 22 years (range 0-100). At least one analyte was detected in 657 (35·0%) of 1875 specimens. The GF Panel had a positive percent agreement for the six analytes evaluated as follows: chikungunya virus 100% (95% CI 86·3-100), dengue virus 94·0% (90·6-96·5), Leptospira spp 93·8% (69·8-99·8), Plasmodium spp 98·3% (96·3-99·4), P falciparum 92·7% (88·8-95·6), and P vivax or P ovale 92·7% (86·7-96·6). The GF Panel had a negative percent agreement equal to or greater than 99·2% (98·6-99·6) for all analytes.This 1 h sample-to-answer, molecular device can detect common causative agents of acute febrile illness with excellent positive percent agreement and negative percent agreement directly in whole blood. The targets of the assay are prevalent in tropical and subtropical regions globally, and the assay could help to provide both public health surveillance and individual diagnoses.BioFire Defense, Joint Project Manager for Medical Countermeasure Systems and US Army Medical Materiel Development Activity, and National Institute of Allergy and Infectious Diseases.
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- 2022
14. Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial
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Shmuel Shoham, Evan M Bloch, Arturo Casadevall, Daniel Hanley, Bryan Lau, Kelly Gebo, Edward Cachay, Seble G Kassaye, James H Paxton, Jonathan Gerber, Adam C Levine, Arash Naeim, Judith Currier, Bela Patel, Elizabeth S Allen, Shweta Anjan, Lawrence Appel, Sheriza Baksh, Paul W Blair, Anthony Bowen, Patrick Broderick, Christopher A Caputo, Valerie Cluzet, Marie Elena Cordisco, Daniel Cruser, Stephan Ehrhardt, Donald Forthal, Yuriko Fukuta, Amy L Gawad, Thomas Gniadek, Jean Hammel, Moises A Huaman, Douglas A Jabs, Anne Jedlicka, Nicky Karlen, Sabra Klein, Oliver Laeyendecker, Karen Lane, Nichol McBee, Barry Meisenberg, Christian Merlo, Giselle Mosnaim, Han-Sol Park, Andrew Pekosz, Joann Petrini, William Rausch, David M Shade, Janna R Shapiro, J Robinson Singleton, Catherine Sutcliffe, David L Thomas, Anusha Yarava, Martin Zand, Jonathan M Zenilman, Aaron A R Tobian, and David J Sullivan
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Microbiology (medical) ,Adult ,Adolescent ,Clinical Trials and Supportive Activities ,Passive ,Medical and Health Sciences ,Microbiology ,Vaccine Related ,Double-Blind Method ,Clinical Research ,Biodefense ,Humans ,Lung ,COVID-19 Serotherapy ,transfusion ,SARS-CoV-2 ,Prevention ,COVID-19 ,Pneumonia ,Biological Sciences ,post-exposure-prophylaxis ,Emerging Infectious Diseases ,Infectious Diseases ,Good Health and Well Being ,convalescent plasma ,Immunization ,Post-Exposure Prophylaxis ,Infection - Abstract
Background The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. Methods This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. Results In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups. Conclusions Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. Clinical Trials Registration NCT04323800.
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- 2023
15. Quality of Life and Long COVID Incidence and Duration in the First 24 Months after Mild to Moderate Acute COVID-19: The OutSMART Prospective Cohort Study
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Zoe O. Demko, Tong Yu, Sarika K. Mullapudi, M. Gabriela Varela Heslin, Chamia A. Dorsey, Christine B. Payton, Jeffrey A. Tornheim, Paul W. Blair, Shruti Mehta, David Lee Thomas, Yukari Manabe, and Annukka A.R. Antar
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- 2023
16. 308. Do lung ultrasound abnormalities change during hospitalization for COVID-19?
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Jimin Hwang, Paul W Blair, Trishul Siddarthan, Gigi Liu, Erjia Cui, Jiawei Bai, Joshua East, Phabiola Herrara, Tiffany Fong, Varun Mahadevan, Shakir Hossen, Stefanie Seo, Olamide Sonuga, Joshua Lawrence, Lalaine Anova, Katherine Fenstermacher, Sophia Shea, Richard E Rothman, Bhakti Hansoti, Laruen Sauer, Ciprian Crainiceanu, and Danielle Clark
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Infectious Diseases ,Oncology - Abstract
Background While point-of-care ultrasound (POCUS) has been used to track disease resolution, temporal trends in lung ultrasound (LUS) findings among hospitalized patients with COVID-19 is not well-characterized. Methods We studied 413 LUS scans in 244 participants ≥ 18 years of age hospitalized for COVID-19 pneumonia within 28 days of symptom onset from April, 2020 until September, 2021 at the Johns Hopkins Hospital, Baltimore Maryland. All patients were scanned using a 12-lung zone protocol and repeat scans were obtained in 3 days (N=114), 7 days (N=53), and weekly (N=9) from the initial scan. Participants were followed to determine clinical outcomes until hospital discharge and vital status at 28-days. Ultrasounds were independently reviewed for lung artifacts, and the composite mean LUS score (ranging from 0 to 3) across lung zones was determined. Trends of mean LUS scores and % lung fields with A-lines (indicating proportion of normal lung fields) were plotted by peak severity (mild, moderate, and severe defined by the World Health Organization Ordinal Scale) over time from symptom onset. Differences in mean LUS score or % A-lines changes over time between peak severity levels were evaluated using a Kruskal-Wallis test and linear mixed-effected models with an exchangeable correlation structure. Results Among 244 patients in our cohort (mean age of 58.2 (SD 15.0) years, and 55.7% female) (Table 1), there was no change in average mean LUS scores between the first two visits by severity groups (Figure 1; Kruskal-Wallis p=0.63). Mean LUS scores were elevated by 0.22 (p< 0.001) in a dose-response manner regardless of duration of illness, but there was no change over time associated with peak severity (p=0.73). Similarly, percentage of A-lines were in 13.9% less lung fields for each increase in peak severity (p< 0.001; Figure 2) regardless of duration of illness. However, a change in mean LUS score did not differ significantly among peak severity levels (p=0.36). Conclusion Mean LUS scores correlated with clinical severity among hospitalized adults when assessed cross-sectionally, however mean LUS score did not change or differ between peak severity levels over the time course of hospitalization. These results do not support serial LUS scans to monitor disease progression. Disclosures All Authors: No reported disclosures.
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- 2022
17. 1169. Derivation And Validation of an International Clinical Prognostication Model for 28-day Sepsis Mortality
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Paul W Blair, Rittal Mehta, Tin Som, Stephen Okello, Ephraim L Tsalik, Abdullah Wailagala, Christopher W Woods, Michael Prouty, Josh Chenoweth, Andrew Letizia, Dennis Faix, Nehkonti Adams, Emily R Ko, Chris Duplessis, Mohammed Lamorde, Alex Owusu-Ofori, Prossy Naluyima, Mubaraka Kayiira, Chris Oppong, Michelle Rozo, Ann Fox, James Lawler, Peter Waitt, Angela Prouty, Te Vantha, Charmagne Beckett, Hannah Kibuuka, George Oduro, Kevin Schully, and Danielle Clark
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Infectious Diseases ,Oncology - Abstract
Background Survival prediction models have largely been derived and validated only in high-resource Western countries or in single center studies. We sought to create a prediction model for 28-day mortality using laboratory and physiologic parameters from 3 international sepsis cohorts and externally validated the model. Methods During 2014 to 2021, adult hospitalized patients with suspected infection were enrolled in Durham, United States (N=180) and those with suspected infection and ≥2 SIRS (Systemic Inflammatory Response Syndrome) criteria in Takeo, Cambodia (N=200), and Kumasi, Ghana (N=187). Twenty-five clinical laboratory and physiologic parameters were candidate covariates and sepsis screening scores included as comparators. First, bivariate Cox regression models were performed to determine risk of individual parameters. Then, a 10-fold cross-validated forward stepwise model selection technique was used to eliminate nonsignificant variables using a p-value < 0.10 and the cross-validated C-statistic was estimated. Lastly, this model was applied to an external cohort of hospitalized adults with suspected infection and ≥2 SIRS in Fort Portal, Uganda (N=331 with 9.3% 28-day mortality). Results Among 567 participants, overall mortality was 16.4% at 28-days. Mortality rate highest in Ghana (31.0%), followed by Cambodia (11.0%) and the United States (7.2%). Bivariate analyses identified hypernatremia ( >145 mEq/L) being associated with the highest risk of death (hazard ratio: 7.42; 95% CI: 3.65 to 15.10; Figure 1). On multivariable analysis, a 28-day mortality model including mean arterial pressure, Glasgow Coma score, blood sodium, lactate, and blood urea nitrogen (Table 1) resulted in a 10-fold cross-validated C-statistic of 0.80 (95% CI: 0.61 to 0.88). This model predicted mortality accurately in the validation cohort with a C-statistic of 0.74 (95%CI: 0.69 to 0.79). Figure 1.Forest plot for bivariate analyses for one month survival across United States, Cambodia, and Ghana cohorts. Conclusion Hypotension, altered mental status, serum sodium, serum BUN, and plasma lactate accurately identified risk of death by 28-days among those with suspected sepsis in 3 international derivation cohorts and in a validation cohort in Uganda. Our findings emphasize the importance of clinical laboratory results for sepsis risk stratification. Disclosures Ephraim L. Tsalik, MD PhD, Danaher Diagnostics, Predigen, and Biomeme: In the past 3 years, I have had held equity and consulted for Predigen and Biomeme. Currently, I am an employee of Danaher Diagnostics. Christopher W. Woods, MD MPH, Predigen, Inc: Co-founder.
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- 2022
18. The performance of screening tools for predicting mortality across multi-site international sepsis cohorts
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Paul W. Blair, Rittal Mehta, Chris Oppong, Tin Som, Emily Ko, Ephraim Tsalik, Josh Chenoweth, Michelle Rozo, Nehkonti Adams, Charmagne Beckett, Christopher W. Woods, Deborah A. Striegel, Mark Salvador, Joost Brandsma, Lauren McKean, Rachael E. Mahle, William Hulsey, Subramaniam Krishnan, Michael Prouty, Andrew Letizia, Anne Fox, Dennis Faix, James V. Lawler, Chris Duplessis, Michael G Gregory, Te Vantha, Alex Owusu-Ofori, Daniel Ansong, George Oduro, Kevin L. Schully, and Danielle V. Clark
- Abstract
BackgroundDirect comparisons of sepsis screening tools for prognostication have largely been limited to single-centre or high-income countries despite a disproportionately high burden of sepsis in low- and middle-income countries (LMICs). We evaluated the performance of commonly used sepsis screening tools across prospective sepsis cohorts in the United States, Cambodia, and Ghana.MethodsFrom 2014 to 2021, participants with 2 or more SIRS (Systemic Inflammatory Response Syndrome) criteria and suspected infection were enrolled in emergency departments and medical wards at hospitals in the Cambodia and Ghana and hospitalized participants with suspected infection were enrolled in the United States. Cox proportional hazards regression was performed, and Harrell’s C-statistic calculated to determine 28-day mortality prediction performance of the qSOFA score ≥2, SIRS score ≥3, NEWS ≥5, MEWS ≥5, or UVA score ≥2, Screening tools were compared to baseline risk (age and sex) with the Wald test.ResultsThe cohorts included 567 participants (42.9% female) including 187 participants from Kumasi, Ghana, 200 participants from Takeo, Cambodia, and 180 participants from Durham, North Carolina in the United States. The pooled mortality was 16.4% at 28-days. The mortality prediction accuracy increased from baseline risk with the MEWS (C-statistic: 0.63, 95% CI: 0.58, 0.68; p=0.002), NEWS (C-statistic: 0.68; 95% confidence interval [CI]: 0.64, 0.73; pConclusionsAmong the cohorts, MEWS, NEWS, qSOFA, and UVA scores performed better than baseline risk, largely driven by accuracy improvements in Ghana, while SIRS scores did not improve prognostication accuracy. Prognostication scores should be validated within the target population prior to clinical use.Key questionsWhat is already known on this topic – While single-centre cohorts and retrospective analyses have been performed, the optimal sepsis screening tool for prognostication in low- and middle-income countries is unknown.What this study adds – The MEWS, NEWS, qSOFA scores, but not SIRS, were additive over baseline risk for prognostication in prospective hospitalized infection cohorts, but with variable additive performance within each cohort.How this study might affect research, practice or policy - Prognostication scores should be validated within the target population prior to clinical use.
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- 2022
19. Post-acute sequelae of SARS-CoV-2 (PASC) impact quality of life at 6, 12 and 18 months post-infection
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Zoe O, Demko, Tong, Yu, Sarika K, Mullapudi, M Gabriela, Varela Heslin, Chamia A, Dorsey, Christine B, Payton, Jeffrey A, Tornheim, Paul W, Blair, Shruti H, Mehta, David L, Thomas, Yukari C, Manabe, and Annukka A R, Antar
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Article - Abstract
Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health.
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- 2022
20. Aetiology of Hospitalized Fever and Risk of Death at Two Rural Tertiary Care Hospitals in Uganda from August 2019 to August 2020
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Paul W. Blair, Kenneth Kobba, Francis Kakooza, Matthew L. Robinson, Emmanuel Candia, Jonathan Mayito, Edgar C. Ndawula, Abraham Kandathil, Alphonsus Matovu, Gilbert Aniku, Yukari C Manabe, and Mohammed Lamorde
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Background: Epidemiology of febrile illness in Uganda is shifting due to increased HIV treatment access, emerging viruses, and increased surveillance. We investigated the aetiology and outcomes of acute febrile illness in adults presenting to hospital using a standardized testing algorithm of available assays in two tertiary care hospitals in Uganda.Methods: We recruited adults with a ≥ 38.0°C temperature or history of fever within 48 hours of presentation. Medical history, demographics, and vital signs were recorded. Testing performed included a complete blood count, renal and liver function, malaria smears, blood culture, and human immunodeficiency virus (HIV). When HIV positive; cryptococcal antigen, CD4 count, and urine lateral flow lipoarabinomannan assay for tuberculosis. Participants were followed during hospitalization and at a 1-month visit. A Cox proportional hazard regression was performed to evaluate for baseline clinical features and risk of death.Results: Of 132 participants, the median age was 33.5 years (IQR 24 to 46) and 58.3% (n=77) were female. Overall, 73 (55.3%) of 132 had a positive microbiologic result. Among those living with HIV, 31 (68.9%) of 45 had at least one positive assay; 16 (35.6%) had malaria, 14 (31.1%) tuberculosis, and 4 (8.9%) cryptococcal antigenemia. The majority (65.9%) were HIV-negative; 42 (48.3%) of 87 had at least one diagnostic assay positive; 24 (27.6%) had positive malaria smears and 1 was Xpert MTB/RIF Ultra positive. Overall, 16 (12.1%) of 132 died; 9 (56.3%) of 16 were HIV-negative, 6 died after discharge. High respiratory rate (≥22 breaths per minute) (hazard ratio [HR] 8.05; 95% CI: 1.81 to 35.69) and low (i.e., Conclusion: In those with hospitalized fever, malaria and tuberculosis were common causes of febrile illness, but most deaths were non-malarial, and most HIV-negative participants did not have a positive diagnostic result. Those with respiratory failure had a high risk of death.
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- 2022
21. Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding
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Nadine Peart Akindele, Deborah Persaud, Heba H. Mostafa, Paul W Blair, Andrea L. Cox, Lauren Sauer, Christine C. Atik, Weiqiang Zhou, Dhananjay Vaidya, Xueting Tao, Hongkai Ji, Oren Gordon, Jessica H. Rubens, Jeanette Beaudry, Katherine Z.J. Fenstermacher, Andrew H. Karaba, Patrizio Caturegli, and Theodore Kouo
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Male ,0301 basic medicine ,Eotaxin ,Chemokine ,Adolescent ,medicine.medical_treatment ,MIS-C ,Antibodies, Viral ,medicine.disease_cause ,Severity of Illness Index ,MIS-A ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Severity of illness ,Major Article ,medicine ,Humans ,Immunology and Allergy ,Serologic Tests ,030212 general & internal medicine ,Child ,Prospective cohort study ,Coronavirus ,biology ,SARS-CoV-2 ,business.industry ,Age Factors ,COVID-19 ,Viral Load ,medicine.disease ,Systemic Inflammatory Response Syndrome ,viral RNA ,Systemic inflammatory response syndrome ,AcademicSubjects/MED00290 ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Child, Preschool ,Host-Pathogen Interactions ,Immunology ,biology.protein ,Cytokines ,RNA, Viral ,Chemokines ,business ,Viral load ,Biomarkers - Abstract
BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood.MethodsHospitalized children ResultsThe median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5–13.9) and 2.2 years (IQR, 1.1–10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1β, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate ConclusionsThe distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.
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- 2021
22. Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology
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Andrea L. Cox, Alexis Figueroa, Weiqiang Zhou, Matthew L Robinson, Leon L. Hsieh, Kathryn Shaw-Saliba, Nada Alachkar, Lauren Sauer, Ramy El-Diwany, Russell Wesson, Richard E. Rothman, Paul W Blair, Katherine Z.J. Fenstermacher, Guido Massaccesi, Sherry Leung, Hongkai Ji, and Andrew H. Karaba
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0301 basic medicine ,Microbiology (medical) ,Chemokine ,medicine.medical_treatment ,030106 microbiology ,Subgroup analysis ,macromolecular substances ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Mediator ,Influenza, Human ,Major Article ,medicine ,Humans ,Obesity ,030212 general & internal medicine ,Risk factor ,Innate immune system ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,medicine.disease ,Influenza ,AcademicSubjects/MED00290 ,Infectious Diseases ,Cytokine ,nervous system ,Immunology ,biology.protein ,Cytokines ,Chemokines ,business - Abstract
Background Several inflammatory cytokines are upregulated in severe coronavirus disease 2019 (COVID-19). We compared cytokines in COVID-19 versus influenza to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. Methods Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was used to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was used to identify cytokines that mediate the effect of BMI and age on disease severity. Results Interleukin-18 (IL-18), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were significantly increased in COVID-19 versus influenza patients, whereas granulocyte macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN-λ1, IL-10, IL-15, and monocyte chemoattractant protein 2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not in severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. Conclusions These findings point to activation of fundamentally different innate immune pathways in severe acute respiratory syndrome coronavirus 2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.
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- 2021
23. Screening tools for predicting mortality of adults with suspected sepsis: an international sepsis cohort validation study
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Paul W Blair, Rittal Mehta, Chris Kwaku Oppong, Som Tin, Emily Ko, Ephraim L Tsalik, Josh Chenoweth, Michelle Rozo, Nehkonti Adams, Charmagne Beckett, Christopher W Woods, Deborah A Striegel, Mark G Salvador, Joost Brandsma, Lauren McKean, Rachael E Mahle, William R Hulsey, Subramaniam Krishnan, Michael Prouty, Andrew Letizia, Anne Fox, Dennis Faix, James V Lawler, Chris Duplessis, Michael G Gregory, Te Vantha, Alex Kwame Owusu-Ofori, Daniel Ansong, George Oduro, Kevin L Schully, and Danielle V Clark
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General Medicine - Abstract
ObjectivesWe evaluated the performance of commonly used sepsis screening tools across prospective sepsis cohorts in the USA, Cambodia and Ghana.DesignProspective cohort studies.Setting and participantsFrom 2014 to 2021, participants with two or more SIRS (Systemic Inflammatory Response Syndrome) criteria and suspected infection were enrolled in emergency departments and medical wards at hospitals in Cambodia and Ghana and hospitalised participants with suspected infection were enrolled in the USA. Cox proportional hazards regression was performed, and Harrell’s C-statistic calculated to determine 28-day mortality prediction performance of the quick Sequential Organ Failure Assessment (qSOFA) score ≥2, SIRS score ≥3, National Early Warning Score (NEWS) ≥5, Modified Early Warning Score (MEWS) ≥5 or Universal Vital Assessment (UVA) score ≥2. Screening tools were compared with baseline risk (age and sex) with the Wald test.ResultsThe cohorts included 567 participants (42.9% women) including 187 participants from Kumasi, Ghana, 200 participants from Takeo, Cambodia and 180 participants from Durham, North Carolina in the USA. The pooled mortality was 16.4% at 28 days. The mortality prediction accuracy increased from baseline risk with the MEWS (C-statistic: 0.63, 95% CI 0.58 to 0.68; p=0.002), NEWS (C-statistic: 0.68; 95% CI 0.64 to 0.73; pConclusionsAmong the cohorts, MEWS, NEWS, qSOFA and UVA scores performed better than baseline risk, largely driven by accuracy improvements in Ghana, while SIRS scores did not improve prognostication accuracy. Prognostication scores should be validated within the target population prior to clinical use.
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- 2023
24. Point-of-care lung ultrasound predicts severe disease and death due to COVID-19: a prospective cohort study
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Paul W. Blair, Trishul Siddharthan, Gigi Liu, Jiawei Bai, Joshua East, Phabiola Herrera, Lalaine Anova, Varun Mahadevan, Shakir Hossen, Stefanie Seo, Olamide Sonuga, Joshua Lawrence, Jillian Peters, Andrea Cox, Yukari C. Manabe, Katherine Fenstermacher, Sophia Shea, Richard E. Rothman, Bhakti Hansoti, Lauren Sauer, Ciprian Crainiceanu, and Danielle V. Clark
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ObjectiveThe clinical utility of point-of-care lung ultrasound (LUS) for disease severity triage of hospitalized patients with COVID-19 is unclear.DesignProspective cohort studySettingA large tertiary care center in Maryland, USA between April 2020 to September 2021.PatientsHospitalized adults (≥18 years of age) with positive SARS-CoV-2 RT-PCR results.InterventionsNone.Measurements and Main ResultsAll patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28-days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean Lung Ultrasound Score (ranging from 0 to 3) across lung zones (mLUSS) was determined. The primary outcome was time to ICU-level care, defined as high flow oxygen, noninvasive, or mechanical ventilation, within 28-days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 59 years and 114 (43.2) % of participants were female. The median mLUSS was 1 (interquartile range: 0.5 to 1.3). Following enrollment, 29 (11.0%) participants went on to require ICU-level care and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (aHR = 3.63; 95% CI: 1.23 to 10.65) and 28-day mortality (aHR = 4.50; 95% CI: 1.52 to 13.31). Pleural line abnormalities were independently associated with disease progression to ICU-level care (aHR = 18.86; CI: 1.57 to 226.09).ConclusionsParticipants with a mLUSS ≥1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.
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- 2022
25. Assessing the use of a micro-sampling device for measuring blood protein levels in healthy subjects and COVID-19 patients
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Joost Brandsma, Josh G. Chenoweth, Melissa K. Gregory, Subramaniam Krishnan, Paul W. Blair, Deborah A. Striegel, Rittal Mehta, Kevin L. Schully, J. Stephen Dumler, CDR Cynthia S. Sikorski, Kelsey O’Connor, Susan A. Reichert-Scrivner, Carmen M. Paguirigan, Catherine F. T. Uyehara, COL Viseth Ngauy, Christopher A. Myers, and Danielle V. Clark
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Blood Specimen Collection ,Multidisciplinary ,COVID-19 ,Humans ,Reproducibility of Results ,Blood Proteins ,Healthy Volunteers ,Specimen Handling - Abstract
Background Venous phlebotomy performed by trained personnel is critical for patient diagnosis and monitoring of chronic disease, but has limitations in resource-constrained settings, and represents an infection control challenge during outbreaks. Self-collection devices have the potential to shift phlebotomy closer to the point of care, supporting telemedicine strategies and virtual clinical trials. Here we assess a capillary blood micro-sampling device, the Tasso Serum Separator Tube (SST), for measuring blood protein levels in healthy subjects and non-hospitalized COVID-19 patients. Methods 57 healthy controls and 56 participants with mild/moderate COVID-19 were recruited at two U.S. military healthcare facilities. Healthy controls donated Tasso SST capillary serum, venous plasma and venous serum samples at multiple time points, while COVID-19 patients donated a single Tasso SST serum sample at enrolment. Concentrations of 17 protein inflammatory biomarkers were measured in all biospecimens by Ella multi-analyte immune-assay. Results Tasso SST serum protein measurements in healthy control subjects were highly reproducible, but their agreements with matched venous samples varied. Most of the selected proteins, including CRP, Ferritin, IL-6 and PCT, were well-correlated between Tasso SST and venous serum with little sample type bias, but concentrations of D-dimer, IL-1B and IL-1Ra were not. Self-collection at home with delayed sample processing was associated with significant concentrations differences for several analytes compared to supervised, in-clinic collection with rapid processing. Finally, Tasso SST serum protein concentrations were significantly elevated in in non-hospitalized COVID-19 patients compared with healthy controls. Conclusions Self-collection of capillary blood with micro-sampling devices provides an attractive alternative to routine phlebotomy. However, concentrations of certain analytes may differ significantly from those in venous samples, and factors including user proficiency, temperature control and time lags between specimen collection and processing need to be considered for their effect on sample quality and reproducibility.
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- 2021
26. Optimizing Highly Infectious Disease Isolation Unit Management: Experiences From the Infectious Diseases Isolation and Research Unit, Fort Portal, Uganda
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Hannah Kibuuka, Isabella Migisha, Danielle V. Clark, Antonia Kwiecien, Rodgers Ayebare, Gerald Kanyomozi, Mohammed Lamorde, David L. Saunders, Paul W Blair, Brenda Muhindo, Abdullah Wailagala, Peter Waitt, Moses Asiimwe, Jacqueline Nalikka, Susan Alum, Peace Okwaro, Stephen Okello, and Nahid Bhadelia
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Health facility ,Isolation (health care) ,Infectious disease (medical specialty) ,Pandemic ,Public Health, Environmental and Occupational Health ,Outbreak ,Operations management ,Resource management ,Business ,Personal protective equipment ,Unit (housing) - Abstract
Infectious disease outbreaks on the scale of the current coronavirus disease 2019 (COVID-19) pandemic are a new phenomenon in many parts of the world. Many isolation unit designs with corresponding workflow dynamics and personal protective equipment postures have been proposed for each emerging disease at the health facility level, depending on the mode of transmission. However, personnel and resource management at the isolation units for a resilient response will vary by human resource capacity, reporting requirements, and practice setting. This study describes an approach to isolation unit management at a rural Uganda Hospital and shares lessons from the Uganda experience for isolation unit managers in low- and middle-income settings.
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- 2021
27. COVID-19 Outcomes Among US Military Health System Beneficiaries Include Complications Across Multiple Organ Systems and Substantial Functional Impairment
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Eric D Laing, Caroline English, Ryan C. Maves, Nikhil Huprikar, Samantha E Bazan, Sharon Chi, Christopher C. Broder, Eugene V. Millar, Josh Chenoweth, Alfred G. Smith, Derek T Larson, Simon Pollett, Anuradha Ganesan, Rupal M. Mody, Charlotte A. Lanteri, Rhonda E Colombo, Katrin Mende, Tahaniyat Lalani, David R. Tribble, Gregory Utz, Stephanie A Richard, Timothy Burgess, Mark P Simons, Anthony C. Fries, David A Lindholm, Brian K. Agan, Paul W Blair, Edward Parmelee, Cristian Madar, and Christopher J Colombo
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Gerontology ,Functional impairment ,Coronavirus disease 2019 (COVID-19) ,U s military ,business.industry ,COVID-19 ,predictive symptoms ,outcomes ,Major Articles ,burden ,AcademicSubjects/MED00290 ,Infectious Diseases ,Oncology ,Medicine ,business ,Organ system ,risk - Abstract
Background We evaluated clinical outcomes, functional burden, and complications 1 month after coronavirus disease 2019 (COVID-19) infection in a prospective US Military Health System (MHS) cohort of active duty, retiree, and dependent populations using serial patient-reported outcome surveys and electronic medical record (EMR) review. Methods MHS beneficiaries presenting at 9 sites across the United States with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, a COVID-19-like illness, or a high-risk SARS-CoV-2 exposure were eligible for enrollment. Medical history and clinical outcomes were collected through structured interviews and International Classification of Diseases–based EMR review. Risk factors associated with hospitalization were determined by multivariate logistic regression. Results A total of 1202 participants were enrolled. There were 1070 laboratory-confirmed SARS-CoV-2 cases and 132 SARS-CoV-2-negative participants. In the first month post–symptom onset among the SARS-CoV-2-positive cases, there were 212 hospitalizations, 80% requiring oxygen, 20 ICU admissions, and 10 deaths. Risk factors for COVID-19-associated hospitalization included race (increased for Asian, Black, and Hispanic compared with non-Hispanic White), age (age 45–64 and 65+ compared with Conclusions Older age, reporting Asian, Black, or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by 1 month.
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- 2021
28. Durability of SARS-CoV-2-Specific T-Cell Responses at 12 Months Postinfection
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Clifton L. Dalgard, Jarina Pena DaMata, Eric D Laing, Katherine Pohida, Camille Lake, Katrin Mende, Timothy Burgess, Batsukh Dorjbal, Anuradha Ganesan, Caroline English, Christopher C. Broder, Stephanie A Richard, David R. Tribble, Marana S Tso, Ryan C. Maves, David A Lindholm, Emily C Samuels, Zhongyan Lu, Charlotte A. Lanteri, Nusrat J. Epsi, Mark P Simons, Julia Rozman, Brian K. Agan, Christopher J Colombo, Simon Pollett, Andrew L. Snow, Paul W Blair, Josh Chenoweth, Rhonda E Colombo, Allison M. W. Malloy, and Nikhil Huprikar
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Adult ,Male ,Time Factors ,T cell ,Antibodies, Viral ,Severity of Illness Index ,Memory T Cells ,Major Articles and Brief Reports ,Immune system ,Immunity ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Longitudinal Studies ,Prospective Studies ,Prospective cohort study ,Antigens, Viral ,Immunity, Cellular ,biology ,business.industry ,SARS-CoV-2 ,COVID-19 ,Middle Aged ,Phenotype ,Infectious Diseases ,medicine.anatomical_structure ,Immunology ,biology.protein ,Female ,Antibody ,business ,Cytometry ,Immunologic Memory ,Biomarkers - Abstract
Background Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2–specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions. Methods We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2–specific antibodies. Results SARS-CoV-2–specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2–specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. Conclusions SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.
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- 2021
29. Durability of SARS-CoV-2-specific T cell responses at 12-months post-infection
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Clifton L. Dalgard, Marana S Tso, Camille Lake, Nikhil Huprikar, Christopher J Colombo, Eric D Laing, Josh Chenoweth, Katherine Pohida, Katrin Mende, Jarina Pena-Damata, Anuradha Ganesan, Allison M. W. Malloy, Andrew L. Snow, Ryan C. Maves, Simon Pollett, Zhongyan Lu, David R. Tribble, David A Lindholm, Nusrat J. Epsi, Julia Rozman, Brian K. Agan, Emily C Samuels, Charlotte A. Lanteri, Stephanie A Richard, Paul W Blair, Timothy Burgess, Mark P Simons, Batsukh Dorjbal, Caroline English, Rhonda E Colombo, and Christopher C. Broder
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biology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,T cell ,Phenotype ,Immune system ,medicine.anatomical_structure ,Immunology ,biology.protein ,Medicine ,Cytotoxic T cell ,Antibody ,Prospective cohort study ,business ,Cytometry - Abstract
BackgroundCharacterizing the longevity and quality of cellular immune responses to SARS-CoV-2 is critical to understanding immunologic approaches to protection against COVID-19. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Further analysis of the function, durability, and diversity of the cellular response long after natural infection, over a wider range of ages and disease phenotypes, is needed to further identify preventative and therapeutic interventions.MethodsWe identified participants in our multi-site longitudinal, prospective cohort study 12-months post SARS-CoV-2 infection representing a range of disease severity. We investigated the function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry. In parallel, the magnitude of SARS-CoV-2-specific antibodies was compared.ResultsSARS-CoV-2-specific antibodies and T cells were detected at 12-months post-infection. Severity of acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12-months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity.ConclusionsOur data show that SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12-months post-infection, with higher frequency noted in those who originally experienced severe disease.
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- 2021
30. Predictive Value of an Age-Based Modification of the National Early Warning System in Hospitalized Patients With COVID-19
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Kyle Everson, Nusrat J. Epsi, Anuradha Ganesan, Sharon Chi, Brian K. Agan, Derek T Larson, Paul W Blair, Rhonda E Colombo, Christopher J Colombo, Steffen Lis, David A Lindholm, Christian C. Conlon, Stephanie A Richard, Ryan C Maves, Timothy Burgess, and Simon Pollett
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medicine.medical_specialty ,Infectious Diseases ,Oncology ,Coronavirus disease 2019 (COVID-19) ,Hospitalized patients ,business.industry ,Emergency medicine ,education ,Early warning system ,Medicine ,business ,Predictive value ,Major Articles - Abstract
Background Early recognition of high-risk patients with coronavirus disease 2019 (COVID-19) may improve outcomes. Although many predictive scoring systems exist, their complexity may limit utility in COVID-19. We assessed the prognostic performance of the National Early Warning Score (NEWS) and an age-based modification (NEWS+age) among hospitalized COVID-19 patients enrolled in a prospective, multicenter US Military Health System (MHS) observational cohort study. Methods Hospitalized adults with confirmed COVID-19 not requiring invasive mechanical ventilation at admission and with a baseline NEWS were included. We analyzed each scoring system’s ability to predict key clinical outcomes, including progression to invasive ventilation or death, stratified by baseline severity (low [0–3], medium [4–6], and high [≥7]). Results Among 184 included participants, those with low baseline NEWS had significantly shorter hospitalizations (P Conclusions NEWS and NEWS+age showed similar test characteristics in an MHS COVID-19 cohort. Notably, low baseline scores had an excellent negative predictive value. Given their easy applicability, these scoring systems may be useful in resource-limited settings to identify COVID-19 patients who are unlikely to progress to critical illness.
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- 2021
31. Rickettsioses and Q Fever in Tanzania: Estimating the Burden of Pervasive and Neglected Causes of Severe Febrile Illness in Sub-Saharan Africa
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Paul W. Blair, Mohammed Lamorde, and J. Stephen Dumler
- Subjects
Causality ,Infectious Diseases ,Fever ,Virology ,Humans ,Rickettsia Infections ,Parasitology ,Q Fever ,Tanzania - Published
- 2022
32. Delayed rise of oral fluid antibodies, elevated BMI, and absence of early fever correlate with longer time to SARS-CoV-2 RNA clearance in a longitudinally sampled cohort of COVID-19 outpatients
- Author
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Yukari C. Manabe, Abhinaya Ganesan, Rebecca L. Ursin, Weiwei Dai, Andrea L. Cox, Kirsten Littlefield, Derek T. Armstrong, Christine Payton, Jaylynn R Johnstone, Lauren Sauer, Oyinkansola T. Kusemiju, Andrew Pekosz, Jeffrey A. Tornheim, Paul W Blair, Joelle Fuchs, Han-Sol Park, Chen Hu, Sara C. Keller, Minyoung Jang, Carolyn Reuland, Nora Pisanic, Curtisha Charles, Kate Kruczynski, Razvan Azamfirei, Jeanne C. Keruly, Sabra L. Klein, Shruti H. Mehta, Mei Cheng Wang, David L. Thomas, Christopher D. Heaney, Vismaya S Bachu, Guido Massaccesi, Samantha N Walch, Taylor Church, Heba H. Mostafa, Annukka A.R. Antar, Brittany Barnaba, Diane M. Brown, Zoe Demko, Thelio T Sewell, Jennifer Townsend, Michelle Prizzi, Justin Hardick, and Tong Yu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,viruses ,RT-PCR ,medicine.disease_cause ,Gastroenterology ,Article ,03 medical and health sciences ,Immune system ,0302 clinical medicine ,Interquartile range ,Internal medicine ,antibody ,medicine ,Major Article ,030212 general & internal medicine ,Coronavirus ,biology ,Proportional hazards model ,Viral culture ,business.industry ,SARS-CoV-2 ,RNA ,COVID-19 ,viral RNA ,Reverse transcription polymerase chain reaction ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Real-time polymerase chain reaction ,AcademicSubjects/MED00290 ,Oncology ,Concomitant ,Cohort ,biology.protein ,Antibody ,business ,Respiratory tract - Abstract
BackgroundSustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection.MethodsNinety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1–3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models.ResultsViral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17–63.5) days post–symptom onset. Sixteen nasal-OP samples collected 2–11 days post–symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8–13 days post–symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92–0.99; P = .020) and body mass index (BMI) ≥25 kg/m2 (aHR, 0.37; 95% CI, 0.18–0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02–4.18; P = .044).ConclusionsWe demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance.
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- 2021
33. Clustering of SARS-CoV-2 infections in households of patients diagnosed in the outpatient setting in Baltimore, MD
- Author
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Anastasia S. Lambrou, Annukka A.R. Antar, David L. Thomas, Shruti H. Mehta, Covid Study Team Ambulatory, Zoe Demko, Diane M. Brown, Heba H. Mostafa, Tong Yu, Jeanne C. Keruly, Derek T. Armstrong, Paul W Blair, Samantha N Walch, and Yukari C. Manabe
- Subjects
medicine.medical_specialty ,2019-20 coronavirus outbreak ,Pediatrics ,Household contact ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,household contact ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Epidemiology ,Outpatient setting ,Medicine ,030212 general & internal medicine ,0101 mathematics ,skin and connective tissue diseases ,business.industry ,SARS-CoV-2 ,Brief Report ,010102 general mathematics ,fungi ,virus diseases ,COVID-19 ,respiratory tract diseases ,body regions ,Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,Cohort ,epidemiology ,business ,Bedroom - Abstract
In an outpatient cohort in Maryland, clustering of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity within households was high, with 76% of 74 households reporting at least 1 other symptomatic person and 66% reporting another person who tested SARS-CoV-2 positive. SARS-CoV-2 positivity among household members was associated with larger household size and bedroom sharing.
- Published
- 2021
34. Differential Cytokine Signatures of SARS-CoV-2 and Influenza Infection Highlight Key Differences in Pathobiology
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Leon L. Hsieh, Andrea L. Cox, Nada Alachkar, Ramy El-Diwany, Lauren Sauer, Paul W Blair, Sherry Leung, Kathryn Shaw-Saliba, Weiqiang Zhou, Hongkai Ji, Alexis Figueroa, Andrew H. Karaba, Katherine Z.J. Fenstermacher, Russell Wesson, Richard E. Rothman, and Guido Massaccesi
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Chemokine ,Innate immune system ,biology ,business.industry ,medicine.medical_treatment ,Inflammation ,Subgroup analysis ,macromolecular substances ,Proinflammatory cytokine ,Mediator ,Cytokine ,Immunology ,medicine ,biology.protein ,medicine.symptom ,Risk factor ,business - Abstract
BackgroundSeveral inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease.MethodsThirty-seven cytokines and chemokines were measured in plasma from 145 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI on disease severity.ResultsIL-18, IL-1β, IL-6, and TNF-α were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-γ, IFN-λ1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity.ConclusionsThese findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.SummarySevere COVID-19 is marked by dysregulated inflammation and is associated with elevated BMI. By comparing cytokines and chemokines in patients with either COVID-19 or influenza, we identified distinct inflammatory pathways and a cytokine mediator of the effect of BMI.
- Published
- 2021
35. Tocilizumab for the Treatment of COVID-19 Among Hospitalized Patients: A Matched Retrospective Cohort Analysis
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Michael T. Melia, Tania Jain, Natasha Chida, Zishan K. Siddiqui, Robin K. Avery, Matthew L Robinson, Kunbo Wang, Brian T. Garibaldi, Brent G. Petty, Andrew H. Karaba, Paul W Blair, Paul G. Auwaerter, Yanxun Xu, and Elisa H. Ignatius
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Secondary infection ,retrospective ,030204 cardiovascular system & hematology ,Major Articles ,03 medical and health sciences ,chemistry.chemical_compound ,tocilizumab ,0302 clinical medicine ,Tocilizumab ,Internal medicine ,medicine ,030212 general & internal medicine ,Interleukin 6 ,IL-6 ,biology ,Proportional hazards model ,business.industry ,SARS-CoV-2 ,Hazard ratio ,COVID-19 ,Retrospective cohort study ,Editor's Choice ,Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,chemistry ,biology.protein ,Observational study ,business - Abstract
Background There is currently no single treatment that mitigates all harms caused by severe acute respiratory syndrome coronavirus 2 infection. Tocilizumab, an interleukin-6 antagonist, may have a role as an adjunctive immune-modulating therapy. Methods This was an observational retrospective study of hospitalized adult patients with confirmed coronavirus disease 2019 (COVID-19). The intervention group comprised patients who received tocilizumab; the comparator arm was drawn from patients who did not receive tocilizumab. The primary outcome was all-cause mortality censored at 28 days; secondary outcomes were all-cause mortality at discharge, time to clinical improvement, and rates of secondary infections. Marginal structural Cox models via inverse probability treatment weights were applied to estimate the effect of tocilizumab. A time-dependent propensity score–matching method was used to generate a 1:1 match for tocilizumab recipients; infectious diseases experts then manually reviewed these matched charts to identify secondary infections. Results This analysis included 90 tocilizumab recipients and 1669 controls. Under the marginal structural Cox model, tocilizumab was associated with a 62% reduced hazard of death (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.21 to 0.70) and no change in time to clinical improvement (aHR, 1.13; 95% CI, 0.68 to 1.87). The 1:1 matched data set also showed a lower mortality rate (27.8% vs 34.4%) and reduced hazards of death (aHR, 0.47; 95% CI, 0.25 to 0.88). Elevated inflammatory markers were associated with reduced hazards of death among tocilizumab recipients compared with controls. Secondary infection rates were similar between the 2 groups. Conclusions Tocilizumab may provide benefit in a subgroup of patients hospitalized with COVID-19 who have elevated biomarkers of hyperinflammation, without increasing the risk of secondary infection., In this retrospective study of adult patients hospitalized with COVID-19, tocilizumab was associated with a 62% reduction in hazard of death. Tocilizumab may have a role as adjunctive therapy for COVID-19 among patients with hyperinflammation including elevated IL-6.
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- 2020
36. Durable SARS-CoV-2 B cell immunity after mild or severe disease
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Andrew Pekosz, Sabra L. Klein, Abhinaya Ganesan, Kirsten Littlefield, Andrea L. Cox, Annukka A.R. Antar, Han Sol Park, Santosh Dhakal, Michael J. Betenbaugh, Yukari C. Manabe, Stuart C. Ray, Clinton O. Ogega, Nicole E. Skinner, Justin R. Bailey, Paul W Blair, and Pranay Ladiwala
- Subjects
Male ,0301 basic medicine ,memory B cell ,Time Factors ,Disease ,Antibodies, Viral ,Severity of Illness Index ,Cohort Studies ,0302 clinical medicine ,Medicine ,Memory B cell ,Neutralizing antibody ,skin and connective tissue diseases ,B-Lymphocytes ,Immunity, Cellular ,biology ,neutralizing antibody ,General Medicine ,Middle Aged ,Acquired immune system ,Vaccination ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,Female ,Antibody ,Research Article ,Adult ,Virus ,Article ,03 medical and health sciences ,Immunity ,Humans ,Pandemics ,B cell ,Aged ,Binding Sites ,SARS-CoV-2 ,business.industry ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Antibodies, Neutralizing ,Immunoglobulin Class Switching ,030104 developmental biology ,Case-Control Studies ,Immunology ,Humoral immunity ,biology.protein ,business ,Immunologic Memory - Abstract
Multiple studies have shown loss of SARS-CoV-2 specific antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from COVID-19. However, memory B cells (MBC) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multi-dimensional flow cytometric analysis of S protein receptor binding domain (S-RBD)-specific MBC in cohorts of ambulatory COVID-19 patients with mild disease, and hospitalized patients with moderate to severe disease, at a median of 54 (39–104) days after onset of symptoms. We detected S-RBD-specific class-switched MBC in 13 out of 14 participants, including 4 of the 5 participants with lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBC (rMBC) made up the largest proportion of S-RBD-specific class-switched MBC in both cohorts. FCRL5, a marker of functional memory when expressed on rMBC, was dramatically upregulated on S-RBD-specific rMBC. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched MBC that phenotypically resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after recovery from mild or severe COVID-19 disease., Graphical Abstract
- Published
- 2020
37. High-value laboratory testing for hospitalized COVID-19 patients: a review
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Andrea L. Cox, Nisha A. Gilotra, Kieren A. Marr, Matthew L Robinson, Wendy S. Post, Daniela Cihakova, Annukka A.R. Antar, Teresa K. Chen, Paul W Blair, Andrew H. Karaba, Michael B. Streiff, Steven Menez, Erin D. Michos, and Maria Veronica Dioverti
- Subjects
medicine.medical_specialty ,Hematology ,biology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Troponin ,Intensive care unit ,Laboratory testing ,law.invention ,Laboratory test ,law ,Virology ,Internal medicine ,D-dimer ,Emergency medicine ,biology.protein ,medicine ,Etiology ,business - Abstract
We present here an evidence-based review of the utility, timing, and indications for laboratory test use in the domains of inflammation, cardiology, hematology, nephrology and co-infection for clinicians managing the care of hospitalized COVID-19 patients. Levels of IL-6, CRP, absolute lymphocyte count, neutrophils and neutrophil-to-lymphocyte ratio obtained upon admission may help predict the severity of COVID-19. Elevated lactate dehydrogenase, ferritin, aspartate aminotransferase, and ᴅ-dimer are associated with severe illness and mortality. Elevated cardiac troponin at hospital admission can alert clinicians to patients at risk for cardiac complications. Elevated proBNP may help distinguish a cardiac complication from noncardiac etiologies. Evaluation for co-infection is typically unnecessary in nonsevere cases but is essential in severe COVID-19, intensive care unit patients, and immunocompromised patients.
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- 2020
38. Intensive Care Unit-Like Care of Nonhuman Primates with Ebola Virus Disease
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James J Sola, Perry D Wiseman, Joseph Henry, Jay Wells, Joshua L. Moore, Christopher W. Schellhase, Xiankun Zeng, Jeremy J Bearss, Kelly S. Stuthman, Luis A. Lugo-Roman, Jennifer Kalapaca, Darrel Wetzel, Elliot Ramos-Rivera, Annie Madar, William D. Pratt, Veronica Soloveva, Ginger Donnelly, Lydia G Downey, Tami Unangst, Nicole L. Garza, Adele Miller, Jesse T. Steffens, Janice A. Williams, Anthony P. Cardile, Mark G. Kortepeter, Paul W Blair, Isaac L Downs, Mark A. Chappell, Ronald B. Reisler, Franco Rossi, Shannon T Marko, Christian Hofer, Jimmy O. Fiallos, Sean A. Vantongeren, Eugene Blue, Cristian Madar, Karen A. Martins, and Sina Bavari
- Subjects
0301 basic medicine ,Primates ,medicine.medical_specialty ,Critical Care ,Disease ,medicine.disease_cause ,law.invention ,03 medical and health sciences ,Major Articles and Brief Reports ,0302 clinical medicine ,law ,Internal medicine ,Intensive care ,medicine ,Immunology and Allergy ,Animals ,030212 general & internal medicine ,Mononegavirales ,Retrospective Studies ,Ebola virus ,biology ,business.industry ,Hazard ratio ,Hemorrhagic Fever, Ebola ,biology.organism_classification ,Ebolavirus ,Intensive care unit ,Macaca mulatta ,Disease Models, Animal ,Intensive Care Units ,030104 developmental biology ,Infectious Diseases ,Blood pressure ,Observational study ,business - Abstract
BackgroundEbola virus disease (EVD) supportive care strategies are largely guided by retrospective observational research. This study investigated the effect of EVD supportive care algorithms on duration of survival in a controlled nonhuman primate (NHP) model.MethodsFourteen rhesus macaques were challenged intramuscularly with a target dose of Ebola virus (1000 plaque-forming units; Kikwit). NHPs were allocated to intensive care unit (ICU)–like algorithms (n = 7), intravenous fluids plus levofloxacin (n = 2), or a control group (n = 5). The primary outcome measure was duration of survival, and secondary outcomes included changes in clinical laboratory values.ResultsDuration of survival was not significantly different between the pooled ICU-like algorithm and control groups (8.2 vs 6.9 days of survival; hazard ratio; 0.50; P = .25). Norepinephrine was effective in transiently maintaining baseline blood pressure. NHPs treated with ICU-like algorithms had delayed onset of liver and kidney injury.ConclusionsWhile an obvious survival difference was not observed with ICU-like care, clinical observations from this model may aid in EVD supportive care NHP model refinement.
- Published
- 2020
39. 508. Biomarker elevation during COVID-19: Differences between ambulatory and hospitalized individuals
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Paul W Blair, Charlotte Lanteri, Deborah Striegel, Brian Agan, Ryan C Maves, Josh Chenoweth, Derek Larson, Katrin Mende, Rhonda Colombo, David Lindholm, Anuradha Ganesan, Stephanie Richard, Chris Colombo, Cristian Madar, Nikhil Huprikar, David Tribble, John S Dumler, Timothy Burgess, and Danielle Clark
- Subjects
medicine.medical_specialty ,biology ,business.industry ,Separation (statistics) ,Intensive care unit ,Procalcitonin ,law.invention ,Ferritin ,AcademicSubjects/MED00290 ,Infectious Diseases ,Oncology ,law ,Relative risk ,Internal medicine ,Poster Abstracts ,Ambulatory ,Cohort ,biology.protein ,Medicine ,Biomarker (medicine) ,business - Abstract
Background While the majority of illness due to COVID-19 does not require hospitalization, little has been described about the host inflammatory response in the ambulatory setting. Differences in the levels of inflammatory signaling proteins between outpatient and hospitalized populations could identify key maladaptive immune responses during COVID-19. Methods Samples were collected from 76 participants (41% female, mean 46.8 years of age) enrolled at five military treatment facilities between March 20, 2020 and June 17, 2020 in an ongoing prospective COVID-19 cohort. This analysis was restricted to those with positive SARS-CoV-2 (severe acute respiratory syndrome–coronavirus 2) RT-PCR testing and included hospitalized (N=29; 10 requiring an ICU stay) and non-hospitalized (N=43) participants. Severity markers (IL6, D-dimer, procalcitonin, ferritin, ICAM-1, IL5, lipocalin, RAGE, TNFR, VEGFA, IFNγ, IL1β) were measured in plasma (mg/dL) using the Ella immunoassay and natural log transformed. Univariate negative binomial regression was performed to determine relative risk of hospitalization. Using the full marker panel, we performed a Principal Component Analysis (PCA) to determine directions of maximal variance in the data. Pearson’s correlation coefficient was determined between analytes and each axis. Results Participants requiring ambulatory-, hospital-, and ICU-level care had samples collected at 44.0 (IQR: 35.0–51.0), 40.0 (13.0–51.0), and 47.5 (21.0–54.0) days, respectively. Higher unadjusted levels of IL6, D-dimer, procalcitonin, or ferritin were each associated with hospitalization (Table 1). The PCA showed a separation along axes between level of care and duration of symptoms (Fig 1). While significant correlations were noted with a number of biomarkers, PC1 most correlated with TNFR1 (r=0.88) and PC2 most correlated with IL6Ra (r=0.95). PC1 axis variation accounted for 36.5% of variance and the PC2 axis accounted for 20.0% of variance. Figure 1. Principal Component Analysis (PCA) of biomarkers by level of care and symptom duration. Conclusion TNFR1 and IL6Ra levels correlated with differences in the proinflammatory states between hospitalized and non-hospitalized individuals including time points late in the course of illness. Further analysis of these preliminary findings is needed to evaluate for differences by stages of illness. Disclosures All Authors: No reported disclosures
- Published
- 2020
40. The Effects of a Systemwide Diagnostic Stewardship Change on West Nile Virus Disease Ordering Practices
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Mustapha Saheed, Kevin Martin, Karen C. Carroll, Michael J. Borowitz, Andrew H. Karaba, and Paul W Blair
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0301 basic medicine ,medicine.medical_specialty ,West Nile virus ,business.industry ,Brief Report ,viral diagnostics ,030106 microbiology ,viral encephalitis ,Disease ,medicine.disease_cause ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,Oncology ,Electronic health record ,medicine ,Nucleic Acid Amplification Tests ,030212 general & internal medicine ,Stewardship ,Intensive care medicine ,business ,health care economics and organizations - Abstract
We report that removing the clinically insensitive West Nile virus CSF nucleic acid amplification test (NAAT) from the electronic health record (EHR) test menu decreased costs and may have improved diagnostic yield. Removing high-cost, low yield tests from the EHR can be an effective diagnostic stewardship intervention.
- Published
- 2019
41. 776. The prevalence of HIV among hospitalized persons with acute febrile illness in rural Uganda, August 2019-June 2020
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Matthew L Robinson, Mohammed Lamorde, Gilbert Aniku, Francis Kakooza, Alphonsus Matovu, Emmanuel Candia, Kenneth Kobba, Richard Walwema, Paul W Blair, and Yukari C. Manabe
- Subjects
Tuberculosis ,medicine.diagnostic_test ,business.industry ,Human immunodeficiency virus (HIV) ,Hepatitis A ,Hepatitis B ,medicine.disease ,medicine.disease_cause ,Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,Environmental health ,Poster Abstracts ,Coinfection ,medicine ,Blood culture ,Lost to follow-up ,business ,Malaria - Abstract
Background In Uganda, in the early PEPFAR era, HIV coinfections were responsible for most hospitalizations with febrile illness (as high as 85% in 2006). Currently, national guidelines recommend universal antiretroviral therapy ideally before the development of AIDS. We evaluated the prevalence of HIV among patients admitted to two regional referral hospitals with febrile illness in the era of ‘Treat All.’ Methods Participants admitted to two regional referral hospitals in Uganda were enrolled at emergency departments or medical wards. Participants uniformly received blood cultures, malaria (rapid diagnostic test), and tuberculosis (Xpert MTB/RIF Ultra), hepatitis A IgM, hepatitis B sAg, and HIV fourth generation testing were performed. Among participants with HIV, cryptococcal antigen testing and urine lipoarabinomannan (LAM) were performed. Results From August 2019-June 2020, 95 participants (58% female) with an average age of 36.2 (SD 14.1) years, presented from 11 districts in Uganda. Participants presented at facilities 4.9 days (SD: 2.5) after onset of symptoms. Additionally, 16.1% of participants had a qSOFA (quick Sepsis Related Organ Failure Assessment) severity score of 2 or greater. By 28 days, 11.0% (n=7) died and 10.8% were lost to follow-up. On admission, 25.3% (n=24) of participants had a known history of HIV, the majority (87.5%) were on ART on hospital presentation. Of the 9.5% (n=9) who were newly diagnosed with HIV during the admission 6 were started on ART during hospitalization or within a month after hospitalization. Microbiologic and rapid diagnostic test results included positive results for tuberculosis (2.1%, 2/95 PCR; 3/16 urine LAM), malaria (29.5%, 28/95), cryptococcal antigen positive (12.5%; 2/15), hepatitis A (1.1%, 1/95), and hepatitis B (5.3%, 5/95). Blood cultures were positive in 11.1% of patients (10/90) with S. pneumoniae being most common isolate (N=4). Conclusion In the universal ART era, the proportion of hospitalized febrile patients with HIV has decreased. Overall, 10% have newly diagnosed infection emphasizing the importance of continuing to test all hospitalized febrile patients. Diagnostic evaluations are needed to assess the burden of other causes of febrile illness in order to reprioritize potential differential diagnoses. Disclosures All Authors: No reported disclosures
- Published
- 2020
42. Mycobacterium fortuitum empyema associated with an indwelling pleural catheter: Case report and review of the literature
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Mahdi Moshgriz, Marc O. Siegel, and Paul W Blair
- Subjects
Lung Diseases ,Male ,0301 basic medicine ,Microbiology (medical) ,Pathology ,medicine.medical_specialty ,030106 microbiology ,Mycobacterium Infections, Nontuberculous ,Pulmonary disease ,03 medical and health sciences ,Catheters, Indwelling ,0302 clinical medicine ,medicine ,Humans ,Pharmacology (medical) ,Empyema ,Respiratory Tract Infections ,Aged ,Cross Infection ,biology ,Respiratory tract infections ,Mycobacterium fortuitum ,business.industry ,biochemical phenomena, metabolism, and nutrition ,equipment and supplies ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,respiratory tract diseases ,Infectious Diseases ,030228 respiratory system ,Catheter-Related Infections ,Pleura ,bacteria ,Pleural catheter ,Sputum ,Indwelling pleural catheter ,medicine.symptom ,business ,Mycobacterium - Abstract
Mycobacterium fortuitum is a rapidly growing mycobacterium (RGM) that is an uncommon cause of healthcare-associated infections. The most common infections caused by M. fortuitum include skin, soft tissue, and catheter-related infections. Although occasionally cultured from sputum samples, M. fortuitum is a rare cause of pulmonary disease. We report a case of M. fortuitum empyema associated with an infected pleural catheter and review M. fortuitum pulmonary infections.
- Published
- 2017
43. 411. Does an Early Cytokine Response During Ebola Virus Disease Improve the Duration of Survival in Rhesus Macaques?
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Paul W Blair, Isaac L Downs, Mark G. Kortepeter, Keebaugh Michael, Keshtkar-Jahromi Maryam, Anthony P. Cardile, and Karen A. Martins
- Subjects
Abstracts ,Infectious Diseases ,Ebola virus ,Oncology ,business.industry ,Immunology ,Poster Abstracts ,medicine ,Disease ,Duration (project management) ,medicine.disease_cause ,business ,Cytokine response - Abstract
Background Ebola virus disease results in a severe cytokine release resulting in organ failure and disseminated intravascular coagulation, often leading to death. An early post-exposure immune response may improve outcomes but that remains poorly characterized. Therefore, we evaluated select serum cytokine markers of immune activation in nonhuman primates (NHPs) for their association with duration of survival. Methods This was a post-hoc analysis of an interventional supportive care NHP study in which 13 rhesus macaques were inoculated intramuscularly with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). We measured cytokines with a Luminex MAGPIX panel at baseline and daily starting day 3 post-exposure until euthanasia. Based on human clinical data, 10 cytokines and proteins were included in our analysis: IL-1ra, IL-6, IL-10, GM-CSF, MCP-1, MIP-1α, MIP-1β, IFN-γ, TNF-α, and C-reactive protein levels. After NHPs were divided into two groups by k-means clustering, we developed Kaplan–Meier curves for time to death (Figure 1). We visually explored Pearson’s correlation and kinetics of serum cytokines and log10viral load (Figure 1; Figure 2). We fitted cox regression models with each cytokine to evaluate the risk of early disease for each cytokine log10 level or log2-fold change. We performed a sensitivity analysis for MIP-1β centering the data at dpe 0. Results Among NHPs with temperature data, 83% (N = 10) developed fevers (>3 SD baseline) from dpe 3 to 4.The macrophage markerMIP-1β was associated with an increased risk of early death (per log10pg/mL increase, HR= 52.83 at dpe 3, adjusted P = 0.045). Surprisingly, this association was also observed at dpe 0 (HR= 36.88 at dpe 0, adjusted P = 0.044). Other cytokine levels or changes were not associated with an increased hazard of death. Conclusion Our findings did not support a role for early systemic cytokine release in improving survival. However, elevated baseline levels of the MIP-1β may predispose NHPs to early death from EVD. This finding could represent a target for therapeutic strategies and should be further researched. Disclosures All authors: No reported disclosures.
- Published
- 2019
44. 1787. The Effects of a Systemwide Diagnostic Stewardship Change on West Nile Virus Disease Ordering Practices
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Andrew H Karaba, Paul W Blair, Kevin M Martin, Mustapha O Saheed, Karen C Carroll, and Mike J Borowitz
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Abstracts ,Infectious Diseases ,Oncology ,Poster Abstracts - Abstract
Background Neuroinvasive West Nile Virus (WNV) often leads to prolonged neurological deficits and carries a high case fatality rate. The CSF IgM (MAC-ELISA) is preferred over the CSF nucleic acid-based test (NAAT) by the CDC due to its higher sensitivity. However, our hospital system was observed to have an over-utilization of NAAT testing compared with MAC-ELISA testing. The primary objective was to compare the number of MAC-ELISA and NAAT WNV tests ordered before and after a diagnostic stewardship intervention. The secondary objectives were to determine whether this change to lead to any cost savings and increased detection of probable cases of WNV-ND. Methods In an effort to increase the use of the MAC-ELISA and to decrease unnecessary NAAT testing, the NAAT test was removed in April 2018 from the test menu in the electronic health record of a health system comprising five hospitals in the Maryland and Washington, D.C. area. NAAT testing remained possible via a paper order form. This study was a retrospective review of WNV testing done on CSF samples from July 2016 through December 2018. The seasonal and yearly number of total tests, positive tests, and total costs were determined from the period of July, 2017 to April, 2018 and were compared with May, 2018 to January, 2019. A paired t-test was performed to evaluate for differences in total testing, total positives, and total costs during non-winter months before and after the intervention. Results A total of 12.59 MAC-ELISA tests/month (95% CI: 10.29, 14.89) increased to 41 tests/month (95% CI: 34.35, 47.65) which was significantly different (P < 0.001). In contrast, there were 46.23 NAAT tests/month (95% CI: 39.55, 52.91) which decreased to 0 NAAT tests/month after the intervention (P < 0.001). This resulted in an average decrease in WNV test spending from $7200 per month to $471 per month (P < 0.001). Preceding the intervention in test ordering, 0.23% of WNV CSF tests were positive (NAAT+MAC-ELISA) while 2.44% WNV CSF tests were positive after the intervention (P = 0.03). Conclusion Elimination of electronic WNV NAAT ordering is an effective way of decreasing inappropriate WNV NAAT testing, decreasing associated costs, and may lead to improved diagnosis of WNV-ND. Disclosures All authors: No reported disclosures.
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- 2019
45. 2493. Marburg Virus Disease: Virulence of Angola vs. Musoke Strain in Cynomolgus Macaques
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Kevin J. Psoter, Maryam Keshtkar-Jahromi, Anthony P. Cardile, and Paul W Blair
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Abstracts ,Infectious Diseases ,B. Poster Abstracts ,Oncology ,Marburg virus disease ,business.industry ,Strain (biology) ,Virulence ,Medicine ,business ,Virology - Abstract
Background From 2004 to 2005, an outbreak of Marburg virus, a filovirus, in Angola led to a case-fatality rate of 90 percent. However, little information is available regarding the virulence of the Angola strain from this outbreak compared with the virulence of other strains. Therefore, we sought to assess time to selected outcomes in non-human primates (NHPs) experimentally infected with either Angola or Musoke Marburg strains. Methods Between 2012 and 2017, nine therapeutic trials at the US Army Medical Research Institute of Infectious Diseases were conducted in Macaca fascicularis monkeys challenged with 1 to 10,000 plaque forming units of Marburg virus administered intramuscularly. The current study population was comprised of 90 control NHPs, of which, 61 were administered Angola strain in four separate trials and 29 with Musoke strain in five trials. Clinical responses including development of rash and oral intake were collected following infection. The primary outcome of interest was time to death or euthanasia post-inoculation between strains evaluated using Cox proportional hazards regression. Secondary endpoints included time to development of a petechial rash and time to decreased appetite. Results Following Marburg virus challenge, all NHPs died and most NHPs experienced decreased food consumption (97%), and petechial rash (96%). The median time to death for Angola-infected NHPs was 8.9 days (25th, 75th percentiles: 7.9, 9.3), whereas Musoke-infected NHPs survived for a median of 10.0 days (25th, 75th percentiles: 9.0, 10.9) (Figure 1). Irrespective of strain, petechial rash was preceded by decreased food consumption by 0.7 days (SD 1.5) on average. Angola strain was associated with statistically significant earlier death (adjusted HR = 21.8; 95% CI: 8.9, 53.2), earlier development of petechiae (adjusted HR = 17.6; 95% CI: 7.0, 44.5) and earlier loss of appetite (adjusted HR = 5.8; 95% CI: 2.9,11.7). Conclusion This was the first study to compare survival and clinical characteristics in NHPs between these strains. Despite sharing the similar genetic lineage, our data strongly supports increased virulence of Angola strain compared with Musoke strain. Pathophysiological mechanisms involved in increased virulence require further study. Disclosures All authors: No reported disclosures.
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- 2018
46. Screening tools for predicting mortality of adults with suspected sepsis: an international sepsis cohort validation study
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Christopher W Woods, Daniel Ansong, Emily Ko, George Oduro, Nehkonti Adams, Andrew Letizia, Charmagne Beckett, Mark G Salvador, William R Hulsey, James V Lawler, Kevin L Schully, Paul W Blair, Rittal Mehta, Chris Kwaku Oppong, Som Tin, Ephraim L Tsalik, Josh Chenoweth, Michelle Rozo, Deborah A Striegel, Joost Brandsma, Lauren McKean, Rachael E Mahle, Subramaniam Krishnan, Michael Prouty, Anne Fox, Dennis Faix, Chris Duplessis, Michael G Gregory, Te Vantha, Alex Kwame Owusu-Ofori, and Danielle V Clark
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Medicine - Abstract
Objectives We evaluated the performance of commonly used sepsis screening tools across prospective sepsis cohorts in the USA, Cambodia and Ghana.Design Prospective cohort studies.Setting and participants From 2014 to 2021, participants with two or more SIRS (Systemic Inflammatory Response Syndrome) criteria and suspected infection were enrolled in emergency departments and medical wards at hospitals in Cambodia and Ghana and hospitalised participants with suspected infection were enrolled in the USA. Cox proportional hazards regression was performed, and Harrell’s C-statistic calculated to determine 28-day mortality prediction performance of the quick Sequential Organ Failure Assessment (qSOFA) score ≥2, SIRS score ≥3, National Early Warning Score (NEWS) ≥5, Modified Early Warning Score (MEWS) ≥5 or Universal Vital Assessment (UVA) score ≥2. Screening tools were compared with baseline risk (age and sex) with the Wald test.Results The cohorts included 567 participants (42.9% women) including 187 participants from Kumasi, Ghana, 200 participants from Takeo, Cambodia and 180 participants from Durham, North Carolina in the USA. The pooled mortality was 16.4% at 28 days. The mortality prediction accuracy increased from baseline risk with the MEWS (C-statistic: 0.63, 95% CI 0.58 to 0.68; p=0.002), NEWS (C-statistic: 0.68; 95% CI 0.64 to 0.73; p
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- 2023
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47. Assessing the use of a micro-sampling device for measuring blood protein levels in healthy subjects and COVID-19 patients.
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Joost Brandsma, Josh G Chenoweth, Melissa K Gregory, Subramaniam Krishnan, Paul W Blair, Deborah A Striegel, Rittal Mehta, Kevin L Schully, J Stephen Dumler, Cdr Cynthia S Sikorski, Kelsey O'Connor, Susan A Reichert-Scrivner, Carmen M Paguirigan, Catherine F T Uyehara, Col Viseth Ngauy, Christopher A Myers, and Danielle V Clark
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Medicine ,Science - Abstract
BackgroundVenous phlebotomy performed by trained personnel is critical for patient diagnosis and monitoring of chronic disease, but has limitations in resource-constrained settings, and represents an infection control challenge during outbreaks. Self-collection devices have the potential to shift phlebotomy closer to the point of care, supporting telemedicine strategies and virtual clinical trials. Here we assess a capillary blood micro-sampling device, the Tasso Serum Separator Tube (SST), for measuring blood protein levels in healthy subjects and non-hospitalized COVID-19 patients.Methods57 healthy controls and 56 participants with mild/moderate COVID-19 were recruited at two U.S. military healthcare facilities. Healthy controls donated Tasso SST capillary serum, venous plasma and venous serum samples at multiple time points, while COVID-19 patients donated a single Tasso SST serum sample at enrolment. Concentrations of 17 protein inflammatory biomarkers were measured in all biospecimens by Ella multi-analyte immune-assay.ResultsTasso SST serum protein measurements in healthy control subjects were highly reproducible, but their agreements with matched venous samples varied. Most of the selected proteins, including CRP, Ferritin, IL-6 and PCT, were well-correlated between Tasso SST and venous serum with little sample type bias, but concentrations of D-dimer, IL-1B and IL-1Ra were not. Self-collection at home with delayed sample processing was associated with significant concentrations differences for several analytes compared to supervised, in-clinic collection with rapid processing. Finally, Tasso SST serum protein concentrations were significantly elevated in in non-hospitalized COVID-19 patients compared with healthy controls.ConclusionsSelf-collection of capillary blood with micro-sampling devices provides an attractive alternative to routine phlebotomy. However, concentrations of certain analytes may differ significantly from those in venous samples, and factors including user proficiency, temperature control and time lags between specimen collection and processing need to be considered for their effect on sample quality and reproducibility.
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- 2022
- Full Text
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