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1.
Mol Ther Methods Clin Dev ; 26: 266-278, 2022 Sep 08.
Article in English | MEDLINE | ID: covidwho-1914874

ABSTRACT

Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p < 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19.

2.
PLoS One ; 17(5): e0268528, 2022.
Article in English | MEDLINE | ID: covidwho-1910646

ABSTRACT

There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes. We analyzed 6255 hospitalized individuals with PCR-confirmed SARS-CoV-2 infection from one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition. Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%. Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and residing in a low-income zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087). Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.


Subject(s)
COVID-19 , Aftercare , COVID-19/epidemiology , COVID-19/therapy , Hospitals , Humans , Patient Discharge , SARS-CoV-2
3.
JAMA Netw Open ; 5(6): e2216649, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1888477

ABSTRACT

Importance: COVID-19 vaccine uptake among urban populations remains low. Objective: To evaluate whether text messaging with outbound or inbound scheduling and behaviorally informed content might increase COVID-19 vaccine uptake. Design, Setting, and Participants: This randomized clinical trial with a factorial design was conducted from April 29 to July 6, 2021, in an urban academic health system. The trial comprised 16 045 patients at least 18 years of age in Philadelphia, Pennsylvania, with at least 1 primary care visit in the past 5 years, or a future scheduled primary care visit within the next 3 months, who were unresponsive to prior outreach. The study was prespecified in the trial protocol, and data were obtained from the intent-to-treat population. Interventions: Eligible patients were randomly assigned in a 1:20:20 ratio to (1) outbound telephone call only by call center, (2) text message and outbound telephone call by call center to those who respond, or (3) text message, with patients instructed to make an inbound telephone call to a hotline. Patients in groups 2 and 3 were concurrently randomly assigned in a 1:1:1:1 ratio to receive different content: standard messaging, clinician endorsement (eg, "Dr. XXX recommends"), scarcity ("limited supply available"), or endowment framing ("We have reserved a COVID-19 vaccine appointment for you"). Main Outcomes and Measures: The primary outcome was the proportion of patients who completed the first dose of the COVID-19 vaccine within 1 month, according to the electronic health record. Secondary outcomes were the completion of the first dose within 2 months and completion of the vaccination series within 2 months of initial outreach. Additional outcomes included the percentage of patients with invalid cell phone numbers (wrong number or nontextable), no response to text messaging, the percentage of patients scheduled for the vaccine, text message responses, and the number of telephone calls made by the access center. Analysis was on an intention-to-treat basis. Results: Among the 16 045 patients included, the mean (SD) age was 36.9 (11.1) years; 9418 (58.7%) were women; 12 869 (80.2%) had commercial insurance, and 2283 (14.2%) were insured by Medicaid; 8345 (52.0%) were White, 4706 (29.3%) were Black, and 967 (6.0%) were Hispanic or Latino. At 1 month, 14 of 390 patients (3.6% [95% CI, 1.7%-5.4%]) in the outbound telephone call-only group completed 1 vaccine dose, as did 243 of 7890 patients (3.1% [95% CI, 2.7%-3.5%]) in the text plus outbound call group (absolute difference, -0.5% [95% CI, -2.4% to 1.4%]; P = .57) and 253 of 7765 patients (3.3% [95% CI, 2.9%-3.7%]) in the text plus inbound call group (absolute difference, -0.3% [95% CI, -2.2% to 1.6%]; P = .72). Among the 15 655 patients receiving text messaging, 118 of 3889 patients (3.0% [95% CI, 2.5%-3.6%]) in the standard messaging group completed 1 vaccine dose, as did 135 of 3920 patients (3.4% [95% CI, 2.9%-4.0%]) in the clinician endorsement group (absolute difference, 0.4% [95% CI, -0.4% to 1.2%]; P = .31), 100 of 3911 patients (2.6% [95% CI, 2.1%-3.1%]) in the scarcity group (absolute difference, -0.5% [95% CI, -1.2% to 0.3%]; P = .20), and 143 of 3935 patients (3.6% [95% CI, 3.0%-4.2%]) in the endowment group (absolute difference, 0.6% [95% CI, -0.2% to 1.4%]; P = .14). Conclusions and Relevance: There was no detectable increase in vaccination uptake among patients receiving text messaging compared with telephone calls only or behaviorally informed message content. Trial Registration: ClinicalTrials.gov Identifier: NCT04834726.


Subject(s)
COVID-19 , Text Messaging , Adult , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Female , Humans , Male , Philadelphia , Reminder Systems , Vaccination
4.
J Clin Invest ; 131(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1591538

ABSTRACT

BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.


Subject(s)
COVID-19/therapy , Pneumonia, Viral/therapy , SARS-CoV-2 , Adult , Aged , Antibodies, Viral , Female , Hospitalization , Humans , Immune Tolerance , Immunization, Passive/methods , Incidence , Male , Middle Aged , Oxygen/therapeutic use , RNA, Viral , Respiration, Artificial , Risk Factors , Treatment Outcome
5.
J Clin Invest ; 131(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1523124

ABSTRACT

BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.


Subject(s)
COVID-19/therapy , Pneumonia, Viral/therapy , SARS-CoV-2 , Adult , Aged , Antibodies, Viral , Female , Hospitalization , Humans , Immune Tolerance , Immunization, Passive/methods , Incidence , Male , Middle Aged , Oxygen/therapeutic use , RNA, Viral , Respiration, Artificial , Risk Factors , Treatment Outcome
6.
Pediatr Pulmonol ; 55(2): 360-368, 2020 02.
Article in English | MEDLINE | ID: covidwho-1064413

ABSTRACT

BACKGROUND: The use of medications to treat respiratory conditions of extreme prematurity is often based upon studies of adults or children over 2 years of age. Little is known about the spectrum of medications used or dosing ranges. To inform the design of future studies, we conducted a prospective analysis of respiratory medication exposure among 832 extremely low gestational age neonates. METHODS: The prematurity and respiratory outcomes program (PROP) enrolled neonates less than 29-week gestation from 6 centers incorporating 13 clinical sites. We collected recorded daily "respiratory" medications given along with dosing information through 40-week postmenstrual age or neonatal intensive care unit discharge if earlier. RESULTS: PROP participants were exposed to a wide range of respiratory medications, often at doses beyond published recommendations. Nearly 50% received caffeine and furosemide beyond published recommendations for cumulative dose. Those who developed bronchopulmonary dysplasia were more likely to receive treatment with respiratory medications. However, more than 30% of PROP subjects that did not develop bronchopulmonary dysplasia also were treated with diuretics, systemic steroids, and other respiratory medications. CONCLUSION: Extremely preterm neonates in PROP were exposed to high doses of medications at levels known to generate significant adverse effects. With limited evidence for efficacy, there is an urgent need for controlled trials in this vulnerable patient population.


Subject(s)
Infant, Premature , Intensive Care Units, Neonatal , Bronchopulmonary Dysplasia/drug therapy , Child , Child, Preschool , Female , Gestational Age , Humans , Infant , Infant, Low Birth Weight , Infant, Newborn , Infant, Premature, Diseases/drug therapy , Male , Patient Discharge , Prospective Studies , Respiratory Tract Diseases/drug therapy , Steroids/therapeutic use
7.
Cell Host Microbe ; 29(1): 23-31.e4, 2021 01 13.
Article in English | MEDLINE | ID: covidwho-956078

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD "up" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.


Subject(s)
COVID-19/therapy , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Animals , Antibodies, Monoclonal/immunology , Binding Sites , COVID-19/immunology , COVID-19 Vaccines/immunology , Female , HEK293 Cells , Humans , Immunization, Passive/methods , Macaca mulatta , Male , Mice, Inbred BALB C , Middle Aged , Neutralization Tests , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Young Adult
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