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1.
Front Med (Lausanne) ; 8: 707895, 2021.
Article in English | MEDLINE | ID: covidwho-1690436

ABSTRACT

Treatment of patients with COVID-19 using convalescent plasma from recently recovered patients has been shown to be safe, but the time course of change in clinical status following plasma transfusion in relation to baseline disease severity has not yet been described. We analyzed short, descriptive daily reports of patient status in 7,180 hospitalized recipients of COVID-19 convalescent plasma in the Mayo Clinic Expanded Access Program. We assessed, from the day following transfusion, whether the patient was categorized by his or her physician as better, worse or unchanged compared to the day before, and whether, on the reporting day, the patient received mechanical ventilation, was in the ICU, had died or had been discharged. Most patients improved following transfusion, but clinical improvement was most notable in mild to moderately ill patients. Patients classified as severely ill upon enrollment improved, but not as rapidly, while patients classified as critically ill/end-stage and patients on ventilators showed worsening of disease status even after treatment with convalescent plasma. Patients age 80 and over showed little or no clinical improvement following transfusion. Clinical status at the time of convalescent plasma treatment and age appear to be the primary factors in determining the therapeutic effectiveness of COVID-19 convalescent plasma among hospitalized patients.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314282

ABSTRACT

Convalescent plasma has been used worldwide to treat patients hospitalized with COVID-19 and prevent disease progression. Despite global usage uncertainty remains regarding plasma efficacy as randomized controlled trials (RCTs) have provided divergent evidence regarding the survival benefit of convalescent plasma. Here, we argue that during a global health emergency, the mosaic of evidence originating from multiple levels of the epistemic hierarchy should inform contemporary policy and healthcare decisions. Indeed, worldwide matched-control studies have generally found convalescent plasma to improve COVID-19 patient survival and RCTs have demonstrated a survival benefit when transfused early in the disease course but limited or no benefit later in the disease course when patients required greater supportive therapies. RCTs have also revealed that convalescent plasma transfusion contributes to improved symptomatology and viral clearance. To further investigate the effect of convalescent plasma on patient mortality, we performed a systematic literature review and used a meta-analytical approach to pool daily survival data from all controlled studies that reported Kaplan-Meier survival plots. Qualitative inspection of all available Kaplan-Meier survival data and an aggregate Kaplan- Meier survival plot revealed a directionally consistent pattern among studies arising from multiple levels of the epistemic hierarchy, whereby convalescent plasma transfusion was generally associated with greater patient survival. Given that convalescent plasma has a similar safety profile as standard plasma, convalescent plasma should be implemented at the immediate onset of future infectious disease outbreaks.

3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Article in English | MEDLINE | ID: covidwho-1662680

ABSTRACT

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.


Subject(s)
Coxsackievirus Infections/complications , Enterovirus B, Human/pathogenicity , Housing, Animal/statistics & numerical data , Myocarditis/pathology , Plastics/adverse effects , Animals , Coxsackievirus Infections/virology , Female , Male , Mice , Mice, Inbred BALB C , Myocarditis/etiology , Myocarditis/virology , Sex Factors
5.
J Clin Invest ; 130(9): 4791-4797, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-1365265

ABSTRACT

BACKGROUNDConvalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODSThus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma.RESULTSThe incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%.CONCLUSIONGiven the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.TRIAL REGISTRATIONClinicalTrials.gov NCT04338360.FUNDINGMayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Compassionate Use Trials , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Female , Humans , Immunization, Passive/adverse effects , Immunization, Passive/mortality , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Safety , Transfusion Reaction/epidemiology , Transfusion Reaction/etiology , Transfusion-Related Acute Lung Injury/epidemiology , Transfusion-Related Acute Lung Injury/etiology , United States/epidemiology , United States Food and Drug Administration , Young Adult
6.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355048

ABSTRACT

COVID-19 convalescent plasma (CCP) is currently under investigation for both treatment and post-exposure prophylaxis. The active component of CCP mediating improved outcome is commonly reported as specific antibodies, particularly neutralizing antibodies, with clinical efficacy characterized according to the level or antibody affinity. In this review, we highlight the potential role of additional factors in CCP that can be either beneficial (e.g., AT-III, alpha-1 AT, ACE2+ extracellular vesicles) or detrimental (e.g., anti-ADAMTS13, anti-MDA5 or anti-interferon autoantibodies, pro-coagulant extracellular vesicles). Variations in these factors in CCP may contribute to varied outcomes in patients with COVID-19 and undergoing CCP therapy. We advise careful, retrospective investigation of such co-factors in randomized clinical trials that use fresh frozen plasma in control arms. Nevertheless, it might be difficult to establish a causal link between these components and outcome, given that CCP is generally safe and neutralizing antibody effects may predominate.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/therapy , SARS-CoV-2/immunology , Anti-Inflammatory Agents/blood , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Autoantibodies/blood , Blood Coagulation Factor Inhibitors/blood , Blood Coagulation Factors/analysis , Cross Reactions , Extracellular Vesicles , Humans , Immunization, Passive/adverse effects , Immunologic Factors/blood , Immunosuppressive Agents/blood
7.
Nat Commun ; 12(1): 4864, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1354101

ABSTRACT

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.


Subject(s)
COVID-19/therapy , Plasma/immunology , Adolescent , Adult , Aged , Antibodies, Viral/immunology , Antibody Specificity , Antigenic Variation , Blood Donors , COVID-19/mortality , Female , Humans , Immunization, Passive/mortality , Male , Middle Aged , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Treatment Outcome , United States/epidemiology , Young Adult
9.
Front Med (Lausanne) ; 8: 684151, 2021.
Article in English | MEDLINE | ID: covidwho-1282395

ABSTRACT

Convalescent plasma has been used worldwide to treat patients hospitalized with coronavirus disease 2019 (COVID-19) and prevent disease progression. Despite global usage, uncertainty remains regarding plasma efficacy, as randomized controlled trials (RCTs) have provided divergent evidence regarding the survival benefit of convalescent plasma. Here, we argue that during a global health emergency, the mosaic of evidence originating from multiple levels of the epistemic hierarchy should inform contemporary policy and healthcare decisions. Indeed, worldwide matched-control studies have generally found convalescent plasma to improve COVID-19 patient survival, and RCTs have demonstrated a survival benefit when transfused early in the disease course but limited or no benefit later in the disease course when patients required greater supportive therapies. RCTs have also revealed that convalescent plasma transfusion contributes to improved symptomatology and viral clearance. To further investigate the effect of convalescent plasma on patient mortality, we performed a meta-analytical approach to pool daily survival data from all controlled studies that reported Kaplan-Meier survival plots. Qualitative inspection of all available Kaplan-Meier survival data and an aggregate Kaplan-Meier survival plot revealed a directionally consistent pattern among studies arising from multiple levels of the epistemic hierarchy, whereby convalescent plasma transfusion was generally associated with greater patient survival. Given that convalescent plasma has a similar safety profile as standard plasma, convalescent plasma should be implemented within weeks of the onset of future infectious disease outbreaks.

10.
Mayo Clin Proc ; 96(5): 1262-1275, 2021 05.
Article in English | MEDLINE | ID: covidwho-1219471

ABSTRACT

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.


Subject(s)
COVID-19/therapy , COVID-19/mortality , Humans , Immunization, Passive/methods , Mortality , SARS-CoV-2/immunology , Time-to-Treatment
11.
J Mol Biol ; 433(10): 166945, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1142054

ABSTRACT

The COVID-19 pandemic entered its third and most intense to date wave of infections in November 2020. This perspective article describes how combination therapies (polytherapeutics) are a needed focus for helping battle the severity of complications from SARS-CoV-2 infection. It outlines the types of systems that are needed for fast and efficient combinatorial assessment of therapeutic candidates. Proposed are micro-physiological systems using human iPSC as a format for tissue-specific modeling of infection, the use of gene-humanized zebrafish and C. elegans for combinatorial drug screens due to the animals being addressable in liquid multi-well formats, and the use of engineered pseudo-typing systems to safely model infection in the transgenic animals and engineered tissue systems.


Subject(s)
COVID-19/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Induced Pluripotent Stem Cells/drug effects , Animals , Animals, Genetically Modified , COVID-19/economics , COVID-19/genetics , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Humans , Zebrafish/genetics
12.
N Engl J Med ; 384(11): 1015-1027, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1057739

ABSTRACT

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).


Subject(s)
Antibodies, Viral/blood , COVID-19/therapy , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/immunology , COVID-19/mortality , Female , Hospitalization , Humans , Immunization, Passive , Immunoglobulin G/blood , Male , Middle Aged , Registries , Respiration, Artificial , Retrospective Studies , Risk Factors , Time-to-Treatment , United States/epidemiology , Young Adult
15.
Mayo Clin Proc ; 95(9): 1888-1897, 2020 09.
Article in English | MEDLINE | ID: covidwho-654169

ABSTRACT

OBJECTIVE: To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients. PATIENTS AND METHODS: From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events was low; these included transfusion reactions (n=78; <1%), thromboembolic or thrombotic events (n=113; <1%), and cardiac events (n=677, ~3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion per se. The 7-day mortality rate was 13.0% (12.5%, 13.4%), and was higher among more critically ill patients relative to less ill counterparts, including patients admitted to the intensive care unit versus those not admitted (15.6 vs 9.3%), mechanically ventilated versus not ventilated (18.3% vs 9.9%), and with septic shock or multiple organ dysfunction/failure versus those without dysfunction/failure (21.7% vs 11.5%). CONCLUSION: These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.


Subject(s)
Coronavirus Infections/therapy , Patient Safety , Pneumonia, Viral/therapy , Adolescent , Adult , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/mortality , Critical Illness , Female , Hospitalization , Humans , Immunization, Passive/adverse effects , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , United States , Young Adult
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