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1.
Trends Mol Med ; 2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1701267
2.
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.

3.
Sci Rep ; 12(1): 637, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1621276

ABSTRACT

Convalescent plasma is used to treat COVID-19. There are theoretical concerns about the impact of pro-coagulant factors in convalescent plasma on the coagulation cascade particularly among patients with severe COVID-19. The aim of this study was to evaluate the coagulation profile of COVID-19 convalescent plasma. Clotting times and coagulation factor assays were compared between fresh frozen plasma, COVID-19 convalescent plasma, and pathogen-reduced COVID-19 convalescent plasma. Measurements included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, von Willebrand factor activity, von Willebrand factor antigen, coagulation factors II, V, VII-XII, protein S activity, protein C antigen, and alpha-2 plasmin inhibitor. Clotting times and coagulation factor assays were not different between COVID-19 convalescent plasma and fresh frozen plasma, except for protein C antigen. When compared to fresh frozen plasma and regular convalescent plasma, pathogen reduction treatment increased activated partial thromboplastin time and thrombin time, while reducing fibrinogen, coagulation factor II, V, VIII, IX, X, XI, XII, protein S activity, and alpha-2 plasmin inhibitor. The coagulation profiles of human COVID-19 convalescent plasma and standard fresh frozen plasma are not different. Pathogen reduced COVID-19 convalescent plasma is associated with reduction of coagulation factors and a slight prolongation of coagulation times, as anticipated. A key limitation of the study is that the COVID-19 disease course of the convalesced donors was not characterized.


Subject(s)
Blood Coagulation , COVID-19/blood , COVID-19/therapy , Adult , Blood Coagulation Tests , Blood Preservation , Blood Transfusion , Female , Humans , Immunization, Passive , Male , Middle Aged
5.
PLoS Med ; 18(12): e1003872, 2021 12.
Article in English | MEDLINE | ID: covidwho-1581903

ABSTRACT

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.


Subject(s)
COVID-19/therapy , Compassionate Use Trials/methods , Health Services Needs and Demand/statistics & numerical data , Hospital Distribution Systems/organization & administration , Registries , Transfusion Reaction/complications , Transfusion Reaction/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Female , Humans , Immunization, Passive/adverse effects , Immunization, Passive/methods , Inpatients , Male , Medically Underserved Area , Middle Aged , Pandemics , Patient Safety , SARS-CoV-2 , Treatment Outcome , United States
6.
J Clin Microbiol ; 59(9): e0123121, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1501537

ABSTRACT

Longitudinal studies assessing durability of the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) humoral immune response have generated conflicting results. This has been proposed to be due to differences in patient populations, the lack of standardized methodologies, and the use of assays that measure distinct aspects of the humoral response. SARS-CoV-2 antibodies were serially measured in sera from a cohort of 44 well-characterized convalescent plasma donors over 120 days post-COVID-19 symptom onset, utilizing eight assays, which varied according to antigen source, the detected antibody isotype, and the activity measured (i.e., binding, blocking, or neutralizing). While the majority of assays demonstrated a gradual decline in antibody titers over the course of 120 days, the two electrochemiluminescence immunoassay Roche assays (Roche Diagnostics Elecsys anti-SARS-CoV-2 [qualitative, nucleocapsid based] and Roche Diagnostics Elecsys anti-SARS-CoV-2 S [semiquantitative, spike based]), which utilize dual-antigen binding for antibody detection, demonstrated stable and/or increasing antibody titers over the study period. This study is among the first to assess longitudinal, rather than cross-sectional, SARS-CoV-2 antibody profiles among convalescent COVID-19 patients, primarily using commercially available serologic assays with Food and Drug Administration emergency use authorization. We show that SARS-CoV-2 antibody detection is dependent on the serologic method used, which has implications for future assay utilization and clinical value.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/therapy , Cross-Sectional Studies , Humans , Immunization, Passive , Kinetics , Sensitivity and Specificity
9.
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
10.
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
13.
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.

14.
JAMA Oncol ; 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1274650

ABSTRACT

Importance: COVID-19 is a life-threatening illness for many patients. Prior studies have established hematologic cancers as a risk factor associated with particularly poor outcomes from COVID-19. To our knowledge, no studies have established a beneficial role for anti-COVID-19 interventions in this at-risk population. Convalescent plasma therapy may benefit immunocompromised individuals with COVID-19, including those with hematologic cancers. Objective: To evaluate the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic cancers and COVID-19 from a multi-institutional cohort. Design, Setting, and Participants: This retrospective cohort study using data from the COVID-19 and Cancer Consortium registry with propensity score matching evaluated patients with hematologic cancers who were hospitalized for COVID-19. Data were collected between March 17, 2020, and January 21, 2021. Exposures: Convalescent plasma treatment at any time during hospitalization. Main Outcomes and Measures: The main outcome was 30-day all-cause mortality. Cox proportional hazards regression analysis with adjustment for potential confounders was performed. Hazard ratios (HRs) are reported with 95% CIs. Secondary subgroup analyses were conducted on patients with severe COVID-19 who required mechanical ventilatory support and/or intensive care unit admission. Results: A total of 966 individuals (mean [SD] age, 65 [15] years; 539 [55.8%] male) were evaluated in this study; 143 convalescent plasma recipients were compared with 823 untreated control patients. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (HR, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity score matching (HR, 0.52; 95% CI, 0.29-0.92). Among the 338 patients admitted to the intensive care unit, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.40; 95% CI, 0.20-0.80). Among the 227 patients who required mechanical ventilatory support, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.32; 95% CI, 0.14-0.72). Conclusions and Relevance: The findings of this cohort study suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic cancers and COVID-19.

15.
Elife ; 102021 06 04.
Article in English | MEDLINE | ID: covidwho-1278700

ABSTRACT

Background: The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. Results: CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = -0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. Conclusions: A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. Funding: There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.


Subject(s)
COVID-19/mortality , COVID-19/therapy , Age Factors , Hospitalization/statistics & numerical data , Humans , Immunization, Passive/methods , Immunization, Passive/statistics & numerical data , Linear Models , Pandemics , SARS-CoV-2
16.
Transfusion ; 61(8): 2503-2511, 2021 08.
Article in English | MEDLINE | ID: covidwho-1243670

ABSTRACT

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.


Subject(s)
COVID-19/complications , COVID-19/therapy , Immune Tolerance , COVID-19/immunology , Hematologic Neoplasms/complications , Hematologic Neoplasms/immunology , Humans , Immunization, Passive/methods , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/immunology , Organ Transplantation/adverse effects , Treatment Outcome
17.
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
19.
Clin Microbiol Newsl ; 43(4): 23-32, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1062296

ABSTRACT

Convalescent plasma has emerged as a promising therapeutic agent for patients with coronavirus disease 2019 (COVID-19), has received emergency use authorization, and is being widely used during the COVID-19 pandemic. Passive antibody therapy via plasma or serum has been successfully used to treat infectious diseases for more than a century. Passive antibody administration is based on the presumption that convalescent plasma or serum contains therapeutic antibodies that can be passively transferred to the plasma recipient. There are numerous examples in which convalescent plasma has been used successfully as post-exposure prophylaxis and treatment of infectious diseases, including previous coronavirus outbreaks. In the context of the COVID-19 pandemic, convalescent plasma was demonstrated to be safe and potentially effective among patients infected with COVID-19. This review provides an overview of the historical uses of convalescent plasma therapy, summarizes current evidence for convalescent plasma use for COVID-19, and highlights future antibody therapies.

20.
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
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