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Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality: Did Convalescent Plasma Hesitancy cost lives?

TL;DR: In this paper, the authors tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data over the course of the year, finding a strong inverse correlation (Pearson's correlation coefficient of -0.5176 with P = 0.00242) between CCP usage/hospital admission and deaths occurring two weeks after admission.
Abstract: The US Food and Drug Administration (FDA) authorized treatment of hospitalized COVID-19 patients with Convalescent Plasma (CCP) via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to the use of CCP in some 500,000 patients during the first year of the pandemic. We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data over the course of the year. CCP usage per admission peaked after issuance of the EUA, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, following reports of randomized controlled trials that failed to show clear benefit from CCP, usage/admissions declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (Pearson’s correlation coefficient of -0.5176 with P = 0.00242) between CCP usage/hospital admission and deaths occurring two weeks after admission, and this finding was robust to examination of deaths taking place one, two or three weeks after admission. Changes in the number of hospital admissions, prevalence of variants, and age of patients could not explain these findings. We estimate that the retreat from CCP usage, a phenomenon we termed ‘plasma hesitancy’, might have resulted in 29,000 to 36,000 excess deaths in the period from mid-November 2020 to February 2021. These results highlight the need for additional studies to ascertain the variables associated with efficacy and/or provide other explanations for the robust relationships observed in this study.

Summary (2 min read)

Introduction

  • In the Spring of 2020, the United States embarked on a historic and unprecedented deployment of plasma derived from patients who survived COVID-19 (COVID-19 Convalescent Plasma (CCP)) for treatment of the disease, and one-year into this effort more than 500,000 individuals have been treated.
  • The demonstration by the summer of 2020 that CCP was safe 3,4, that antibody in plasma correlated with survival in people treated before ventilation 5 along with initial suggestions of efficacy 6-8, fueled interest in and use of this product.
  • The interpretation of the potential efficacy of CCP is complex as many of the positive findings arose through post hoc examinations and subgroup comparisons.
  • Later in the pandemic several larger RCTs reported no mortality benefit 10-12, raising doubts as to CCP efficacy.
  • On March 13, 2021 the New York Times reported that COVID-19 mortality remained high with nearly 1,500 daily deaths despite a drop in the number of new infections since earlier in the year 18.

Materials and Methods

  • CCP usage was inferred from the distribution of plasma units to hospitals in the USA from data obtained from Blood Centers of America (BCA, West Warwick, RI).
  • Units transfused in the EAP were reported by providers as part of the official case report forms and each transfusion could comprise one or two units.
  • For the analysis, which was based on weekly aggregated data, a two-week shift was selected to align the mortality with the median and upper quartile estimates in these reports.
  • In scenario 2 a constant 50% CCP utilization ratio was set over the entire study period.
  • A final scenario estimated the CFR that may have been observed had CCP not been used at all (i.e., the y-intercept from the model).

Results

  • The FDA first allowed compassionate use of CCP on a case-by-case basis in late March 2020, but very quickly initiated the Expanded Access Program in early April 2020.
  • The comparison of curves showed a trough in deaths per admission coinciding with the peak of CCP usage per admission.
  • A comparison of this number with that from USA studies shows reasonable agreement between with the average mortality of 23.5% in patients not receiving CCP (Table S3).
  • Nevertheless, it is possible to use these efficacy numbers to estimate what the effect on deaths would have been had the United States continued to use CCP at the height of its usage in early Fall 2020, when more than 40% of all patients received plasma therapy.
  • The two-week lagged mortality ratio for hospitalized patients was 18.16%.

Discussion

  • The use of CCP in hospitalized patients peaked from mid-September to the end of October 2020 shortly after the FDA allowed its widespread use under the EUA of August 23, 2020.
  • Of concern, the drop in per capita CCP utilization appeared to be associated with an increase in mortality among hospitalized COVID-19 patients.
  • Convalescent plasma has proven effective in individuals with defective humoral immunity and B cell defects 30,31.
  • Patients treated with CCP manifest reduced inflammatory markers 35-37 that can lead to host damage.
  • This inference is strengthened by the fact that mortality from COVID-19 among hospitalized patients decreased substantially over most of 2020, consistent with worldwide trends 19, but then began to rise in late November and early December 2020, a period that coincided with precipitous reduction in CCP/admission.

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Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality:
Did Plasma Hesitancy cost lives?
Arturo Casadevall MD, PhD
1*
; Quigly Dragotakes PhD
1
; Patrick W. Johnson BS
2
, Jonathon W. Senefeld
PhD
3
, Steven A. Klassen PhD
3
, R. Scott Wright MD
4
, Michael J Joyner MD
3#
, Nigel Paneth MD
5#
; Rickey E.
Carter PhD
2#
1
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health,
Baltimore, MD;
2
Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL;
3
Department
of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN;
4
Department of Cardiology,
Mayo Clinic, Rochester, MN;
5
Department of Epidemiology and Biostatistics and Department of
Pediatrics and Human Development, College of Human Medicine, Michigan State University, East
Lansing, MI.
*Address Correspondence: Arturo Casadevall, 615 N. Wolfe Street, Room E5132, Baltimore, Maryland
21205, acasade1@jhu.edu
#
MJJ, NP and REC share last authorship.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 16, 2021. ; https://doi.org/10.1101/2021.04.07.21255089doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Abstract
Background. The US Food and Drug Administration authorized 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 US.
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 two weeks after admission, and this
finding was robust to examination of deaths taking place one, two or three 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.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 16, 2021. ; https://doi.org/10.1101/2021.04.07.21255089doi: medRxiv preprint

Introduction
In the Spring of 2020, the United States embarked on a historic and unprecedented deployment of
plasma derived from patients who survived COVID-19 (COVID-19 Convalescent Plasma (CCP)) for
treatment of the disease, and one-year into this effort more than 500,000 individuals have been treated.
The synergism created by the lack of effective alternate therapies, a plentiful supply of plasma from an
efficient and high-capacity blood banking network, motivated donors and strong community partners
fueled this deployment. Sensible US FDA regulatory oversight was provided first by its Expanded Access
Program (EAP) in partnership with the Mayo Clinic, with first transfusion on early April 2020,
1
and then
by its Emergency Use Authorization (EUA) of August 23, 2020, both of which restricted CCP use to
hospitalized patients
2
.
The demonstration by the summer of 2020 that CCP was safe
3,4
, that antibody in plasma correlated with
survival in people treated before ventilation
5
along with initial suggestions of efficacy
6-8
, fueled interest
in and use of this product. However, the interpretation of the potential efficacy of CCP is complex as
many of the positive findings arose through post hoc examinations and subgroup comparisons.
Nonetheless, the use of CCP rose rapidly without the ideal evidence base of efficacy from randomized
controlled clinical trials (RCT), since early RCTs though generally trending positively, were unsatisfactory,
mostly due to small size or premature termination as the epidemic abated in the early surge regions
9
.
Later in the pandemic several larger RCTs reported no mortality benefit
10-12
, raising doubts as to CCP
efficacy. However, these latter trials were undertaken in hospitalized patients treated late in the course
of disease and some used plasma with variable antibody levels
9
, and contrasted with a highly successful
trial in elderly patients treated within 3 days of illness onset prior to hospitalization
13
. Despite potential
explanations for the negative studies, the results of these studies were sometimes accompanied by
editorials that reinforced message of futility with the British Medical Journal calling CCP ‘ineffective’
14
,
Nature Biotechnology reported that CCP fell ‘flat’
15
and JAMA published a meta-analysis of RCT
concluding that there was no evidence of benefit from CCP therapy
16
. On February 17, 2021 the Wall
Street Journal reported that Mount Sinai Hospital, which had been a leader in deploying CCP and
reported early encouraging results
8
, had stopped using plasma in patients with COVID-19, and the
report specifically mentioned the negative results from CCP RCTs in this decision
17
.
On March 13, 2021 the New York Times reported that COVID-19 mortality remained high with nearly
1,500 daily deaths despite a drop in the number of new infections since earlier in the year
18
. This
finding was surprising in light of an apparent reduction in the mortality of hospitalized patients as the
epidemic progressed, thought to be from improved management of the disease as clinical experience
grew
19
. Analyzing weekly reports from the blood banking industry, we noted that plasma use was on
the decline, based on the ratio of units dispensed to hospital admissions. The increase in mortality
combined with the reduction in CCP use led us to hypothesize first, that the two phenomena were
related, and second, that the decline in CCP use reflected reduced use following the disappointing trial
findings. The blood banking network maintains careful and complete records for every blood product
unit used including time, date and geographic provenance and destination, providing a virtually
complete record of trends in CCP use for the US. We therefore examined the use of CCP units as a
function of time, assessing the relationship of CCP use to COVID-19 mortality, denominating both
plasma units and deaths to hospital admissions. The aim of the study was to determine whether the
reduction in plasma use was associated with any change in the pattern of mortality seen in patients
hospitalized for COVID-19.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 16, 2021. ; https://doi.org/10.1101/2021.04.07.21255089doi: medRxiv preprint

Materials and Methods
Convalescent Plasma Usage. CCP usage was inferred from the distribution of plasma units to hospitals in
the USA from data obtained from Blood Centers of America (BCA, West Warwick, RI). Data fields
included collections, distributions to hospitals, distributions to research or other use. This file
consolidated all the reports from regional blood bank reports and provided a total of collected units and
units distributed to hospitals. The data file did not have information on whether a unit was actually
transfused but BCA can infer usage from hospital re-ordering information and there has been a strong
correlation between the total number of units shipped to a hospital and the units transfused by that
hospital. Hence, the CCP units dispensed to hospitals represent a reasonable proxy value for the total
number of units being transfused to patients. To validate this assumption, we compared the numbers of
plasma units dispensed to those used by the EAP. There was a powerful and significant correlation
between the weekly counts of units distributed in the United States and those used to treat patients as
part of the EAP between April 06 and August 23, 2020. (Spearman rho = 0.953, P<0.001) (Figure S1).
Units transfused in the EAP were reported by providers as part of the official case report forms and each
transfusion could comprise one or two units.
Admission and mortality data. For population level data on COVID-19 admissions and mortality we
relied on publicly available databases. Specifically, we used information from the Our World in Data
(OWID) (
https://ourworldindata.org/coronavirus) database. Data used for this analysis were
downloaded on March 18, 2021 and are available as Supplemental Table S1. We confirmed these
findings using Centers for Disease Control (CDC, Atlanta, GA) data on admissions and deaths
https://covid.cdc.gov/covid-data-tracker/#new-hospital-admissions and https://covid.cdc.gov/covid-
data-tracker/#trends_dailytrendsdeaths. CDC data were downloaded on 3/31/2021, and are available
as Supplemental Table S2.
Statistical analysis. Preliminary descriptive analyses were used to explore the associations of the ratio of
number of CCP units dispersed to the number of hospitalizations (CCP utilization ratio) with the ratio of
national deaths to national admissions, the latter being a reasonable proxy for the case fatality rate. No
individual-level data were available to link the mortality events directly to the individuals hospitalized to
permit a calculation of the true case-fatality rate. To address this limitation, the mortality counts
reported by the CDC were shifted to better align the deaths with the admitted patients. Since the
overwhelming majority of COVID-19 deaths occur in hospitals
20,21
, since CCP is only authorized for use in
hospitals, and since death generally occurs a few days to weeks after admission, mortality was adjusted
for the time lag between admission and death. The median time between admission and death has been
reported as 9 days in the US
22
and 6.7 days in Belgium
23
. For the analysis, which was based on weekly
aggregated data, a two-week shift was selected to align the mortality with the median and upper
quartile estimates in these reports. The Pearson correlation coefficient was used to describe the
relationship of the CCP utilization ratio with CFR. To further define this relationship, a linear statistical
model was used to regress the utilization ratio onto CFR. This statistical model was weighted by the
number of hospitalizations per week. The fit of the model was examined using standard residual-based
diagnostic plots and the fit was deemed acceptable using only a linear fit of the CCP utilization ratio.
Three in silico scenarios were created to summarize the effect of alterations to the CCP utilization ratio
using the fitted model. In scenario 1, the effect of maintenance of plasma usage was considered. To
define maintenance of use, a weighted average of the utilization ratio over the months of August
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 16, 2021. ; https://doi.org/10.1101/2021.04.07.21255089doi: medRxiv preprint

through September 2020 was estimated. This value was then used to estimate the number of deaths
that would be expected to occur throughout the study period (admissions starting 8/3/2020
2/22/2021). In scenario 2 a constant 50% CCP utilization ratio was set over the entire study period. The
utilization rate was approximately the value observed in the early October 2020 period. A final scenario
estimated the CFR that may have been observed had CCP not been used at all (i.e., the y-intercept from
the model). Model contrasts were used to estimate the change in expected deaths among these
scenarios in addition to a fourth condition the actual number of events reported by the CDC. Values
are summarized based on the observed number of hospitalized patients over the study period along
with the same values indexed into expected mortality events per 1000 hospitalizations. Pointwise
confidence bands for each scenario were obtained by multiplying the model-predicted CFR, and its
associated 95% confidence interval, by the number of hospitalizations per week. Cumulative
summations were used to describe the differences in expected deaths over the entire study period. This
analysis was repeated independently a third time using a weighted average of utilization ratio of the
months October-November on a separate database (OWID) to investigate stability between reporting
bodies. As a final method for estimating the overall effect of the changes in CCP utilization, the CDC data
were grouped into two time periods representing relative use. The difference in the CFR was used to
estimate the expected value for the changes in the expected number of deaths.
Statistical analyses were conducted using R version 3.6.2.
24
95% confidence intervals and two-sided p-
values were used to summarize association and test for significance at the alpha=0.05 level of
significance, respectively.
Results
Convalescent plasma use.
The FDA first allowed compassionate use of CCP on a case-by-case basis in late March 2020, but very
quickly initiated the Expanded Access Program in early April 2020. The EAP was, in effect, a registry of
all CCP use in the US from April to August 2020 and led to a sharp rise in CCP use. The findings of the
EAP, which established that CCP was as relatively safe
3,4
, and that high antibody titer was associated
with lower mortality in unventilated plasma recipients
5
, were major considerations behind the
Emergency Use Authorization of August 23, 2020, which broadened its use. Distribution of CCP to
hospitals rose to 25,000 - 30,000 weekly units by the December 2020 to January 2021 time period, but
this rise in plasma distribution largely reflected the great increase in hospital admissions for COVID in
those months. (Figure 1). When CCP distributions are analyzed as a function of the number of new
hospital admissions per week, peak utilization per capita occurred much earlier, in early October 2020
and declined sharply in the following months (Figure 2).
Correlation between CCP and mortality.
To explore whether there was a relationship between CCP distribution in the USA and mortality we first
compared the doses per patient versus reported COVID-19 deaths per hospital admission from publicly
available databases (Figure 2). The comparison of curves showed a trough in deaths per admission
coinciding with the peak of CCP usage per admission. A plot of mortality versus doses per hospitalized
patient using mortality per admission data from the OWID database revealed a strong negative
correlation (Pearson’s correlation coefficient of -0.52 with P = 0.002) (Figure 3). To account for lags in
the reporting of death that vary by state, we also investigated whether this correlation was maintained
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 16, 2021. ; https://doi.org/10.1101/2021.04.07.21255089doi: medRxiv preprint

Citations
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TL;DR: This large, diverse, multicenter cohort study demonstrated that CP, compared to matched controls, is significantly associated with reduced risk of in-hospital mortality and suggests the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19.
Abstract: BACKGROUNDEvidence supporting convalescent plasma (CP), one of the first investigational treatments for coronavirus disease 2019 (COVID-19), has been inconclusive, leading to conflicting recommendations. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19.METHODSThe multicenter, electronic health records-based, retrospective study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare-affiliated community hospitals. Coarsened exact matching (1:k) was employed, resulting in a sample of 3774 CP and 10,687 comparison patients.RESULTSExamination of mortality using a shared frailty model, controlling for concomitant medications, date of admission, and days from admission to transfusion, demonstrated a significant association of CP with lower mortality risk relative to the comparison group (adjusted hazard ratio [aHR] = 0.71; 95% CI, 0.59-0.86; P < 0.001). Examination of patient risk trajectories, represented by 400 clinico-demographic features from our real-time risk model (RTRM), indicated that patients who received CP recovered more quickly. The stratification of days to transfusion revealed that CP within 3 days after admission, but not within 4 to 7 days, was associated with a significantly lower mortality risk (aHR = 0.53; 95% CI, 0.47-0.60; P < 0.001). CP serology level was inversely associated with mortality when controlling for its interaction with days to transfusion (HR = 0.998; 95% CI, 0.997-0.999; P = 0.013), yet it did not reach univariable significance.CONCLUSIONSThis large, diverse, multicenter cohort study demonstrated that CP, compared with matched controls, is significantly associated with reduced risk of in-hospital mortality. These observations highlight the utility of real-world evidence and suggest the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19.FUNDINGThis research was supported in whole by HCA Healthcare and/or an HCA Healthcare-affiliated entity, including Sarah Cannon and Genospace.

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Abstract: BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for COVID-19. METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients ≥18 years, admitted to hospital for≤48 h (not intensive care) with a positive SARS-CoV-2 RT-PCR test, were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on February 1, 2021. A total of 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median of 9.0 DAOH14 (IQR, 3-11) versus. 9.0 DAOH14 (IQR, 7-10) in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for 1 patient in the intervention group versus. 2 patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for 9 patients in the intervention group versus. 6 patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

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Posted ContentDOI
27 Jul 2021-medRxiv
TL;DR: A randomized, two-arm, controlled, multi-center trial to evaluate the efficacy and safety of COVID-19 hyper-immune globulin (HIG) solution is presented in this article.
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04 Aug 2020-JAMA
TL;DR: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days.
Abstract: Importance Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, −10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49];P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32];P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63];P = .83) (Pfor interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.59 [95% CI, 0.22-1.59];P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.95];P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18];P Conclusion and Relevance Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration Chinese Clinical Trial Registry:ChiCTR2000029757

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04 Feb 2021-Nature
TL;DR: The relative risk of COVID-19-associated death for younger individuals (under 65) is consistent across countries and can be used to robustly compare the underlying number of infections in each country, and the age distribution of deaths in younger age groups is very consistent across different settings.
Abstract: Estimating the size of the coronavirus disease 2019 (COVID-19) pandemic and the infection severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made challenging by inconsistencies in the available data. The number of deaths associated with COVID-19 is often used as a key indicator for the size of the epidemic, but the observed number of deaths represents only a minority of all infections1,2. In addition, the heterogeneous burdens in nursing homes and the variable reporting of deaths of older individuals can hinder direct comparisons of mortality rates and the underlying levels of transmission across countries3. Here we use age-specific COVID-19-associated death data from 45 countries and the results of 22 seroprevalence studies to investigate the consistency of infection and fatality patterns across multiple countries. We find that the age distribution of deaths in younger age groups (less than 65 years of age) is very consistent across different settings and demonstrate how these data can provide robust estimates of the share of the population that has been infected. We estimate that the infection fatality ratio is lowest among 5-9-year-old children, with a log-linear increase by age among individuals older than 30 years. Population age structures and heterogeneous burdens in nursing homes explain some but not all of the heterogeneity between countries in infection fatality ratios. Among the 45 countries included in our analysis, we estimate that approximately 5% of these populations had been infected by 1 September 2020, and that much higher transmission rates have probably occurred in a number of Latin American countries. This simple modelling framework can help countries to assess the progression of the pandemic and can be applied in any scenario for which reliable age-specific death data are available.

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Q1. What are the contributions in "Convalescent plasma use in the united states was inversely correlated with covid-19 mortality: did plasma hesitancy cost lives?" ?

The US Food and Drug Administration authorized 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 US. 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. It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Since the overwhelming majority of COVID-19 deaths occur in hospitals 20,21, since CCP is only authorized for use in hospitals, and since death generally occurs a few days to weeks after admission, mortality was adjusted for the time lag between admission and death. 

the use of CCP rose rapidly without the ideal evidence base of efficacy from randomized controlled clinical trials (RCT), since early RCTs though generally trending positively, were unsatisfactory, mostly due to small size or premature termination as the epidemic abated in the early surge regions 9. 

Had the rate of CCP utilization observed during August through October 2002 carried over for the remaining months, the expected number of deaths was 327,516 (95%: CI: 293,811 to 361,221), which would result in 29,018 (95% CI: 3535 to 54,501) fewer deaths than observed. 

The authors note that the FDA reaffirmed the EUA status of CCP in February 2021 2 by permitting its continued use in hospitalized patients if used early in COVID-19 and with units that have a sufficient content of specific antibody. 

In addition, interim guidelines for American Association of Blood Banks 48 and Brazil 49 emphasize that CCP is more likely to be effective when used in early COVID-19 with units having high content of specific antibody. 

A poll by the American Association of Blood Banks revealed a 50% increase in the number of institutions planning to stop offering CCP between February and March 2021, which cited lack of stronger efficacy data as the major reason for this decision 28. 

In this regard, the authors note that both the vaccines being administered in the USA and CCP are being used under a EUA regulatory framework, since neither has full approval status and that these hesitancies lead to avoidance behaviors based on the interpretation of available data by the public and health care providers, respectively. 

Distribution of CCP to hospitals rose to 25,000 - 30,000 weekly units by the December 2020 to January 2021 time period, but this rise in plasma distribution largely reflected the great increase in hospital admissions for COVID in those months. 

This variant was identified in the United States in early winter 2021 but as of January only 76 cases had been described in 12 states, which was estimated to be <0.5% of the infections at the time 42. 

The FDA first allowed compassionate use of CCP on a case-by-case basis in late March 2020, but very quickly initiated the Expanded Access Program in early April 2020. 

Even as late as mid-March 2021 the CDC estimated that B.1.1.17 variant comprised only 25% of US isolates and increased mortality from these infections would not manifest itself until times later than their analysis 43. 

it is possible to use these efficacy numbers to estimate what the effect on deaths would have been had the United States continued to use CCP at the height of its usage in early Fall 2020, when more than 40% of all patients received plasma therapy.