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\begin{document}

\title{Safety and efficacy of convalescent plasma therapy for the management of
COVID-19: A systematic review}



\author[1]{Sitaram Khadka}%
\author[2]{Muhammad Saleem}%
\author[3]{Dhan Shrestha}%
\author[4]{Pravash Budhathoki}%
\affil[1]{Shree Birendra Hospital}%
\affil[2]{Government College University Faisalabad}%
\affil[3]{Mangalbare Hospital, Morang}%
\affil[4]{Dr Iwamura Memorial Hospital}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aim: Till date, no proven treatment exists for coronavirus disease
(COVID-19), though different types of treatment modalities are being
practiced around the world. Small-scale convalescent plasma (CP)
therapies from COVID-19 recovered donors have shown favorable results
with fewer adverse consequences. In this systematic review, we aimed to
determine the safety and efficacy of CP as a therapy for COVID-19.
Methods: The English language databases of PubMed, Google Scholar, and
ScienceDirect were searched upto 22 May 2020. Eligibility for inclusion,
risk of bias assessment, and data extraction from the included studies
was determined and a narrative synthesis was conducted. Results: A total
of 12 studies were selected for review. The overall risks of bias was
high. The results revealed that the initiation of CP therapy during the
early stages of viremia was significant in a safety and efficacy
viewpoint. The patients were also receiving concomitant drugs and other
supportive therapies in 10 studies. Viral loads were documented to
decrease and become negative in 8 studies within 3-26 days
post-transfusion. The improvement in clinical symptoms following CP
therapy was demonstrated in 9 studies. Most of the patients experienced
very few adverse effects. There were a total of 622 mortalities out of
5079 patients in total studies. Conclusions: The rational practice of CP
therapy based on a risk-benefit judgment can prove to be an efficacious
therapeutic option until the approval of any therapeutic and/or
prophylactic agent(s), though substantial randomized controlled trials
(RCTs) are necessary to validate the effectiveness of such therapy.%
\end{abstract}%



\sloppy


\textbf{Abstract}

\textbf{Aim} : Till date, no proven treatment exists for coronavirus
disease (COVID-19), though different types of treatment modalities are
being practiced around the world. Small-scale convalescent plasma (CP)
therapies from COVID-19 recovered donors have shown favorable results
with fewer adverse consequences. In this systematic review, we aimed to
determine the safety and efficacy of CP as a therapy for COVID-19.

\textbf{Methods:} The English language databases of PubMed, Google
Scholar, and ScienceDirect were searched upto 22 May 2020. Eligibility
for inclusion, risk of bias assessment, and data extraction from the
included studies was determined and a narrative synthesis was conducted.

\textbf{Results} : A total of 12 studies were selected for review. The
overall risks of bias was high. The results revealed that the initiation
of CP therapy during the early stages of viremia was significant in a
safety and efficacy viewpoint. The patients were also receiving
concomitant drugs and other supportive therapies in 10 studies. Viral
loads were documented to decrease and become negative in 8 studies
within 3-26 days post-transfusion. The improvement in clinical symptoms
following CP therapy was demonstrated in 9 studies. Most of the patients
experienced very few adverse effects. There were a total of 622
mortalities out of 5079 patients in total studies.

\textbf{Conclusions} : The rational practice of CP therapy based on a
risk-benefit judgment can prove to be an efficacious therapeutic option
until the approval of any therapeutic and/or prophylactic agent(s),
though substantial randomized controlled trials (RCTs) are necessary to
validate the effectiveness of such therapy.

\textbf{INTRODUCTION}

COVID-19 is a respiratory tract infection caused by a new strain of
coronavirus called severe acute respiratory syndrome conoravirus -2
(SARS-CoV-2) that spread so rapidly from its first outbreak in late
December 2019 in Wuhan, Hubei province of China. There are altogether
5,267,419 confirmed cases with the death toll climbing at 341,155
worldwide as of 25 May 2020.\textsuperscript{1} This infectious disease
is associated with mild to severe symptoms such as fever, cough,
fatigue, shortness of breath to acute respiratory disease syndrome
(ARDS), sepsis, multi-organ failure including acute kidney injury and
cardiac injury in a complicated status resulting in
death\textsuperscript{2}. Old age, immune-compromised cases, and
comorbidities are the risk factors that lead to death in
COVID-19.\textsuperscript{2,3} A recent structural analysis indicated
the probable origin of the virus as a bat, from where it has transmitted
to humans after mutation in the spike glycoprotein and nucleocapsid
protein.\textsuperscript{4} Then human to human transmission started
mainly through contact with an infected person as it gets airborne and
by touching the face by hand after contact with an object containing the
virus.\textsuperscript{5} The world health organization (WHO) has
already declared it as a pandemic on 11 March 2020 due to the over
118,000 reported cases from 110 countries around the world by that time
with the sustained risk of further global spread.\textsuperscript{6}

Still, there is no proven treatment to cure the condition due to the
lack of substantial evidence. The time constraint and pandemic outbreak
are the major challenges to deal with COVID-19. Supportive care has been
practiced as stated in the WHO interim guidance for COVID-19 management
with a major focus on oxygenation, ventilation, symptomatic treatment,
fluid management, and prevention of complications based on the clinical
status of patients.\textsuperscript{2} Different therapeutic agents are
being used in clinical settings around the world, some of which are like
a combination of azithromycin and hydroxychloroquine, antivirals like
remdesivir, oseltamivir, ganciclovir, combination of lopinavir and
ritonavir, and steroids.\textsuperscript{7} Recently conducted RCT has
shown a lower rate of seroconversion and more adverse effects with
hydroxychloroquine among mild to moderate COVID-19
cases.\textsuperscript{8} Other observational studies also showed no
clinical efficacy with hydroxychloroquine.\textsuperscript{9} As a ray
of hope, the emergency use of remdesivir has been recently approved by
the US-Food and Drug Administration (US-FDA) to be used in certain
conditions\textsuperscript{10}, though its use has not led to
significant benefit in RCT conducted by China.\textsuperscript{11}

CP therapy is one of the approaches adopted following the guidance
provided by the US-FDA to use CP as an investigational product during
such a global health crisis.\textsuperscript{12,13} The lack of
effective intervention has made it necessary to explore and review CP
therapy as a potential therapeutic modality for COVID-19. It is a
classical adaptive immunotherapy where antibodies from the plasma
samples of patients recovered from a virus are transfused with adequate
neutralizing antibody titers to the patient affected by the same virus
as a therapy or a prophylactic measure to patients exposed to the same
virus.\textsuperscript{14,15}

\textbf{Figure 1}: Convalescent plasma therapy process for COVID-19

\textbf{METHODS}

This review article was based on the PRISMA
protocol.\textsuperscript{16}

\textbf{Search strategy}

PubMed, Google Scholar, and Science Direct were searched for
``COVID-19'', ``Convalescent plasma therapy'', ``COVID-19 plasma
therapy'', ``Plasma therapy coronavirus'', and ``SARS-CoV-2 plasma
therapy'' for articles published till 25 May 2020. The search strategies
used can be found in\textbf{supplementary data 2}.

\textbf{Inclusion criteria}

The original research articles including case reports, case series,
observational studies, retrospective studies, randomized or controlled
studies about CP therapy for the treatment of COVID-19 were reviewed and
included.

\textbf{Exclusion criteria}

The exclusion criteria considered were articles about other viral
pandemics without any discussion of COVID-19 and its management with CP
therapy. Review articles, viewpoints, editorials, letters, perspectives,
comments, and protocols were excluded along with non-English literature
and articles with no full text.

\textbf{Extraction of data}

Data were extracted by two reviewers separately and a table was filled
according to the data. Studies were selected by two reviewers (SK and
PB) owing to the criteria and any differences between articles
selections were resolved based on the review of a third person (DBS).

\textbf{Assessment of bias}

The overall bias for our study was determined to be high. All our
studies were non-randomized. The sample size was small in most of the
studies except Joyner's study (n = 5000), but it was a non-randomized
trial. We found the selection bias to be high among all our studies. No
blinding of treating physicians and patients was done in most of the
cases. In a few studies, the lack of proper follow up of the patient's
outcome was mentioned like Joyner's study. In most studies, other
prognostic factors like chronic medical conditions were not taken into
account. The detailed bias assessment is done in the\textbf{figure 2}.

\textbf{Statistical analysis}

It was not possible for a meta-analysis because of the inadequacy of
research articles.

\begin{enumerate}
\tightlist
\item
  \textbf{RESULTS}
\item
  \textbf{Study selection}
\end{enumerate}

A total of 1128 potentially eligible articles were retrieved from the
initial database searches. After the exclusion of 132 duplicates, the
abstracts of 996 articles were reviewed. 939 articles were excluded
because of the unavailability of full texts, other languages, and being
predominantly not related to plasma therapy and COVID 19. Full texts of
57 articles were extracted and among them, we selected 12 studies for
review as depicted in \textbf{figure 3} .

Figure 3: Prisma flow diagram of the study process

Out of the 12 studies included; 6 studies were case-series, 3 case
reports, and the rest of the 3 studies were a single-arm prospective
intervention, retrospective observational study, and clinical trial. The
extracted studies are mentioned in \textbf{table 1} , including their
important particulars. Eight studies were conducted in China, three in
the United States (US), and the rest in South Korea.

\textbf{Study population}

A total of 5079 patients were involved in 12 studies with 3197 males,
1856 females, and 23 other genders. The age range of the people was 19
-- 97 across the 12 studies. Two pregnant patients were present in
studies.\textsuperscript{17,18} Comorbidities like chronic obstructive
pulmonary disease (n = 2), hypertension (n = 17), and diabetes
mellitus(DM) (n = 16) were present in the 7
studies.\textsuperscript{14,17-23}

\textbf{Dosage and neutralizing antibody titer}

The dosage of CP therapy was varied from 200 -- 2500 ml across 12
studies. The most frequently used dosage was 200 ml across 7 studies.
Only 2 studies conducted by Shen et al and Duan et al mentioned the
neutralizing antibody titer following CP therapy, which was found to be
1:80-1:480 and 1:640, respectively.\textsuperscript{14,19}

\textbf{Initiation of CP therapy}

CP therapy was initiated 1-37 days after admission to the hospital or 4
-- 31 days after onset of symptoms. Initiation of CP therapy during the
early stages of viremia has generally been shown to be more beneficial
in various studies.\textsuperscript{18,23} The quickest initiation of CP
therapy on the first day of admission was done in the study of Anderson
et al.\textsuperscript{18}

\textbf{Intensive care unit (ICU) admission and mechanical ventilation}

A total of 3391 patients were admitted to ICU in 12 studies. 49 patients
were mechanically ventilated in 10 studies. In nine studies, nine
patients received low oxygen flow therapy, while 17 patients received
high flow oxygen therapy. According to Joyner et al, 72\% (n=3600)
patients had respiratory failure and most likely required ventilator
support or other forms of oxygen therapy, but the modality has not been
mentioned.\textsuperscript{24} ARDS was diagnosed in 1750 cases across
10 studies except for Pei et al and Joyner et al.

\textbf{Concomitant therapy}

Antiviral, interferon, and steroids were widely used across all studies.
Remdesvir was used in 2 studies done in the US by Andersen et al and
Salazar et al.\textsuperscript{18,23} Antibacterials like azithromycin,
levofloxacin, and vancomycin were used along with antifungals.
Hydroxychloroquine was used in 4 studies. Azithromycin,
hydroxychloroquine, and remdesevir were used concomitantly in 2 studies
done by Salazar et al and Andersen et al in the
US.\textsuperscript{18,23} The Chinese herbal medication was practiced
in a study by Tan et al in China.\textsuperscript{25}

\textbf{Clinical benefit and discharge following CP therapy}

The improvement in clinical symptoms following CP therapy has been
mentioned in 9 studies. Studies conducted by Joyner et al and Pei et al
did not properly mention such improvement.\textsuperscript{24,26} About
75 patients in 9 studies required different forms of respiratory support
at baseline. In Tan's study, the patient was clinically stable before CP
therapy and remained stable until the end.\textsuperscript{25}

Shen et al reported a normal temperature of patients within 3 days (n =
4).\textsuperscript{19} An increase in PaO2/FiO2 was obtained within 12
days (Range: 172 -- 276 before and 284 - 366 after) despite patients
having severe ARDS before CP therapy. Neutralizing antibody titers
increased (Range: 40 - 60 before and 80 - 320 on day 7) with the
resolution of ARDS (n = 4) at 12 days and weaning of mechanical
ventilation (n = 3) in 2 weeks. Three patients were discharged 32-35
days post CP therapy.

Zhang et al described extubation of 2 patients in 31 and 39 days of
hospital stay, although all 4 patients had severe ARDS at
baseline.\textsuperscript{20} Three patients were discharged from 7 --
27 days post CP therapy. One patient got shifted to the ICU. Chest
computed tomography (CT) showed a complete resolution in 1 case.

Ahn et al reported an increase in PaO2/ FiO2 to 230 and 300 on days 9
and 18 in 2 patients who had severe ARDS at
baseline.\textsuperscript{21} Weaning from ventilation and tracheostomy
was done in 1 patient. Another patient was extubated and discharged at
18 days post CP therapy.

Duan et al mentioned improvement in clinical symptoms in 1-3 days
following CP therapy and decreased respiratory support in 4 of the 10
patients.\textsuperscript{14} The resolution of CT abnormalities was
seen in 7 days. Normal lab findings and improvement in pulmonary
functions reported after CP therapy. Then, 3 cases were discharged and 7
were prepared for discharge.

Ye et al reported improvement in clinical symptoms and resolution of CT
scans in 4 patients requiring oxygen support following CP
therapy.\textsuperscript{17} Four patients were discharged 4 - 10 days
post-transfusion.

Zeng et al described the discharge of 2 patients, one from treatment and
another from the control group.\textsuperscript{22} Nothing was
mentioned about the clinical benefit following CP therapy with a primary
focus on the clearance of viral load. All 21 patients were in ICU from
both control and treatment groups at baseline.

Pei et al described 2 successful cases of CP therapy who were discharged
on 7 and 14 days post-transfusion. The patient who had anaphylaxis to
such therapy was discharged later than successful cases on 23 days post
failed transfusion.\textsuperscript{26}

Salazar et al described changes in clinical status on day 7 and day 14
using a 6 point WHO ordinal scale.\textsuperscript{23} All 25 patients
were in critical condition and admitted to ICU at baseline. At day 7
post-transfusion, 9 patients got improvement, while 13 remained static
and 3 deteriorated. At day 14 post-transfusion, 19 patients got
clinically better, while 3 were unchanged, 3 deteriorated, and 1 died.
At days 7 and 14, the discharged cases were 7 and 11, respectively. This
was a prospective study that demonstrated clinical benefit following CP
therapy.

Anderson et al described a patient who required high flow oxygen on the
day of CP therapy and was intubated a day post CP
transfusion.\textsuperscript{18} She was extubated after 9 days, oxygen
support was withdrawn after 10 days, and discharged after 13 days
post-transfusion. The patient was continued on remdesivir which affects
the certainty of evidence regarding the benefit being solely due to CP
therapy.

Yang et al described a patient who required non-invasive positive
pressure ventilation at baseline. Upon 4 doses of CP therapy, the
clinical and radiological improvement was demonstrated after 3 days of
the fourth plasma transfusion.\textsuperscript{27}

\textbf{Mortality}

Out of 5079 patients across 12 studies, the mortality reached 622. No
mortalities were there in 9 studies (n=33). Among the rest 3 studies; 1
mortality in Salazar's study, 19 in Zeng's study where 5 in treatment
and 14 in the control group, and 602 mortality in 7 days after CP
therapy in Joyner's study were demonstrated.\textsuperscript{22-24}

\textbf{Viral load after CP therapy}

Viral loads were documented to decrease and become negative in 8
studies.\textsuperscript{14,17,19-22,25} The time frame for negative
viral load post CP therapy varied from 3-26 days. Zeng et al performed a
retrospective observational study in which viral clearance was 100 \% in
the treatment group (n = 6) and only 21.4\% in control group, which
supports the evidence of quicker viral clearance with CP
therapy.\textsuperscript{22} Similarly, a study conducted by Tan et al
demonstrated a negative viral load a day after
transfusion.\textsuperscript{25}

\textbf{3.10 Adverse effects}

Most of the patients experienced very few adverse effects. The incidence
of adverse effects and mortality rate were \textless{} 1 \% and 0.3\%,
respectively, as stated by Joyner et al. Transfusion-associated
circulatory overload (TACO) (n = 7), transfusion-related lung injury
(TRALI) (n = 11) , and severe allergic reactions (n = 3) were
reported.\textsuperscript{24} This is the largest study done and was
focused especially on the safety of CP therapy. Besides, a study done by
Pei et al. showed anaphylaxis as a severe side effect of CP therapy, but
the number of study subjects was small.\textsuperscript{26} Some
abnormal skin reactions like red spots or morbilliform rash have been
explained in only one patient each in the study done by Duan and Salazar
et al.\textsuperscript{14,23} Fever was seen in a study done by Tan et
al following CP therapy.\textsuperscript{25}

Table 1\textbf{:}Studies on CP therapy for~COVID-19 treatment

Currently, 75 clinical trials are being done all around the
world\textsuperscript{28}(Supplementary data 3 \textbf{-- Clinical
trials/ Table 2} ). With most of the 30 trials in the US, followed by
other trials in Colombia-5 trials, Mexico-5 trials, Italy- 4 trials, and
Egypt-3 trials. Switzerland, Chile, France, Canada, Sweden, Spain, and
India are conducting 2 trials each. While countries like North
Macedonia, Russian Federation, Saudi Arabia, Pakistan, Netherlands,
Bahrain, China, Hungary, Indonesia, Argentina, Iran, and Denmark are
also conducting 1 trial each. No location is being provided in the case
of 2 trials. A total of 40 trials are recruiting participants while 24
trials have not yet begun recruiting. There are 2 active and not
recruiting trials, 3 trials are enrolled by invitation, and 6 trials are
in available status. A total of 2 trials are observational and 6
available trials are of expanded excess type, while the rest of the
trials are RCTs. The smallest trial enrollment is 10 while the largest
trial enrollment is 2000.\textsuperscript{28}

\textbf{DISCUSSION}

The review was primarily done to focus on the therapeutic efficacy and
safety of CP therapy among COVID 19 patients. For this purpose, we
included 12 different studies ranging from case series, case reports,
case trials, observational cohort study, retrospective study, and
single-arm intervention study.

Only one CT has been done so far, which has primarily focused on the
early safety of CP therapy.\textsuperscript{24} Based on the trial,
there has been preliminary evidence of CP therapy being a safe treatment
with \textless{} 1 \% mortality. Due to the lack of studies focusing on
the therapeutic efficacy of CP therapy alone, a query remains to
comprehend whether the results of the studies were due to natural
disease progression, CP therapy, or other concomitant treatments. Major
outcomes are discussed below:

\textbf{Mortality following CP therapy}

There were a total of 622 mortalities out of 5079 patients across the 12
studies. The majority of mortalities were found in the clinical trials
with a total of 602 mortalities in Joyner's study, but this trial is in
the early phase and more reporting is still to be done as only 5000/8932
trial reports are mentioned in this study.\textsuperscript{24} Zeng's
study has 19 mortalities out of 21 patients which can be considered
high, but CP therapy was given at a median of 21.5 days after infection,
and there is theoretical evidence that such therapy is only most
effective when given early in the disease
course.\textsuperscript{22}Salazar's study had just 1 mortality out of
25 patients as CP therapy was given early with a median of 10 days from
the onset of symptoms.\textsuperscript{23} Therefore, early initiation
of CP therapy might have a positive impact on mortality. However, in 10
studies except for Joyner's and Pie's study, the patients received
concomitant drug therapy, which puts a query in the determination of the
exact effect of CP therapy even though the CP therapy was initiated
earlier.

\textbf{Improvement of clinical symptoms}

Clinical improvements were seen in 9 studies following CP therapy,
though most of the patients required respiratory support at baseline.
Finally, most patients were weaned from ventilator support and other
forms of oxygen therapy.

\textbf{ICU Admission and discharge}

The range for the discharge of patients was from 4 - 35 days following
CP therapy across 9 studies. The total number of patients discharged was
49 out of 79 across 11 studies except for the study conducted by Joyner
et al. Among the studies reviewed, a total of 3391 patients were
admitted to ICU. Most of the patients did not need ICU at the end and
some got discharged in 10 studies. The studies conducted by Joyner et al
and Pei et al did not mention the patients' status at the
end.\textsuperscript{24,26}

\textbf{Viral load and antibody titer}

Viral loads were negative following CP therapy in 8 studies and antibody
titers following such therapy were measured only in 2
studies.\textsuperscript{14,19}. It is important to conduct trials on
known antibody titers following CP therapy as it is important to
determine the protective titer that is necessary for safeguarding
against COVID-19. US-FDA has recommended the~titer~of 1:160 for the
donation of blood for plasma.\textsuperscript{13}~The
protective~titer~of the antibody for Middle East respiratory syndrome
was found to be 1:80 in a study conducted by Ko et
al.\textsuperscript{29} Two of the reviewed studies found the antibody
titer following CP therapy to be 1:80-1:480 and
1:640.\textsuperscript{14,19} In Zhang's study, the IgG antibody titer
after 29-46 days of 6 patients who recovered from COVID-19 without the
use of CP therapy was found to be more than 1:320 among 5 of the 6
donors.\textsuperscript{30} It is not clear whether the antibody titers
mentioned in the 2 studies were due to CP therapy alone or as an innate
immune response to the infection like in Zhang's study.

\textbf{Adverse effects}

Because of the large clinical trials done in the US where the results of
5000 people are out, it is remarkable that CP therapy is a safe
treatment option for COVID-19 as only \textless{} 1\% adverse events
have been observed with 0.3\% mortality.\textsuperscript{24} However,
the trial was not randomized and early reporting of 5000 cases may have
led to selection bias in the studies. Based on multiple studies, the
adverse events found were severe allergic reactions including
anaphylaxis, TACO, TRALI, transient red macular spots, morbilliform
rash, and fever.\textsuperscript{14,23-26}

\textbf{LIMITATIONS OF THE STUDY}

Most of the included studies were case reports and case series. Only one
clinical trial was included which focused solely on side effects and was
non-randomized and had early reporting. Because of incomplete clinical
trials focusing on the therapeutic efficacy of CP therapy so far, we
could not include these in our study. Most of our studies lacked a
control group except for the one conducted by Zeng et al. There was a
moderate to high risk of biases in our studies.

\textbf{CONCLUSION}

Based on data from the reviewed studies; CP therapy, in addition to
concomitant drug therapy and other supportive therapies, has shown
superior evidence in clinical improvement, viral clearance, safety, and
survival rate. The perplexities remain for getting a conclusion about
the possible favorable outcome is due to CP therapy alone based on given
evidence and not due to natural disease progression or additional
therapies. This question can only be answered after the ongoing RCTs
focusing on therapeutic efficacy in terms of mortality rates,
requirements of respiratory support, changes in viral load, and antibody
titers following therapy are completed. In the end, it is noteworthy to
tackle the global pandemic by CP therapy as a last resort along with
additional therapies accompanied by risk-benefit judgment until the
availability of therapeutic and/or prophylactic agent(s) for use.

\textbf{Acknowledgment}

We are highly thankful to Ms. Pragya Pandey, Kathmandu, and Muhammad
Abdul Jabar Adnan, Lecturer Department of Sports Science and Physical
Education, University of the Punjab, Lahore, for their help in the
finalization of this manuscript.

\textbf{Conflict of interest}

We have no conflict of interest for writing this review

\textbf{Authors' contributions}

SK and MS conceived the idea. MS reviewed the manuscript and guided in a
systematic analysis. SK, DBS, and PB contributed to the literature
search and systematic analysis and drafted the manuscript.

All the co-authors read and approved the final manuscript.

\textbf{Funding statement}

We have not received any funding for this work.



\textbf{REFERENCES}

1. Coronavirus (COVID-19). WHO. https://who.sprinklr.com/. Published
2020. Accessed May 25, 2020.

2. Clinical management of severe acute respiratory infection (SARI) when
COVID-19 disease is suspected. WHO.
file:///C:/Users/Admin/Downloads/WHO-2019-nCoV-clinical-2020.4-eng.pdf.
Published 2020. Accessed May 21, 2020.

3. CDC. Coronavirus Disease.
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html.
Published 2020. Accessed May 25, 2020.

4. Benvenuto, D., Giovanetti, M., Ciccozzi, A., Spoto, S., Angeletti,
S., \& Ciccozzi M. The 2019-new coronavirus epidemic: evidence for virus
evolution. \emph{J Med Virol} . 2020;92(4):455-459.

5. Shereen, M. A., Khan, S., Kazmi, A., Bashir, N., \& Siddique R.
COVID-19 infection: origin, transmission, and characteristics of human
coronaviruses. \emph{J Adv Res} . 2020;24:91-98.
doi:https://doi.org/10.1016/j.jare.2020.03.005

6. World Health Organization Declares COVID-19 a ``Pandemic.'' Here's
What That Means. \emph{Time} . March 2020.
https://time.com/5791661/who-coronavirus-pandemic-declaration/.

7. Cunningham, A. C., Goh, H. P., \& Koh D. Treatment of COVID-19: old
tricks for new challenges. \emph{Crit Care} . 2020;24(91).
doi:https://doi.org/10.1186/s13054-020-2818-6

8. Tang, W., Cao, Z., Han, M., Wang, Z., Chen, J., Sun, W., \ldots{} \&
Chen W. Hydroxychloroquine in patients with mainly mild to moderate
coronavirus disease 2019: open label, randomised controlled
trial.\emph{BMJ} . 2020;369:m1849. doi:https://doi.org/10.1136/bmj.m1849

9. Mah\selectlanguage{ngerman}évas, M., Tran, V. T., Roumier, M., Chabrol, A., Paule, R.,
Guillaud, C., \ldots{} \& Schlemmer F. Clinical efficacy of
hydroxychloroquine in patients with covid-19 pneumonia who require
oxygen: observational comparative study using routine care
data.\emph{BMJ} . 2020;369:m1844. doi:https://doi.org/10.1136/bmj.m1844

10. Coronavirus (COVID-19) Update: FDA Issues Emergency Use
Authorization for Potential COVID-19 Treatment. US-FDA.
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment.
Published 2020. Accessed May 21, 2020.

11. Wang, Y., Zhang, D., Du, G., Du, R., Zhao, J., Jin, Y., \ldots{} \&
Hu Y. Remdesivir in adults with severe COVID-19: a randomised,
double-blind, placebo-controlled, multicentre trial. \emph{Lancet} .
2020. doi:https://doi.org/10.1016/S0140-6736(20)31022-9

12. Chen, L., Xiong, J., Bao, L., \& Shi Y. Convalescent plasma as a
potential therapy for COVID-19. \emph{Lancet Infect Dis} .
2020;20(4):398-400.

13. Recommendations for Investigational COVID-19 Convalescent Plasma.
US-FDA.
https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma.
Published 2020. Accessed May 25, 2020.

14. Duan, K., Liu, B., Li, C., Zhang, H., Yu, T., Qu, J., \ldots{} \&
Peng C. Effectiveness of convalescent plasma therapy in severe COVID-19
patients. \emph{Proc Natl Acad Sci} . 2020;117(17):9490-9496.
doi:https://doi.org/10.1073/pnas.2004168117

15. Casadevall, A., \& Pirofski LA. The convalescent sera option for
containing COVID-19. \emph{J Clin Invest} . 2020;130(4).

16. Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P.
C., Ioannidis, J. P., \ldots{} \& Moher D. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that evaluate
health care interventions: explanation and elaboration. \emph{Ann Intern
Med} . 2009;151(4):W-65.

17. Ye, Mingxiang., Fu, Dian., Ren, Yi., Wang, Faxiang., Wang, Dong.,
Fang, Zhang., Xia, Xinyi., \& Lv T. Treatment with convalescent plasma
for COVID\selectlanguage{english}-19 patients in Wuhan, China. \emph{J Med Virol} . 2020.
doi:https://doi.org/10.1002/jmv.25882

18. Anderson, J., Schauer, J., Bryant, S., \& Graves CR. The use of
convalescent plasma therapy and remdesivir in the successful management
of a critically ill obstetric patient with novel coronavirus 2019
infection: A case report. \emph{Case Reports Women's Heal} .
2020;27:e00221. doi:https://doi.org/10.1016/j.crwh.2020.e00221

19. Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., \ldots{}
\& Wei J. Treatment of 5 critically ill patients with COVID-19 with
convalescent plasma. \emph{Jama} . 2020;323(16):1582-1589.
doi:10.1001/jama.2020.4783

20. Zhang, B., Liu, S., Tan, T., Huang, W., Dong, Y., Chen, L., \ldots{}
\& Zou Y. Treatment with convalescent plasma for critically ill patients
with SARS-CoV-2 infection. \emph{Chest} . 2020.
doi:https://doi.org/10.1016/j.chest.2020.03.039

21. Ahn JY, Sohn Y, Lee SH et al. Use of Convalescent Plasma Therapy in
Two COVID-19 Patients with Acute Respiratory Distress Syndrome in
Korea.\emph{J Korean Med Sci} . 2020;35(14).
doi:10.3346/JKMS.2020.35.E149

22. Zeng, Q. L., Yu, Z. J., Gou, J. J., Li, G. M., Ma, S. H., Zhang, G.
F., \ldots{} \& Li C. Effect of convalescent plasma therapy on viral
shedding and survival in COVID-19 patients. \emph{J Infect Dis} . 2020.
doi:https://doi.org/10.1093/infdis/jiaa228

23. Salazar, E., Perez, K. K., Ashraf, M., Chen, J., Castillo, B.,
Christensen, P. A., \ldots{} \& Subedi S. Treatment of COVID-19 Patients
with Convalescent Plasma in Houston, Texas. \emph{medRxiv} . 2020.
doi:https://doi.org/10.1101/2020.05.08.20095471

24. Joyner, M., Wright, R. S., Fairweather, D., Senefeld, J., Bruno, K.,
Klassen, S., \ldots{} \& Rea R. Early Safety Indicators of COVID-19
Convalescent Plasma in 5,000 Patients. \emph{medRxiv} . 2020.
doi:https://doi.org/10.1101/2020.05.12.20099879

25. Tan, L., Kang, X., Zhang, B., Zheng, S., Liu, B., Yu, T., \ldots{}
\& Miao H. A special case of COVID-19 with long duration of viral
shedding for 49 days. \emph{medRxiv} . 2020.
doi:https://doi.org/10.1101/2020.03.22.20040071

26. Pei, S., Yuan, X., Zhang, Z. Z., Yao, R. R., Xie, Y., Shen, M. M.,
\ldots{} \& Yin M. Convalescent plasma to treat covid-19: Chinese
strategy and experiences. \emph{medRxiv} . 2020.
doi:https://doi.org/10.1101/2020.04.07.20056440

27. Yang, X., Sui, Y., Liu, F., Kang, Z., Wu, S., Zhao, J., \ldots{} \&
Zhang Y. Clinical Characteristics and Convalescent Plasma Therapy in
Severe and Critically Ill COVID-19 Patients. \emph{Prepr with LANCET} .
2020. https://papers.ssrn.com/sol3/papers.cfm?abstract\_id=3576894.

28. ClinicalTrials.gov. NIH U.S. National Library of Medicine.
https://clinicaltrials.gov/ct2/results?term=covid+19+convalescent+plasma\&Search=Search.
Published 2020. Accessed May 25, 2020.

29. Ko, J. H., Seok, H., Cho, S. Y., Ha, Y. E., Baek, J. Y., Kim, S. H.,
\ldots{} \& Cho D. Challenges of convalescent plasma infusion therapy in
Middle East respiratory coronavirus infection: a single centre
experience. \emph{Antivir Ther} . 2018;23(7):617-622.
doi:10.3851/imp3243

30. Zhang, L., Pang, R., Xue, X., Bao, J., Ye, S., Dai, Y., \ldots{} \&
Yi Y. Anti-SARS-CoV-2 virus antibody levels in convalescent plasma of
six donors who have recovered from COVID-19. \emph{Aging (Albany NY)} .
2020;12(8):6536-6542. doi:10.18632/aging.103102\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-(Convalescent-plasma-therapy-process-for-COVID-19)/Figure-1-(Convalescent-plasma-therapy-process-for-COVID-19)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-(Bias-Assessment)/Figure-2-(Bias-Assessment)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-(Prisma-Flow-Diagram)/Figure-3-(Prisma-Flow-Diagram)}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1 (Studies Reviewed).docx`  available at \url{https://authorea.com/users/329335/articles/456329-safety-and-efficacy-of-convalescent-plasma-therapy-for-the-management-of-covid-19-a-systematic-review}

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