Received: 23 April 2020 Revised: 4 June 2020 Accepted: 10 June 2020

DOI: 10.1002/jca.21806

CONCISE REVIEW

Convalescent plasma therapy in patients with COVID-19

çe Nur Yig

Tug
enog

lu1 | Tuba Hacıbekirog _

lu2 | Ilhami Berber3 |
Mehmet Sinan Dal1 | Abdülkadir Baştürk4 | Sinem Namdarog
lu5 |
Serdal Korkmaz6 | Turgay Ulas7 | Tuba Dal8 | Mehmet Ali Erkurt3 |
Burhan Turgut9 | Fevzi Altuntaş1,10
1
Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, University of Health
Sciences, Ankara, Turkey
2
School of Medicine, Department of Internal Medicine, Division of Hematology, Sakarya University, Sakarya, Turkey
3
School of Medicine, Department of Internal Medicine, Division of Hematology, Inonu University, Malatya, Turkey
4
School of Medicine, Department of Internal Medicine, Division of Hematology, Selcuk University, Konya, Turkey
5
Bozyaka Training and Research Hospital, Department of Hematology, University of Health Sciences, Izmir, Turkey
6
Kayseri Training and Research Hospital, Department of Hematology, University of Health Sciences, Kayseri, Turkey
7
School of Medicine, Department of Internal Medicine, Division of Hematology, Near East University, Nicosia, Cyprus
8
School of Medicine, Department of Clinical Microbiology, Ankara Yıldırım Beyazıt University, Ankara, Turkey
9
School of Medicine, Department of Internal Medicine, Division of Hematology, Namık Kemal University, Tekirda
g, Turkey
10
School of Medicine, Department of Internal Medicine, Division of Hematology, Ankara Yıldırım Beyazıt University, Ankara, Turkey

Correspondence
Tu
gçe Nur Yi
geno
glu, Department of Abstract
Hematology and Bone Marrow There are currently no licensed vaccines or therapeutics for COVID-19. Anti-
Transplantation Center, Ankara Oncology
SARS CoV-2 antibody-containing plasmas, obtained from the recovered indi-
Training and Research Hospital,
University of Health Sciences, Ankara, viduals who had confirmed COVID-19, have been started to be collected using
Turkey. apheresis devices and stored in blood banks in some countries in order to
Email: [email protected]
administer to the patients with COVID-19 for reducing the need of intensive
care and the mortality rates. Therefore, in this review, we aim to point out
some important issues related to convalescent plasma (CP) and its use in
COVID-19. CP may be an adjunctive treatment option to the anti-viral therapy.
The protective effect of CP may continue for weeks and months. After the
assessment of the donor, 200-600 mL plasma can be collected with apheresis
devices. The donation interval may vary between countries. Even though lim-
ited published studies are not prospective or randomized, until the develop-
ment of vaccines or therapeutics, CP seems to be a safe and probably effective
treatment for critically ill patients with COVID-19. It could also be used for
prophylactic purposes but the safety and effectiveness of this approach should
be tested in randomized prospective clinical trials.

KEYWORDS
convalescent plasma, COVID-19, SARS CoV-2

J Clin Apher. 2020;35:367–373. wileyonlinelibrary.com/journal/jca © 2020 Wiley Periodicals LLC. 367

368 YIĞENOĞLU ET AL.

1 | INTRODUCTION need of intensive care. Therefore, in this review, we aim

to point out some important issues related to convales-
At the end of 2019, pneumonia patients with an uni- cent plasma (CP) and its use in COVID-19.
dentified cause were started to be observed in Wuhan,
Hubei Province, China.1 After the genetic analysis of the
virus, it was understood that these pneumonia cases were 2 | TREATMENT O F I NFECTIOUS
caused by the 2019 Novel Coronavirus (2019-nCoV).2 On DISEASES WITH CONVALESCENT
11 February 2020; the disease was officially named as PLA SMA : H ISTOR IC AL EXAM P LES
COVID-19, by the World Health Organization (WHO).3
This novel coronavirus was named as SARS-CoV-2 by the In the past, plasma-mediated treatments have been used
International Committee on Taxonomy of Viruses.4 It against many pathogens. Passive immunization obtained
was declared a pandemic by the WHO on 11 March 2020. from sheep serum against diphtheria toxin was first given
As of 17 April 2020, in the worldwide, there have been to a child with diphtheria in 1891 and saved his life. Ger-
2 175 130 confirmed cases of COVID-19, including man scientist Emil Adolf von Behring received the 1901
145 184 deaths, as reported to WHO.3 The mortality rate Nobel Prize for his discovery of passive immunization
of COVID-19 is higher than the mortality rate of seasonal against diphtheria toxin. CPs have been used in epi-
influenza in which the mortality rate is reported usually demics of viral infections like poliomyelitis, measles,
less than 0.1%.3 Patients with any comorbidity and/or mumps and flu.6
older age are associated with poorer clinical outcomes Experience in the use of CP against coronavirus was
than younger patients or those without any comorbidity. obtained from Severe Acute Respiratory Syndrome 1
As the number of comorbidities increases, the clinical (SARS-COV-1) outbreaks in 2003. In the retrospective
outcome gets worse. Smoking, chronic obstructive pul- non-randomized study conducted by Soo et al, 40 SARS
monary disease, diabetes, hypertension, cardiovascular patients refractory to ribavirin and 1.5 g of pulsed meth-
diseases, and malignancy are reported to be the risk fac- ylprednisolone received either 200-400 mL CP (n = 19) or
tors for severe COVID-19 and increased mortality.5 a further dose of pulsed methylprednisolone (n = 21). In
Although there are clinical trials regarding the develop- patients who received CP, higher discharge rate up to
ment of therapeutics and vaccines, there are currently no 22 days from the hospital (77.8% vs 23%; P = .004) and
licensed vaccines or therapeutics for COVID-19. Because lower mortality rate (0% vs 23.8%; P = .049) was observed
of the higher mortality rate and the high number of compared to the patients who received steroids. The
infected cases, it is important to find a treatment in a authors also observed that patients receiving CP after day
short time. 16 had a poor clinical response and concluded that CP
Passive antibody therapy involves administering anti- administration was more effective when given early in
bodies against a particular agent to a susceptible individ- the course of the disease.8 In Taiwan, Yeh et al reported
ual in order to protect or treat an infectious disease three healthcare workers with SARS-COV-1, who had
associated with this agent. On the contrary, active vacci- failed to respond to steroids, ribavirin, intravenous
nation requires stimulation of an immune response that immunoglobulin and protease inhibitors, were treated
takes time to develop. Therefore, passive antibody admin- with 500 mL CP. All of the patients survived after CP
istration is the only way to immunize susceptible people transfusion.9 Besides, Cheng et al evaluated the efficacy
immediately. Passive antibody therapy has a history of CP in the treatment of patients with SARS in 2003 and
going back to the 1890s and was the only method of found a higher day-22 discharge rate among patients who
treating some infectious diseases before the development received CP before day 14 of illness.10
of antimicrobial therapy in the 1940s.6 Currently, passive CP was also used in the West African Ebola epidemic
antibody therapy is mainly consisting of pooled immuno- in 2013. Eighty-four patients received 500 mL of CP.
globulin preparations that includes high concentrations When compared to the historical control group, the CP
of antibodies. On the other hand, CP has been used group had a shorter duration of symptoms than did the
emergently in epidemics where there is insufficient time control group. From day 3 to day 16 after diagnosis, the
to produce immunoglobulin preparations.7 risk of death was 31% in the CP group and 38% in the
Anti-SARS COV-2 antibody containing plasma, control group. Even though the transfusion of up to
obtained from the recovered individuals who had con- 500 mL CP improved the symptoms, no significant sur-
firmed COVID-19, have been started to be collected by vival benefit was observed.11 Treatment with CP was also
apheresis devices and stored in blood banks in some reported in three patients with Middle East Respiratory
countries such as Turkey and the United States of Amer- Syndrome (MERS) in South Korea. In this study, 3 of 13
ica in hopes of reducing mortality rates and reduce the MERS patients with respiratory failure received 4 CP
YIĞENOĞLU ET AL. 369

infusions from recovered MERS-CoV-infected patients, Turkish Ministry of Health allowed the use of CP in
and only two of them showed neutralizing activity. After severe COVID-19.17 Therapeutic apheresis centers
the infusion of CP with a neutralizing activity titer of licensed by the Ministry of Health and Turkish Red Cres-
1:80, serological response was achieved but no response cent carry out activities for obtaining CP from donors. In
was achieved after the infusions of CP with a neutralizing Turkey, multidisciplinary working groups which have
activity titer of 1:40.12,13 been attended by a large number of scientists were
formed. These groups provide information and experi-
ence sharing among themselves by following donor selec-
3 | TREATMENT O F COVID-19 tion, product standard, treatment management, patient-
WITH CONVALESCENT PLASMA donor follow-up, and scientific developments in the
world. CP administrations are carried out under the con-
CP has been used in the recent global outbreak for the trol of intensive care, infectious disease specialists and
treatment of patients with COVID-19 in China. In the pulmonologists.
study conducted by Shen et al, 5 critically ill COVID-19
patients refractory to steroid and antiviral treatment,
received 400 mL CP from 5 different donors. All the 4 | C O NV A L E SC E NT P L A SM A :
donors had SARS-CoV-2-specific ELISA antibody titer THE MEC HANIS M OF AC TION
higher than 1:1000; and neutralizing antibody titer
greater than 40. After CP transfusion; in 4 (80%) of 5 The exact mechanism of CP in COVID-19 has not been
patients, the body temperature normalized within 3 days; clearly identified yet. However, previous studies revealed
the Sequential Organ Failure Assessment Score that the mechanism of action of CP in other viral infec-
decreased, and PaO2/FiO2 increased within 12 days tions such as Ebola virus and Respiratory Syncytial Virus
(range, first 172-276 and then 284-366); viral loads is mainly viral neutralization. The other mechanisms are
decreased and became negative within 12 days; ELISA antibody-induced cellular cytotoxicity, complement acti-
and neutralizing antibody titers increased. After 12 days, vation and phagocytosis. Neutralizing antibodies deliv-
acute respiratory distress syndrome (ARDS) improved in ered with CP can provide control of the viral load. Non-
4 patients (80%); after 2 weeks, 3 patients extubated; 3 of neutralizing antibodies may also contribute to prophy-
the 5 patients (60%) were discharged from the hospital laxis and/or enhance recovery.18,19
and the other two patients were stable after 37 days.14 In
a recent study, researchers treated 10 critically ill
COVID-19 patients with antiviral therapy and steroid, 5 | STEPS O F THE
plus a dose of 200 mL CP that had a neutralized antibody CONVALES CENT PLAS MA
titer of at least 1:640. Researchers prospectively compared COLLECTIONS
symptoms and laboratory findings 3 days after CP infu-
sion. Among all patients, CP was well tolerated. It signifi- The regulations of every single step of CP collections is
cantly increased neutralizing antibodies at a high level; very important. Starting from assessment of donor to the
within 7 days, viremia disappeared; clinical symptoms administration of CP to the patients, all of the steps
resolved rapidly in 3 days. There was an improvement in should be organized carefully and should be performed
lymphocyte count and in SaO2; on radiological examina- by experienced health workers.
tion, they reported that lung lesions changed significantly
within 7 days.15 Although these studies involve a small
number of patients, available information suggests that 5.1 | Donor eligibility
CP administration is safe and reduces the viral load.
On March 24, the American Food and Drug Adminis- The criteria for eligibility of CP donors may vary between
tration (FDA) published a recommendation with the countries. According to the FDA, individuals who meet
“COVID-19 Convalescent Plasma Research - Emergency” the following criteria can be a CP donor16:
declaration. FDA stated that certain standards have been
established for donation and that CP use is allowed for 1 Recovered from COVID-19, blood donor tests were
patients under certain conditions. Of note, FDA does not done and suitable for donation;
allow the use of CP for prophylaxis. With the “Blood Reg- 2 Evidence of COVID-19 documented by a laboratory
ulatory Network”, WHO suggested using CP when vac- test either by a diagnostic test (eg, nasopharyngeal
cines and anti-viral drugs are not available in the swab) at the time of illness, or a positive serological
treatment of critically ill patients with COVID-19.16 test for SARS-CoV-2 antibodies after recovery, if prior
370 YIĞENOĞLU ET AL.

diagnostic testing was not performed at the time 94.3% (IgM), and 79.8% (IgG) since day-15 after onset.
COVID-19 was suspected. RNA detectability decreased from 66.7% in samples col-
3 Complete resolution of symptoms at least 14 days prior lected before day-7 to 45.5% during days 15-39. The
to donation. authors suggested that combining RNA and antibody
4 Male donors, or female donors who have not been detections significantly improved the sensitivity of diag-
pregnant, or female donors who have been tested since nosis for COVID-19 in the first 1-week since onset.26 Cur-
their most recent pregnancy and results interpreted as rently, the findings that have been reported suggest that
negative for HLA antibodies. CPs that are collected ≥14 days after resolution of symp-
5 When measurement of neutralizing antibody titers is toms contain high titers of antibodies.22-25 According to
available, neutralizing antibody titers of at least 1:160 FDA if testing can be conducted, neutralizing antibody
is recommended. A titer of 1:80 may be considered titers should be at least 1:160 but a titer of 1:80 may be
acceptable if an alternative matched unit is not considered acceptable if an alternative matched unit is
available. not available.16

5.2 | Pre-donation evaluation of donors 5.3 | Donor recruitment

Real-time reverse transcriptase-PCR (RT-PCR) is cur- Blood centers may play a role in recruitment of donors in
rently a favored assay for the detection of coronavirus. collaboration with partner hospitals. In Turkey, thera-
However, RNA detectability was low in samples collected peutic apheresis centers licensed by the Ministry of
before day-7 and during days 15-39. For this reason, coro- Health and Turkish Red Crescent carry out activities for
navirus pre-donation screening tests should be supported obtaining CP from donors.
by antibody detecting tests.20 Each donor must meet all
eligibility criteria and be evaluated by all test required for
normal blood donation. Female donors with a history of 5.4 | Collection of convalescent plasma
pregnancy should be screened for HLA antibodies to at apheresis centers
minimize the risk of transfusion-related acute lung injury
(TRALI). In addition, a blood sample should be obtained Donors who have successfully completed pre-donation
for antibody testing before referring the donor to an evaluation are directed to the apheresis centers. CP
apheresis procedure. Unfortunately, neutralizing anti- should be collected by apheresis to take larger volumes in
body assays are not available in most centers. Quantita- short intervals. Approximately 200-600 mL plasma can
tive assays (eg, ELISA) are available but commercially be collected with apheresis devices depending on the
available assays have not been optimally validated. In total blood volume of the donor. The collected plasma
addition, the relationship between total anti-SARS-CoV-2 volume (excluding the anticoagulant solution) should not
antibodies and neutralizing anti-SARS-CoV-2 antibodies exceed 750 mL for each procedure. With the consent of
is not clear. There is also uncertainty as to whether total the donor, an appointment can be arranged for plasma
antibodies or subclasses (eg, IgM, IgG, or IgA) are the donation again. The donation interval may vary between
optimal measures, and which antigen is most informa- countries. CP is stored by freezing or applied within
tive.21,22 Limited data are currently available on the 6 hours without freezing. Freezing should be started
ELISAs. In a previous study, the efficacy of the antibody within the first 6 hours after the apheresis process is com-
test for the detection of IgM and IgG, has shown a sensi- pleted. Plasma components should be labeled using the
tivity and specificity of 88.7% and 90.6%, respectively. The ISBT128 coding system for traceability. The collected
antibody titer will differ according to the duration products can be individually labeled as 200 mL of divided
between the collection time and onset of infection. In ingredients and defined as 1 unit. Barcoded products
previous studies, seroconversion has been observed to should be stored at or below minus 18/25 in a separate
occur between 8 and 21 days after the onset of symp- storage cabinet. Appropriate patients can be given 200-
toms.22-25 In a study conducted in 173 patients with 400 mL of CP in accordance with the clinical research
COVID-19, the seroconversion rate for total antibodies protocol. ABO blood group should preferably be compati-
(Ab), IgM and IgG was 93.1%, 82.7%, and 64.7%, respec- ble. For pathogen inactivation process; amotosalen + UV
tively. The median seroconversion time for total Ab, IgM light, riboflavin + UV light, methylene blue or a solvent/
and then IgG were day-11, day-12 and day-14, separately. detergent may be used. But we would like to highlight
The presence of antibodies was <40% within 1-week that there has been no study that compared Anti-SARS-
since onset but rapidly increased to 100.0% (total Ab), CoV-2 CP that had undergone pathogen inactivation
YIĞENOĞLU ET AL. 371

process to those of not. In order to maximize transfusion • multiple organ dysfunction

safety, it is recommended that the CP should undergone
pathogen inactivation process. It should be irradiated if it
will be given to the patient without being frozen within 6 8 | PROPHYLAXIS
hours after the plasma collection. Otherwise, the frozen
plasma does not need to be irradiated. There is no clear indication and evidence of benefit by
using CP for prophylaxis for those who have been
exposed to SARS-CoV-2, this issue is still controversial
6 | THE DOSE OF CONVALESCENT and FDA does not allow the use of CP for prophylaxis
PLASMA outside of approved clinical trials.7,16 However, histori-
cally, it has been stated that passive antibody therapy is
In the previous studies, the dosing of CP is highly vari- most effective when administered prophylactically or
able. In clinical trials, one unit of plasma (200 mL) has used early after the onset of symptoms.30,31 The new,
been planned for use for prophylaxis and one to two units phase 2-3 trial is recruiting patients and still evaluating
have been planned for treatment. The antibodies' dura- the use of post-exposure prophylactic plasma in COVID-
tion of efficacy is unknown but is estimated to last in 19 patients who have had close contact exposure, but
weeks to a few months.25,27,28 In previous use of CP ther- have not yet presented symptoms.32
apy in SARS, 5 mL/kg of plasma at a titer of 1:160 was
used.10 A quarter or half of the treatment dose was used
for prophylactic purposes in earlier studies. According to 9 | R I S K S O F CO N V A L E S C E N T
linear proportionality, 3.125 mL/kg of plasma with a titer PLA SMA
of >1:64 would provide an equivalent immunoglobulin
level to one-quarter of 5 mL/kg plasma with a titer of The risks of CP administration are similar to those of
1:160.7 standard plasma. Infection with another infectious dis-
In pediatric transfusions, dose by body weight should ease agent (viral transmission or bacterial contamina-
be used. COVID-19 is rarely symptomatic in the pediatric tion), immunological reactions such as serum disease,
age group. Therefore, every procedure in this age group non-hemolytic transfusion reactions (tremors, fever, urti-
should be performed within the scope of clinical research caria), transfusion-associated circulatory overload and
in cooperation with national and international health TRALI can be observed.33 No serious adverse events have
authorities. been reported in any study of CP. Two observational
studies during the SARS-CoV-1 outbreak did not report
any complications related to CP.8 In developed countries,
7 | P A T I E N T SE L E C T I O N for HIV, hepatitis B and hepatitis C viruses, the risk of
transfusion-transmissible infection is less than one infec-
There are several clinical trials that are ongoing that have tion per two million donations.34 The risk of TRALI is
very different eligibility criteria from the severely affected generally less than one for every 5000 transfused units,
to post exposure individuals.29 The patient selection may but in COVID-19, the risk of TRALI is one of the major
vary between countries. The FDA allowed the use of CP concerns about CP because most of the critically ill
to patients who met the following criteria16: patients have ARDS and disseminated intravascular coag-
ulation. Both of these situations are risk factors for the
• Laboratory confirmed COVID-19 development of TRALI.35 Specific risk about Anti-SARS-
• Severe or immediately life-threatening COVID-19. CoV-2 CP is transfusion-transmitted SARS-CoV-2. This
 Severe disease is defined as one or more of the remains theoretical because there has been no report of
following: SARS-CoV-2 transmission by blood transfusion. This risk
• Dyspnea, is particularly important in prophylactic use since criti-
• Tachypnea ≥ 30/min, cally ill patients are already infected. In addition, only 1%
• blood oxygen saturation ≤ 93%, of symptomatic patients have been reported to have
• PaO2/FiO2 < 300, detectable SARS-CoV-2 RNA in their blood.36,37 Between
• lung infiltrates >50% within 24-48 hours January 25 to March 4, 2020; 2430 blood donations were
 The life-threatening disease is defined as one or screened in Wuhan and only one (0.04%) donor was
more of the following: found to be positive for SARS-CoV-2 RNA. Between
• respiratory failure, December 21 to January 22, 2020; 4995 blood donations
• septic shock, were screened and a second (0.02%) donor was found to
372 YIĞENOĞLU ET AL.

be positive for SARS-CoV-2 RNA.38 The other theoretical caused by the novel coronavirus as COVID-19. https://www.
risk of CP is an antibody-dependent enhancement who.int/emergencies/diseases/novel-coronavirus-2019.
(ADE). Antibodies that developed during a previous Accessed on April 17, 2020.
4. Gorbalenya AE, Baker SC, Baric RS, et al. Severe acute respira-
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may exacerbate clinical severity.39 Previous infection with a statement of the Coronavirus Study Group. bioRxiv. 2020.
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the risk of ADE in COVID-19 and the geographic varia- 5. Guan WJ, Liang WH, Zhao Y, et al. Comorbidity and its impact
tion in disease severity may be attributed to this mecha- on 1590 patients with Covid-19 in China: a nationwide analy-
nism.40 In the current pandemic, there has been no sis. Eur Respir J. 2020;55:2000547. https://doi.org/10.1183/
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6. Graham BS, Ambrosino DM. History of passive antibody
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