Keywords
convalescent plasma - coronavirus - COVID-19 - immunotherapy - SARS-CoV-2
Introduction
Novel coronavirus disease 2019 (COVID-19) has become a pandemic now. The spectrum
of clinical presentation of COVID-19 ranges from usual respiratory symptoms to more
serious life-threatening events such as acute respiratory distress syndrome (ARDS),
shock, cardiac injury, thromboembolic phenomenon, and even death.[1]
[2] The uncertain pathophysiology and varied clinical course are the major hurdles in
its management. Various pharmacological options (antiviral, anti-inflammatory agents,
alone or in combination, monoclonal antibodies) have been tried so far with variable
results without any definitive evidence on the efficacy of any of these agents. Other
supportive treatments currently employed are oxygen supplementation, vasopressors,
and mechanical ventilation, and extracorporeal membrane oxygenation ([ECMO] for severe
cases).
Passive immunotherapy with convalescent plasma (CP) from recovered COVID-19 cases
is now being explored as a treatment option for those cases classified as critical
(respiratory failure, septic shock, multiorgan dysfunction).[3] Passive immunotherapy involves administration of antigen-specific antibodies in
an individual to achieve short-term immunity against the said pathogen to eradicate
it from the bloodstream. CP has been used in the treatment of patients during previous
outbreaks of coronaviruses (Middle-East respiratory syndrome [MERS] and severe acute
respiratory syndrome [SARS]), H1N1 and H5N1 influenza A pandemics, as well as in hemorrhagic
fevers caused by Ebola and Junín virus.[4]
[5]
[6]
[7]
[8]
[9] Many ongoing studies are trying to explore the role of CP in COVID-19 cases, but
its efficacy in COVID-19 management is still unclear. This review aims to provide
the readers with an overview of available evidence for the use of CP in severe acute
respiratory illness (SARI) of viral etiology and information about the trials on CP
use in COVID-19 patients.
Rationale for Convalescent Plasma
Rationale for Convalescent Plasma
Convalescent blood or blood products are collected from an individual recently cured
of a disease and developed humoral immunity against the pathogen, hence serve as the
human source for specific antibodies. The presence of high titers of neutralizing
antibodies in patients who recovered from the viral infection and the absence of such
antibodies to the novel virus in the general population forms the basis of this treatment.
The proposed mode of action is the rapid reduction in viremia (<48 hours following
transfusion) followed by suppression of the proinflammatory state. This helps in rapid
patient recovery from various complications such as ARDS. Use of CP in COVID-19 reduces
the chances of emergence of antiviral drug resistance, and the polyclonal nature of
these antibodies minimizes the risk of escape mutant (which can occur with monoclonal
antibody treatment) and faster reduction of viremia as compared with antiviral medications.
Selection of Donors
During the previous SARS outbreak, the criteria adopted for CP donor selection included
afebrile status for at least 7 days, chest radiographic improvement by at least 25%,
no requirement of oxygen supplementation, and a minimum of 14 days following symptom
onset.[5] Similar criteria may be chosen for the present pandemic of COVID-19 because both
outbreaks are caused by coronavirus, which primarily affects the respiratory system,
progressing eventually to involve multiple system dysfunction. The most recent evidence
available for CP in COVID-19 is a randomized trial comparing plasma therapy with standard
treatment alone in 103 patients wherein laboratory-confirmed (reverse transcriptase-polymerase
chain reaction [RT-PCR]) cases of COVID-19, fully recovered and discharged from hospital
for more than 2 weeks with at least two negative follow-up RT-PCR, were considered
for plasma donation.[3] Similar criteria have been proposed by other authors as well.[10] In a recent pilot study on COVID-19 patients, the donors chosen were the patients
who were 3 weeks postsymptom onset and 4 days postdischarge.[11] The patient and donor eligibility criteria for CP therapy taken out from the U.S.
Food and Drug Administration (FDA) guidelines are summarized in [Table 1]. This FDA guideline has recommendations for health care providers and investigators
on the administration and study of investigational CP collected from individuals who
have recovered from COVID-19. It also guides on the topics of pathways of use of CP,
patient eligibility, collection of plasma, labeling, and record-keeping.[12] However, these FDA guidelines provide only information on the use of plasma and
do not elaborate on indications for use, dosage, contraindications, or cautions. Nevertheless,
it is imperative for the donors to be seropositive for coronavirus and screened negative
for hepatitis B and C, HIV, and syphilis. It is prudent to follow previous World Health
Organization (WHO) recommendations for the selection of blood donors considering important
factors such as age, anemia, obesity, and other comorbidities.[13] Informed consent of the donor for CP donation is mandatory.
Table 1
Summary of the patient and donor criteria for CP therapy[12]
|
Patient eligibility criteria
|
|
Abbreviations: COVID-19, coronavirus disease 2019; CP, convalescent plasma; HLA, human
leukocyte antigen; NAT, neutralizing antibody titer; SARS-CoV-2, severe acute respiratory
syndrome coronavirus 2.
|
-
Laboratory-confirmed COVID-19.
-
Severe or immediately life-threatening disease. Severe disease is defined as one or
more of the following: dyspnea, tachypnea (≥30/min), SpO2 ≤ 93%, PaO2/FiO2 < 300, and lung infiltrates > 50% within 24 to 48 h. The presence of respiratory failure,
septic shock, and multiorgan dysfunction or failure is defined as life-threatening.
-
Informed consent provided by the patient or healthcare proxy.
|
|
Donor eligibility criteria
|
-
Evidence of COVID-19 documented by a laboratory test either diagnostic (nasopharyngeal
swab) at the time of illness or positive serology (SARS-CoV-2 antibodies) after recovery
if prior diagnostic testing was not performed at the time COVID-19 was suspected.
-
Either complete resolution of symptoms at least 28 days prior to donation or complete
resolution of symptoms at least 14 days prior to donation along with negative results
for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular
diagnostic test from blood.
-
Male donors, or female donors who have not been pregnant, or female donors who have
been tested since their most recent pregnancy and results interpreted as negative
for HLA antibodies.
-
SARS-CoV-2 NAT testing: when testing is available, neutralizing antibody titers of
at least 1:160 is recommended. A titer of 1:80 may be considered acceptable if an
alternative matched unit is not available. A sample maybe stored for estimation at
a later date if measures for antibody titer estimation are not available at the time
of collection/transfusion.
|
Plasma Collection
Collection of plasma by apheresis technique and its use as a therapeutic pool is preferred
as it allows for larger volumes of collection, more frequent donations (2 weekly intervals),
and the possibility of reinfusion of red blood cells to donors, which eliminates any
risk of lowering donor hemoglobin levels.[14] The allowable plasma volume collection by apheresis is 625 mL for donors, with a
bodyweight of 50 to 80 kg, and it can be performed at 2 weekly intervals.[15] Although a recent FDA statement has termed guidelines for volume collection obsolete, it is preferable to restrict to this limit in the current scenario.[16] This short time interval between two donations (2 weeks), when compared with the
interval of 3 months for whole blood donations, is advantageous, although large-scale
availability of apheresis machines and trained operators pose major obstacles.[17] Similar to fresh frozen plasma, COVID-19 CP should be frozen within 8 hours after
collection, stored in aliquots of 200 mL each, and stored at a temperature of–18°C
or lower.
Estimation of Antibody Titers
Estimation of Antibody Titers
Transfusion of CP containing high neutralizing antibody titer (NAT) helps to achieve
an earlier and effective seroconversion. The titer of antibody is important as apparent
from the fact that during the MERS outbreak, the use of CP did not help in clinical
recovery, and one of the possible reasons suggested was the lack of proper estimation
of NAT. It was hypothesized that the plasma transfused to the patients could have
had low antibody titers since it was collected from cases who recovered from a mild
illness and hence did not develop high antibody levels.[4]
[18]
[19] The other problem with low serum antibody titers is an antibody-dependent enhancement
(ADE) of the virus, which will be discussed later.[20] Li et al in their study on COVID-19 patients estimated the antibody titer against
a spike protein on the receptor-binding domain (S-RBD) and showed that titers of at
least 1:640 were required for transfusion.[3] Evidence from the use of CP during previous viral outbreaks indicates toward the
clinical efficacy of CP with an antibody titer of 1:160 in SARS and H1N1 influenza
A.[5]
[6] In their recommendations for investigational plasma treatment for COVID-19, the
FDA suggests a NAT of 1:160, if the estimation is available.[12]
Volume of Convalescent Plasma Transfusion
Volume of Convalescent Plasma Transfusion
Cheng et al in their study on CP in SARS patients used a mean plasma transfusion volume
of 279 mL (range: 160–640 mL; 4–5 mL/kg) with a NAT of 1:160 in 80 adult patients
(median age: 45 years). They found that the outcome was more dependent on the time
of administration than the volume infused.[5] Recent studies on COVID-19 patients in China reported the transfusion of one dose
of 200 mL of inactivated CP with neutralization activity of >1:640 within 4 hours
of collection.[3]
[11] Shen et al reported the effects of plasma transfusion in five critically ill patients
suffering from COVID-19, where 400 mL of plasma was transfused.[21] A study on CP for Ebola patients used a strategy of total transfusion of 400 to
500 mL in two aliquots in an hour.[22]
[23] Based on the current evidence, the use of standard aliquots of 200 mL of CP (4–5
mL/kg) in adults seems to be a rational choice.
Repeat Dose: When and How Much to Give?
Repeat Dose: When and How Much to Give?
Ko et al reported their experience of CP transfusion in the management of the MERS
outbreak in 2015. Out of the 13 patients with respiratory failure, 3 patients received
CP and 1 patient received a repeat transfusion 1 week after the initial dose as no
seroconversion was observed after the initial dose.[4] Arabi et al in their study planned to transfuse 2 units of plasma (250–350 mL/unit)
in MERS CoV patients after assessing the feasibility of procuring CP from donors,
but their study did not progress to this phase as they did not find donors with adequate
antibody titers.[18] One case report during the SARS outbreak mentions the use of 500 mL of CP, (250
mL transfused 12 hours apart). Despite clinical recovery with the initial dose, the
second dose was also transfused as they planned to deliver 5 g of immunoglobulin (10
g/L of plasma).[24]
Ideal Time of Administration of Convalescent Plasma
Ideal Time of Administration of Convalescent Plasma
Most viral illnesses have maximum viremia at around the end of the first week of infection
followed by activation of host immune responses and viral clearance after 2 weeks.
In COVID-19, after an incubation period of 2 to 12 days (mean: 5–6 days), patients
develop clinical symptoms that progress to severe illness around day 8 (5–10 days
of symptom onset).[25] It is therefore ideal to administer CP early in the course of illness. In the study
by Li et al, the median duration between symptom onset and randomization to the CP
group was 27 days (interquartile range: 22–39). This finding is in stark contrast
to all the available literature that favors the early administration of CP (less than
14 days).[5]
[26] It is suggested that the lack of a significant outcome difference in this study
(time to clinical improvement, discharge or mortality) compared with standard treatment
is due to the delayed administration of plasmatherapy.[3]
[27]
Monitoring for Response to Therapy
Monitoring for Response to Therapy
Assessment of response to CP treatment is based on various parameters like a clinical
improvement (normalization of body temperature and oxygen saturation, and relief of
dyspnea), changes in radiological parameters (resolution of lung lesions on chest
CT), and estimation of viral load. A favorable response is usually evident within
2 to 3 days of plasma transfusion. Mair-Jenkins et al in their meta-analysis on the
effectiveness of CP on SARI mentioned only one retrospective study that reported nonsignificant
reductions in the duration of mechanical ventilation and ECMOfollowing CP.[28]
[29] The other published studies, they reported, did not show adequate data on critical
care support and plasma therapy. Lymphocytopenia is a common finding in COVID-19 and
is supposedly related to the consumption and inhibition of the host’s immune function
by the virus. An increase in lymphocyte count was observed after CP and was associated
with clinical recovery.[11]
[30] Although a reduction in viral load is evident as early as 24 hours of transfusion,
its estimation is overshadowed by the more favored clinical, laboratory, and radiological
recovery.
Adverse Events Following CP Transfusion
Adverse Events Following CP Transfusion
Febrile reactions and mild allergy in the form of urticaria can occur in 1% of those
receiving plasma transfusions and are managed with supportive care, antihistamines,
and small doses of corticosteroids if required. Risk of severe allergy and anaphylaxis
is seen in <1 in 1,00,000 of cases. Rare complications include citrate toxicity (citrate
induced hypocalcemia), transfusion-related acute lung injury (TRALI), and transfusion-associated
circulatory overload.[31] Although rare, significant attention needs to be paid toward TRALI as it may exacerbate
the pulmonary injury caused by coronavirus.[4] The other common adverse events are transient elevation of body temperature, jaundice,
and phlebitis. Nonmatched ABO blood administration can lead to serious complications
including anaphylaxis.[32] The risk of transfusion-related transmission of blood pathogen is very minimal with
the current screening techniques employed. A rare complication that can occur is an
ADE of the virus, which was initially observed in the dengue vaccine recipient. It
was observed that the risk of severe secondary dengue in the form of dengue hemorrhagic
fever (DHF) or dengue shock syndrome (DSS) was high in those with a low antibody titer
from either previous illness or vaccination. Though not demonstrated in previous viral
outbreaks such as SARS, MERS, and Ebola, a theoretical risk remains with a lower antibody
titer in the donor plasma, which may enhance viral penetration in the host cells and
hence their replication.[20]
Limitations of Convalescent Plasma
Limitations of Convalescent Plasma
None of the published studies on viral outbreaks, except one recent trial on COVID-19,
has compared CP with other forms of treatment. Most of all studies mention CP as a
last resort and given along with standard care including antiviral agents and corticosteroids
in some cases, and hence the therapeutic efficacy of CP alone could not be asserted.
Even the recent randomized trial was limited by its sample size due to early termination
as the disease spread was contained. Limitations of treatment exist at various levels,
ranging from donor selection, collection of plasma, estimation of antibody titers,
transfusion into the recipient, to its effects on the patient. The selected donor
must be free from the virus at the time of selection or else it exposes the health
care worker to the disease during screening and collection. Convalescent plasma collection
may result in a reduction in the collection of whole blood and blood products, resulting
in a shortage/crisis. Given the reports of reinfection following clinical recovery
and negative molecular reports, it becomes mandatory to include retesting for the
virus in a potential donor even if he/she has tested negative already.
In an unexpected outbreak with a large requirement of plasma, it may not be feasible
to estimate NAT as it requires biosafety level 3 laboratory and may have to rely on
ELISA (enzyme-linked immunosorbent assay) for estimation immunoglobulin (Ig) M/IgG.[33] Accordingly, if plasma with inadequate NAT is transfused, seroconversion in recipient
may not occur or produce an immediate response leading to worsening.[4] There is no certainty regarding the optimal dose and dosage of plasma transfusion
in COVID-19. Furthermore, there are no data or trials to support transfusions in pediatric
patients.
Available Literature and Current Trials
Available Literature and Current Trials
[Table 2] provides a summary of studies on CP therapy in SARI of viral etiology. A Cochrane
review on CP in COVID-19 that was recently published assessed eight studies (seven
case series and one prospective single-arm intervention study) with a total of 32
participants. They identified “very low-certainty” evidence on the clinical effectiveness
(weaning off respiratory support and mortality outcomes) and safety of CP, with all
included studies having low reporting quality and high risk of bias; the results of
47 ongoing studies (22 randomized controlled trials) are awaited.[34] In the Indian context, a “Phase-II, Open-label, Randomised Controlled Trial to Assess
the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications
in Moderate Disease” (PLACID Trial) is currently undergoing under the Indian Council
for Medical Research. This study is planned as a multicenter clinical trial with an
estimated sample size of 452 and 46 participating institutions in India. This study
involves administration of 2 doses of 200 mL each of CP to laboratory-confirmed cases
of COVID-19 with moderate disease (as defined by respiratory rate > 24/minute; PaO2:FiO2 of 200–300) and assesses the avoidance of progression to severe ARDS or mortality
at 28 days. Seven other trials are ongoing at various centers in the country and are
in the recruitment phase, with results awaited. Most of them are designed as randomized
trials to compare the efficacy of CP transfusion with the usual standard of care.[35]
[36] “National COVID-19 Convalescent Plasma Project” is currently undergoing in the United
States to assess the efficacy of CP.[37]
Table 2
Summary of evidence for convalescent plasma therapy in SARI of viral etiology[3]
[4]
[5]
[6]
[11]
[21]
[22]
[26]
[28]
[32]
[38]
[39]
|
Disease
|
Study details
|
Donor detailsa
|
Recipient detailsb
|
Summary of findingsc
|
|
Type
|
Sample size
|
Author
|
NAT
|
Day of sample collection
|
Dose and dosage
|
Time of administration
|
|
Abbreviations: CP, convalescent plasma; ECMO, extracorporeal membrane oxygenation;
IgG, immunoglobulin G; IQR, interquartile range; LFT, liver function test; MERS, Middle
East respiratory syndrome; NAT, neutralizing antibody titer; PRNT, plaque reduction
neutralization test; S-RBD, spike protein receptor-binding domain; RT-PCR, reverse
transcriptase-polymerase chain reaction; SARI, severe acute respiratory illness; SARS,
severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus
2.
aAll donors were fully recovered cases with negative RT-PCR for the virus, ABO compatibility,
and pathogen screening mandatory in accordance with the World Health Organization
guidelines. bMost recipients were critically ill and CP was used as rescue therapy. cAll recipients received standard care apart from CP: antivirals, corticosteroids,
or both. No serious adverse effects were reported. dELISA (enzyme-linked immunosorbent assay) for IgG.
|
|
SARS-CoV-2
|
Open-label randomized trial
|
103
|
Li et al[3]
|
1:640 (s-RBD-specific IgG)
|
More than 2 weeks after recovery
|
Single dose: 200 mL
|
27 days after symptom onset (IQR: 22–39)
|
52 (CP group) vs. 51 (control)
Primary outcome: clinical improvement in 28 days
Secondary outcome: 28-days mortality
No statistical difference in outcomes between the study groups
No significant outcome difference among subgroups (severe and life-threatening) who
received CP
Limitation: small sample size, early termination of study
|
|
SARS CO-V2
|
Case series
|
4
|
Zhang et al[38]
|
Not provided
|
Not provided
|
300 mL (average); two patients received multiple doses (3-8)
|
Earliest: day 12
Last dose: day 30
|
Negative RT-PCR and off-ventilator 3–4 days after the last dose
ECMO in two patients prior to transfusion; weaned off later
Postpartum female: longer course of recovery
|
|
SARS CO-V2
|
Case series
|
5
|
Shen et al[21]
|
>40
|
10 days after recovery
|
Single dose: 400 mL
|
10–22 days of admission
|
Critically ill patients on mechanical ventilation
↑PaO2/FiO2, normal temperature, and resolution of chest lesions on imaging after CP
|
|
SARS CO-V2
|
Cohort
|
10
|
Duan et al[11]
|
>1:640
|
3 wk postsymptom onset and 4 days after discharge
|
Single dose: 200 mL
|
Median: 16.5 days (IQR: 11–19.9)
|
Better outcome if transfused <14 days of admission
Correction of lymphocytopenia, correction of LFT
Limitation: non-randomized
|
|
Ebola
|
Nonrandomized comparative
|
84 cases vs. 418 controls
|
van Griensven et al[22]
|
Not done
|
Details not available
|
200–250 mL; two doses; children: 10 mL/kg
|
2 days after diagnosis
|
Controls received only standard care before enrolling cases
Plasma collection from recovered cases with mild illness
No significant survival benefit (mortality 31 vs. 38%) due to low seroconversion
Minor reactions to transfusions, such as fever, skin rash, requiring interruption
or reduction of dosing
|
|
SARI
|
Meta-analysis
|
1,327 patients from 32 studies
|
Mair-Jenkins et al[28]
|
|
|
|
|
Survival benefit if given early in disease ↓ mortality in SARI (CP vs. placebo/no
therapy) (Odds ratio: 0.25 [95% CI: 0.14–0.45])
|
|
SARS
|
Retrospective nonrandomized case/control
|
19 (plasma) vs. 21 (steroid)
|
Soo et al[26]
|
160–2,560
|
Not mentioned
|
Single dose: 200–400 mL
|
Not mentioned
|
600–900 mL plasma collected from donors
Good response: discharge at day 22
74% (plasma) vs. 19% (steroid)
Poor clinical response if given after day 16
|
|
SARS
|
Case series
|
3
|
Yeh et al[39]
|
Not mentioned
|
Negative RT-PCR, standard screening
|
Single dose: 500 mL
|
Immediately in one patient and on days 10 and 11 in the other two patients
|
500 mL of plasma collected and transfused
Viremia cleared in 24 hours
|
|
SARS
|
Retrospective
|
80
|
Cheng et al[5]
|
Not done
|
>14 days of symptom onset and at least 7 days of recovery
|
Mean: 279 mL (range: 160–640 mL)
|
14 days of admission (range: 7–30 d)
|
600–900 mL plasma collected and stored in aliquots of 200–225 mL each
Survival benefit if given within 14 days of onset
Time of therapy and RT-PCR positivity at the time of infusion significantly affect
outcome
|
|
MERS
|
Case series
|
3
|
Ko et al[4]
|
PRNTd of 1:40 and 1:80
|
Two negative RT-PCRs, no clinical symptoms, third week of illness
|
Not mentioned
|
Between 8 and 14 days of illness
|
Seroconversion achieved in only one patient where PRNT was 1:80
All three patients survived
Second dose was required in one patient
|
|
H1N1
|
Prospective cohort study
|
93
|
Hung et al[6]
|
>1:160
|
|
Single dose: 500 mL
|
<7 days of symptom onset and requiring intensive care
|
21 patients transfused
CP reduced mortality (odds ratio: 0.2)
Suppression of cytokine storm 5 days after transfusion
|
|
Spanish influenza
|
Systematic review and meta-analysis
|
1,703 patients/eight studies
|
Luke et al[32]
|
Not mentioned
|
3–60 days after recovery (average: >10 d)
|
One to two doses: 100–250 mL
|
Specific range not mentioned
|
Early transfusion enhances recovery
Fever, chills, jaundice, phlebitis reported
No blinding
No randomization
|
Future Directions
The current literature on CP focuses mainly on its use in critically ill patients.
Considering the frequent and unexpected outbreaks of viral illness in this century
thus far, it is important to consider plasma as an option not only for treatment in
severe cases but also for prophylaxis. Postexposure prophylaxis in the vulnerable
population (health care workers, immunocompromised, individuals with comorbidities,
etc.) would certainly offer clinical as well as social benefits. Trials are required
to test the efficacy of plasma in patients presenting with mild/moderate illness to
prevent their worsening to a stage requiring mechanical ventilation. Also, there is
no evidence for its use in the pediatric population as they also form a part of the
vulnerable population.
Conclusion
At present, CP offers scope as a rescue therapy in the current pandemic COVID-19,
even though it is inadequately supported with large randomized trials. Hopefully,
more evidence will be available in the near future to support or refute the safety
and efficacy of CP not just as a rescue therapy but also as a prophylactic measure
in COVID-19 management.
