INTRODUCTION — Convalescent plasma and/or hyperimmune globulin have been used as means of providing passive immunity in several notable viral outbreaks. Early in the coronavirus disease 2019 (COVID-19) pandemic, convalescent plasma was collected by major blood centers in the United States and was reimbursed through a government funded mechanism. Amid unprecedented blood shortages (whereby collection of convalescent plasma competed for critical frontline staff), along with the advent of effective vaccines and vaccine coverage and a growing body of evidence that COVID-19 convalescent plasma was not effective in late-stage disease, demand for the product waned and blood centers reduced or stopped collection of COVID-19 convalescent plasma. As successive viral variants have emerged, some blood centers have intermittently continued collections, albeit not in sufficient quantities to match the scale of the early phase of the pandemic (during 2020 and the early part of 2021).
This topic discusses practical aspects of obtaining and administering convalescent plasma for COVID-19.
Separate topic reviews discuss other aspects of COVID-19 management and plasma administration:
●COVID-19 – (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of the intubated adult" and "COVID-19: Management of adults with acute illness in the outpatient setting".)
●Plasma – (See "Clinical use of plasma components" and "Plasma derivatives and recombinant DNA-produced coagulation factors" and "Pathogen inactivation of blood products".)
GENERAL CONCEPTS
Overview of products — Convalescent plasma and hyperimmune globulin are obtained from individuals who have recovered from an infection and have generated an immune response against the infecting pathogen. Neutralizing antibodies are thought to be the main active component; other immune mediators may also contribute.
Until herd immunity has been attained (through mass vaccination and/or natural infection), these products have the potential to provide passive antibody-based immunity to previously unexposed individuals to reduce the risk of disease or to lessen its clinical impact if already infected. (See 'Mechanism of action' below.)
●Convalescent plasma – Convalescent plasma (also called immune plasma or hyperimmune plasma) is similar to standard Fresh Frozen Plasma (FFP) or Plasma Frozen within 24 hours after phlebotomy (PF24). (See "Clinical use of plasma components", section on 'Plasma products'.)
The major difference from other plasma products is that convalescent plasma is obtained from donors who have recovered from a specific infection (or in principle, those who have been vaccinated, although in the United States convalescent plasma has not been approved based on vaccination alone). Ideally, it contains polyclonal antibodies to the pathogen at sufficient titer and biologic activity to provide passive immunity to the recipient. (See 'Plasma donation' below.)
Convalescent plasma is typically obtained by apheresis in a blood center, although it can also be obtained from whole blood units. The plasmapheresis collection takes approximately one to two hours. Plasma proteins are replenished rapidly in the donor, and according to the US Food and Drug Administration (FDA), individuals can donate plasma by apheresis as frequently as twice in a seven-day period (at least two days apart), as long as the health of the donor is preserved [1]. (See 'Apheresis versus whole blood collection' below.)
Convalescent plasma is administered as a standard plasma transfusion; typically, one or two units are given. Typically it will come from a blood center frozen and is thawed prior to use. (See 'Optimal dose' below.)
During the coronavirus 2019 (COVID-19) pandemic, COVID-19 convalescent plasma became routinely available in the United States, under an Emergency Use Authorization (EUA) by the FDA; over 250,000 units of convalescent plasma have been administered either as part of an expanded access program, EUA or through a clinical trial [2]. (See 'Access to therapy' below.)
Historically, although convalescent plasma has been made available for other pathogens at times of disease epidemics or pandemics, its usage has not been as widespread as during the COVID-19 pandemic, nor has its efficacy been studied in as much detail.
Once an epidemic has subsided, convalescent plasma is likely to become unavailable unless a process has been put in place to bank plasma for future use (plasma has an expiration date of one year from collection). (See 'Maintaining the supply' below.)
Optimal characteristics of convalescent plasma include [3,4]:
•Sufficient titer of the relevant antibodies (see 'Optimal timing and titer (or antibody level)' below)
•Lack of infectious particles (see 'Infectious disease screening and pathogen inactivation' below)
•Demonstrated safety and efficacy when used for the specific condition (see "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)' and 'Safety' below)
●Hyperimmune globulin – During the COVID-19 pandemic, manufacture of hyperimmune globulin has been pursued in parallel with investigation of convalescent plasma [3]. Hyperimmune globulin is a licensed product manufactured from convalescent plasma from a large number of donors (thousands) and is subject to pathogen reduction technologies and other standardization [5]. It consists of a concentrated polyclonal immune globulin fraction with well-defined properties. (See 'Hyperimmune globulin' below.)
●Monoclonal antibodies – Monoclonal antibodies (mAbs) with neutralizing potential are another approach to providing passive immunity [6]. Additional development and manufacturing steps are involved. Each mAb recognizes a single antigen. Use in COVID-19 is discussed separately. (See "Overview of therapeutic monoclonal antibodies", section on 'Target is an infectious organism' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)
Mechanism of action — Convalescent plasma can provide passive immunity in the form of neutralizing antibodies (and/or possibly other immune mediators) against the infectious pathogen. Various immunoglobulin subclasses including IgG, IgM, and IgA may be useful.
Antibodies that bind to a virus can potentially decrease viral entry into cells and enhance viral clearance via antibody-dependent phagocytosis or antibody-dependent cellular toxicity; the mechanism for viral clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus that causes COVID-19) has not been determined [7,8].
For individuals who have not previously been exposed to or vaccinated against the pathogen, it can take as long as two to three weeks to mount an antibody response [9]. Providing antibodies has the potential to prevent illness or shorten the duration or severity of illness sufficiently to prevent serious or life-threatening complications [4,10]. (See "The adaptive humoral immune response", section on 'Passive humoral immunity'.)
Once infection has progressed to the point that organ damage or other consequences of massive inflammation have occurred, it is uncertain to what extent convalescent plasma provides benefit, as it is not expected to treat these complications. This is the rationale for providing plasma early in the disease course [10]. (See 'Optimal timing and titer (or antibody level)' below.)
SARS-CoV-2 has four major structural proteins, two of which appear to be the main antigenic targets [11-13]:
●Spike protein – The spike protein (S) is a transmembrane surface glycoprotein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor on respiratory epithelial cells and gastrointestinal cells and mediates viral entry [14]. In principle, anti-S, especially antibodies targeting its receptor-binding domain (RBD), might block viral entry into respiratory epithelium, which could reduce the severity or duration of infection [10]. Many variants of concern cause amino acid substitutions that affect the spike protein. Studies of the mechanism of action are ongoing. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)
●Nucleocapsid protein – The nucleocapsid protein (N) interacts with the viral nucleic acid (RNA) and contributes to the assembly of functional virions [15]. Antibodies to N generally develop along with anti-S, but their role in recovery from infection is less well understood.
Assays that rely on antibody binding, such as enzyme-linked immunosorbent assay (ELISA)-type assays, have been developed for antibodies against both S and N. Testing of individuals recovering from COVID-19 suggest that in the majority, IgM anti-S and anti-N begin to appear within approximately one week and continue to increase over two weeks, while IgG appears a few days later (typically, by the third week), with faster class switching in non-intensive care unit (ICU) patients than in ICU patients [11]. ELISA-type immunoassays and biologic (functional) assays for antiviral activity of convalescent plasma are in use, as discussed below. (See 'Antibody measurements and definition of "high titer"' below.)
Comparison with other antibody-based therapies — Other antibody therapies include monoclonal antibodies and hyperimmune globulin. (See 'Hyperimmune globulin' below and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)
There are several differences among these therapies, and none have been compared to each other in randomized trials, making it challenging to assess relative efficacy.
●Advantages of purified antibody products include greater standardization and avoidance of exposure to plasma, which can cause transfusion reactions. Disadvantages include reduced efficacy when viral antigenic drift occurs, cost, and lack of availability [16-18].
●Advantages of convalescent plasma include ease and rapidity of collection, potential for greater likelihood of matching antibody specificity to currently circulating viral variants, polyclonality, lower cost, and potentially greater availability [19]. The first monoclonal antibody against SARS-CoV-2 took nearly a year to become available, whereas production of COVID-19 convalescent plasma began much earlier in the pandemic (by January 2020, within weeks of the first cases).
Experience with other viruses — Prior to the COVID-19 pandemic, convalescent plasma had been applied to diverse pathogens with mixed success.
●The best evidence for the efficacy of convalescent plasma in other viral infections comes from a randomized trial in patients with Argentine hemorrhagic fever (caused by Junin virus, an arenavirus), in which 217 patients were assigned to receive 500 mL of convalescent plasma or control plasma within eight days of symptom onset [20]. Mortality was lower in the convalescent plasma group (1 versus 16.5 percent). In comparison, patients treated after nine or more days from symptom onset did not have a survival benefit.
●A 2015 meta-analysis identified a number of observational studies that suggested reduced mortality and other clinical benefits when convalescent plasma was used for other coronaviruses (such as severe acute respiratory syndrome virus [SARS]) and influenza viruses [21]. The reviewed studies were generally considered of low quality due to high risk of bias and lack of control groups.
PLASMA DONATION
Who can donate — Blood centers may suspend or restart collection of COVID-19 convalescent plasma depending on society recommendations and demand. (See 'Maintaining the supply' below.)
The need for convalescent plasma donation has shifted during the pandemic, with massive collection and use during the first year, reduction in use by late 2021, and intermittent collection in 2022. Interest continues at certain centers, especially with the emergence of variants that are less susceptible to neutralization by existing vaccines and monoclonal antibodies. (See 'Comparison with other antibody-based therapies' above.)
Approaches to donor recruitment during the early phases of the pandemic varied depending on the region of the world, type of health care system, local disease prevalence, and evolution of the pandemic. Initial strategies relied on donor self-identification, social media campaigns, and clinician referrals. Plasma donors must meet standard criteria for blood donation and must have fully recovered from COVID-19 for at least two weeks. (See "Blood donor screening: Medical history".)
The length of time that donors continue to produce high titers of antibodies to SARS-CoV-2 (and hence the period they can continue to donate convalescent plasma) is variable. One study suggested that many individuals had persistent antibodies for at least four months [22]. Another serial testing study suggested that the optimal time for high antibody levels is between four to eight weeks [23]. In one cohort of nearly 300 recovered individuals, anti-RBD antibody levels were relatively stable over 10 weeks but declined over the course of several donations [24]. Some donors may continue to produce high levels of antibodies outside this range. US Food and Drug Administration (FDA) recommendations state that the donation should be within six months of diagnosis. Only plasma from donors who qualify at the time of donation will be used.
Information from clinical trials suggests that many individuals who have recovered from COVID-19 did not have sufficient antibody titers to provide benefit, emphasizing the importance of testing the antibody level or titer prior transfusing the plasma. (See 'Antibody measurements and definition of "high titer"' below.)
Advanced age, male sex, and severity of illness are associated with high-titer antibody responses [25]. However, titer cannot be inferred from clinical criteria alone.
●A study that evaluated 126 potential COVID-19 convalescent plasma donors at a median of 43 days after an initial positive test for infection found that males had higher antibody levels than females, older individuals had higher levels than younger individuals, and those who were hospitalized had higher levels than outpatients [26]. Of these parameters, having been hospitalized was the strongest predictor [27].
●A study that evaluated immune responses in a series of 175 individuals recovering from mild SARS-CoV-2 infection reported development of neutralizing antibodies, assayed by pseudo-virus neutralization, in the majority of individuals within the first 10 to 15 days [8]. As many as 30 percent had very low titer neutralizing antibodies; in approximately 6 percent, the antibodies were below the limits of detection. Titers of neutralizing and spike-binding antibodies were higher in older (60 to 85 years) and middle-age (40 to 59 years) individuals compared with younger individuals (15 to 39 years). There was a trend toward higher neutralizing antibody titers in males versus females and a positive correlation with C-reactive protein (CRP) levels. (See "Acute phase reactants".)
●A study that compared immune responses in a cohort of 37 asymptomatic individuals with confirmed SARS-CoV-2 infection and a cohort of 37 symptomatic individuals found that the symptomatic individuals had slightly higher levels of virus-specific IgG and slightly longer persistence in the circulation during the early convalescent phase (first eight weeks after hospital discharge) [28].
Historically, receipt of an investigational (ie, non-licensed) vaccine has required a deferral period (eg, 12 months) from blood donation. This policy was modified for COVID-19 to allow for convalescent plasma donation, with the proviso that the individual must meet all other convalescent plasma donation criteria including prior COVID-19 diagnosis or evidence of SARS-CoV-2 antibodies from natural infection.
Maintaining the supply — Supply and demand of convalescent plasma have varied over the course of the pandemic. There are challenges to maintaining a supply after an outbreak starts to resolve, as the number of recently affected, highly-motivated individuals may decline, and the infrastructure and resources for collecting and/or storing convalescent plasma may no longer be present. However, demand may also wane as other therapies are developed. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)
General approaches for maintaining the supply for future outbreaks or a second wave of an outbreak might include (not currently available):
●Banking units for future use
●Immunizing selected individuals to generate high-titer units
●Immunizing animals, as is done with rabies immune globulin from horses
●Generating immortalized lymphocytes to produce monoclonal or polyclonal antibodies
PREPARATION
Apheresis versus whole blood collection — Plasma can be obtained via apheresis or separated from whole blood collected as a standard blood donation.
Apheresis collection is strongly preferred for several reasons [4]:
●Greater yield – A single apheresis donation can provide two to four units of convalescent plasma, versus one unit of plasma from one unit of donated whole blood.
●Donation frequency – Apheresis donations can be performed from the same person repeatedly (as often as twice in a seven-day period according to guidance from the US Food and Drug Administration [FDA]) [29]. However, in practical terms, repeated apheresis plasma donation, if indicated, would likely be performed at approximately two- to four-week intervals. In contrast, donations of whole blood (from which plasma is separated) require a longer recovery (at least 56 days; varies by blood collection center). (See "Blood donor screening: Overview of recipient and donor protections", section on 'Donation frequency'.)
●Donor safety – Since apheresis only removes plasma and not red blood cells, individuals are not made transiently anemic.
Apheresis has been the major mode of collection in high-income countries. However, the higher technical complexity and associated costs may limit its use in low- and middle-income countries [30]. (See 'Resource-limited settings' below.)
Donation after COVID-19 vaccination (vax-plasma) — COVID-19 vaccination is not a contraindication to donating convalescent plasma, but vaccination in the absence of SARS-CoV-2 infection does not qualify an individual to donate.
Plasma from vaccinated individuals ("vax-plasma") elicits high titer antibody response with demonstrated efficacy against the original virus and subsequent variants of concern [31]. One study that tested plasma pre- and post-vaccination found increases in neutralizing activity of several logs and against multiple variants [32]. Other studies demonstrated that vaccination following COVID-19 led to further increases in antibody levels [33,34].
Individuals who have been vaccinated for COVID-19 can donate regular plasma, platelets, and red blood cells, provided standard donation criteria are met. (See "Blood donor screening: Medical history", section on 'COVID-19 pandemic considerations'.)
Antibody measurements and definition of "high titer" — Antibodies are typically measured using either a functional assay (measures neutralizing activity against the virus or a pseudovirus by making serial dilutions of the plasma sample to derive a quantitative titer of neutralizing antibody) or in a serologic assay (measures antibody binding to specific viral epitopes). (See 'Types of assays' below.)
Efficacy is believed to depend on sufficient antibody levels; optimal antibody thresholds were uncertain early in the pandemic.
Under the revised Emergency Use Authorization (EUA) recommendations from the FDA, nine assays have been approved to qualify units of COVID-19 convalescent plasma for clinical use in hospitalized patients and to be labeled as high titer [35]. Each system reports results in unique units and minimum requirements to qualify a product as High Titer COVID-19 Convalescent Plasma. This is also consistent with guidance from the Association for the Advancement of Blood and Biotherapies [36,37].
Previously, titers of 1:160 or even 1:80 using a variety of different assays were considered acceptable if higher-titer units were not available [38-41]. It is the responsibility of the blood collection facility providing the plasma for clinical use to ensure that the plasma is properly categorized. Units that meet the requirements specified in the EUA document are labeled as "High Titer COVID-19 Convalescent Plasma" or "High Titer CCP" [38-40]. Units with lower titers may be labeled as "COVID-19 Convalescent Plasma of Low Titer."
The antibody level cannot be manipulated within the plasma unit (ie, plasma cannot be concentrated as a means of raising the titer or antibody level). In contrast, hyperimmune globulins and monoclonal antibodies can be concentrated. (See 'Hyperimmune globulin' below.)
Donor characteristics that may correlate with antibody titer or level are discussed above. (See 'Who can donate' above.)
Types of assays — Antibodies can be measured functionally or serologically:
●Bioassays – Bioassays assess the effect of the plasma on virus viability (also called viral neutralization) and are reported as a titer (often referred to as a plaque reduction neutralizing titer [PRNT]). These bioassays are not as commonly used as serologic assays because they require propagation of live virus and require specialized expertise to avoid infection of laboratory or other personnel. They are also difficult to standardize across different laboratories and are logistically complex and have slow turnaround times.
As an alternative, viral components may be expressed in a vector to create a "pseudo-virus" that can be used in a neutralization assay [8,42]. In these assays, individual viral proteins (but not live virus) can be expressed in cell culture, and their ability to infect cells can be assayed in the presence and absence of plasma. These assays also have the problem of standardization across different laboratories.
●Serologic binding assays – Many programs use a serologic assay that measures antibody binding to a target antigen (using either an enzyme-linked immunosorbent [ELISA]-type assay, or a chemiluminescence assay, which is more sensitive). Measurements using serologic assays are generally qualitative (ie, positive/reactive versus negative/nonreactive) but can be semiquantitative when reported in terms of signal-to-cutoff (S/C) ratio. Technically this is not a titer.
Bioassays are more representative of clinical effectiveness, but serologic binding assays are easier to perform, automate, and scale. Correlations between a titer obtained from a live virus or pseudo-virus neutralization assay and an S/C ratio reported in a serologic assay may be challenging to infer and will be specific to a given manufacturer's assay.
Improvements in testing for SARS-CoV-2 have continued to occur as performance characteristics of the individual bioassays and serologic assays are correlated [8,12,43,44]. Investigation as to how various elements (assay type, titer, antigenic target, plasma dose) impact patient outcomes is ongoing.
Which to assay (donor or unit) — Antibodies (neutralization titer or serologic binding assay) can be measured on the donor or the plasma unit.
Several approaches have been used for qualification of units of convalescent plasma. Early studies collected plasma first and measured the antibody titer on the plasma unit, as this was considered more efficient when serologic assays were not widely available. As testing became more widely available, testing the donor during a pre-donation visit was used. This approach has been retained for some research studies in which a specific titer is required.
Infectious disease screening and pathogen inactivation — Convalescent plasma donors need to satisfy the same eligibility criteria for community blood donation, and the plasma undergoes the same infectious disease screening as all blood donations. (See "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)
Plasma is not routinely tested for SARS-CoV-2, the virus that causes COVID-19. The FDA does not recommend testing donated blood for the virus as respiratory viruses are not known to be transmitted by transfusion [45]. (See "Blood donor screening: Laboratory testing", section on 'Emerging infectious disease agents'.)
Pathogen inactivation may be used to further decrease infectious risk. Pathogen inactivation technologies are treatments that can be applied as a means of inactivating viable cells, microorganisms, and viruses. Methods include solvent/detergent treatment or photochemical inactivation; the latter involves addition of a number of lipid- or nucleic acid-binding compounds that are activated by ultraviolet or visible light. While some countries routinely perform pathogen inactivation on plasma, most do not; pathogen inactivation has not been widely adopted in the United States for convalescent plasma. Pathogen inactivation does not appear to reduce the function of plasma proteins such as antibodies or to increase the risk of adverse effects [46,47]. (See "Pathogen inactivation of blood products".)
Screening for antibodies that mediate hemolysis and TRALI — Other screening for plasma includes:
●Blood type – ABO and RhD type are determined so that ABO compatible plasma can be transfused. This is because antibodies in the plasma directed against ABO antigens on recipient RBCs could cause hemolysis. (See 'ABO compatibility' below.)
●Anti-HLA – For previously pregnant female donors, testing for antibodies against human leukocyte antigens (anti-HLA) is recommended to reduce the risk of transfusion-related acute lung injury (TRALI). Ideally, this is undertaken during pre-donation qualification, given that a third of parous females are expected to have anti-HLA antibodies [48]. Units (and donors) with anti-HLA antibodies should not be used for plasma transfusion. (See "Transfusion-related acute lung injury (TRALI)", section on 'Prevention'.)
ADMINISTRATION
Overview of therapeutic considerations — Convalescent plasma may be most appropriate for individuals at risk of severe disease when alternative therapies (direct antiviral agents or monoclonal antibodies) are not available. While this is often the case early in an outbreak, it may also occur when the supply of more specific therapies is insufficient, especially in selected populations such as individuals with immunosuppressing conditions. Convalescent plasma may be combined with other disease-specific and supportive care interventions. The plasma should ideally be collected from donors who have recovered from a contemporary or recently circulated variant [49]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)
Recommendations for appropriate use have evolved as new data accrue, guidelines from various societies are summarized in a discussion from mid-2022 and listed separately [37,50]. (See "Society guideline links: COVID-19 – Transfusion (including convalescent plasma)".)
Indications for COVID-19 convalescent plasma are presented separately:
●Symptomatic outpatients at risk for progression to severe disease if other therapies cannot be used. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'High-titer convalescent plasma'.)
●Selected inpatients with immunocompromising conditions. (See "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)'.)
Available evidence suggests that the greatest likelihood of efficacy will occur when plasma is administered earlier relative to disease onset and with a higher antibody level (or titer) [37]. Trials showing a benefit have used high-titer convalescent plasma early in the disease course, especially in the outpatient setting. (See 'Optimal timing and titer (or antibody level)' below.)
There are challenges in establishing an outpatient convalescent plasma transfusion service, including infrastructure, staffing, infection control, communications, and transport [51].
A website was created under the auspices of the COVID-19 Convalescent Plasma Project (CCPP) to collect data and resources related to the use of convalescent plasma for COVID-19 in the United States (US) (https://ccpp19.org) [52].
Optimal timing and titer (or antibody level) — Convalescent plasma has primarily been used in an attempt to improve the clinical course of disease in individuals who have already become ill. Limited evidence suggests that convalescent plasma is not effective as post-exposure prophylaxis [53].
●Timing – Evidence continues to accumulate indicating that treatment in late disease is not beneficial. A meta-analysis from early 2021 that included randomized trials and observational studies, mostly in hospitalized patients, concluded that convalescent plasma was associated with a survival benefit [54]. Statistical significance depended on which trials were included; when the analysis was restricted to only include randomized trials, a trend towards improved survival did not reach statistical significance (odds ratio [OR] 0.76; 95% CI 0.54-1.09); however, after elimination of one trial that included many individuals receiving plasma with low antibody titers, the benefit became statistically significant (mortality, 11 versus 16 percent; OR 0.65; 95% CI 0.43-0.98). Evidence for benefit was further increased when the analysis was restricted to trials that administered plasma within three days of diagnosis (OR, 0.44; 95% CI 0.32-0.61), which is consistent with the perceived mechanism of action (reducing viral entry into cells and/or increasing viral clearance). (See 'Mechanism of action' above.).
The major trial in outpatients found that administration within nine days of symptom onset provided clinically significant benefit [55]. Ongoing trials are examining use of convalescent plasma in selected patient populations such as individuals with immunocompromising conditions.
●Antibody level – The level of antibodies against SARS-CoV-2 is believed to be an important determinant of efficacy, as the primary mechanism of action is antibody-mediated (see 'Mechanism of action' above). However, the optimal antibody level or titer is unknown.
Plasma is tested by the collection facility for antibody titer (a functional assay of virus or pseudo-virus neutralization using serial dilutions, which requires additional biosafety measures) or antibody level (a serologic binding assay for the presence of antibodies against a specific viral antigen, which is easier to perform and does not require enhanced biosafety protocols). The clinician who requests the plasma does not specify the titer needed or the assay used. Donors and convalescent plasma units are generally qualified based on immunoassays rather than viral neutralization assays. By June 2021, all COVID-19 convalescent plasma transfused under the EUA was required to be "high titer" [56]. (See 'Antibody measurements and definition of "high titer"' above.)
The following evidence from clinical trials demonstrated outcomes from convalescent plasma early in the disease course and using plasma with higher levels of SARS-CoV-2-specific antibodies:
●Early administration, good titer – Randomized trials using convalescent plasma early in the course of disease have shown improved survival.
•Outpatients – In a randomized trial from the United States involving 1181 adult outpatients who were randomly assigned to receive high-titer convalescent plasma or control plasma within nine days of symptom onset, receipt of convalescent plasma reduced the risk of hospitalization [55]. Hospitalization was required in 17 of 592 (2.9 percent) participants in the convalescent plasma group and 37 or 589 (6.3 percent) in the control plasma group (absolute risk reduction, 3.4 percent [95% CI 1.0-5.8]; relative risk reduction, 54 percent) Serious adverse events were more common in the control plasma group, mostly related to a higher rate of pneumonia. There were three deaths, all in individuals who were hospitalized and who had received control plasma. Another trial involving 511 outpatients found no benefit of convalescent plasma in reducing disease progression, but there were several methodologic concerns (inclusion of individuals who required hospital admission, individuals who were randomized but not transfused) [57].
In a randomized trial from Argentina involving 160 outpatients age ≥65 years who were within 72 hours of symptom development (mild disease), convalescent plasma was associated with a lower likelihood of progression to severe disease (respiratory rate ≥30; O2 saturation <93 percent) than controls (16 versus 31 percent) and a lower likelihood of life-threatening disease or death (9 versus 15 percent) [58]. There was a dose-response relationship based on titer; higher titer plasma was more likely to prevent disease progression (relative risk [RR] compared with controls 0.27; 95% CI 0.08-0.68) than lower titer plasma, which did not provide a statistically significant benefit in preventing disease progression (RR 0.69; 95% CI 0.34-1.31).
•Inpatients – A Cochrane review that summarized randomized trials concluded that convalescent plasma was not effective in improving outcomes when given in late stage disease [59]. A small randomized trial from Spain involving 81 hospitalized individuals within a median of 8 days of disease onset found that survival and likelihood of progression was better in the convalescent plasma group (mortality at 15 and 29 days, 0 percent with convalescent plasma and 9 percent [4 of 43] in controls) [60]. The trial reached less than 30 percent of the planned target enrollment and as a result lacked statistical power to fully evaluate the intended outcome.
•Observational data – An observational study from the US involving over 35,000 patients treated with convalescent plasma reported lower mortality when the plasma was given within three days of diagnosis than when given four or more days after diagnosis (seven-day mortality of 9 percent versus 12 percent) and when antibody levels in the plasma were higher (seven-day mortality of 9, 12, and 14 percent for high, medium, and low IgG levels, respectively) [61]. Another report from the US found a dose-response relationship between titer and improved outcomes (30-day mortality with high-titer plasma 22 percent; with medium-titer plasma 27 percent; with low-titer plasma 30 percent) [62]. Similar findings were seen in another observational study from a Texas health care system involving 351 patients treated with convalescent plasma, which found that convalescent plasma reduced mortality only in the subset of individuals who were not intubated and received convalescent plasma within 72 hours of hospital admission (60-day mortality 4 percent, versus 12.3 percent in propensity-matched controls who did not receive convalescent plasma) [63]. Antibody levels were high (anti-RBD IgG ELISA ≥1:1350; median Ortho VITROS IgG signal/cutoff [S/C] ratio of 24). (See 'Antibody measurements and definition of "high titer"' above.)
Another observational study from the US that compared outcomes in 263 adults hospitalized with severe or life-threatening COVID-19 and 263 matched controls reported lower mortality at 7 and 14 days (9 versus 20 percent at 7 days; 15 versus 24 percent at 14 days) [64]. The trend toward lower mortality was no longer statistically significant at 28 days (25 versus 27 percent). There were also trends towards decreased oxygen requirements with convalescent plasma. The interval from disease onset to plasma transfusion was not specified.
●Early administration, insufficient titer – A randomized trial from India involving 464 hospitalized individuals with moderate disease who were randomly assigned to receive usual care with or without two units of convalescent plasma did not show a benefit in a composite outcome of survival (85 versus 86 percent) or disease improvement/stabilization at 28 days [65]. The median duration of illness prior to plasma transfusion was short (six days), but the median neutralizing titer of the plasma (assayed after administration) was 1:40, which was lower than the median neutralizing antibody titer in the recipients prior to transfusion (1:90) and lower than the threshold generally considered sufficient for efficacy. A subgroup analysis did not find benefit in those who received plasma with neutralizing antibody titers >1:80, but numbers were small.
●Late administration – There are two potential reasons that late administration is less likely to be effective:
•Most individuals will have begun to mount their own antibody response by 8 to 10 days after initial infection, and donor plasma may not boost antibody levels above the endogenous response. (See 'Mechanism of action' above.)
•As the disease progresses, severe manifestations may be more strongly associated with the host inflammatory response to the virus rather than to the effects of the virus itself. (See "COVID-19: Clinical features", section on 'Acute course and complications'.)
A randomized trial from Argentina involving 334 individuals with confirmed COVID-19 pneumonia and severe disease found no survival benefit with convalescent plasma [66]. The interval between development of symptoms and transfusion of convalescent plasma was not stated but is assumed to be long, with a median time from infection to symptom onset of eight days and further deterioration prior to trial enrollment.
A randomized trial from China involving 103 individuals with severe or life-threatening disease who were assigned to receive standard care with or without convalescent plasma showed a trend toward better outcomes that did not reach statistical significance (mortality at 28 days, 16 versus 24 percent; p = 0.30; odds ratio [OR] 0.59; 95% CI 0.22-1.59; time to improvement, 2.2 days shorter; 95% CI, 5.3 days shorter to 1 day longer) [67,68]. The interval between development of symptoms and transfusion of convalescent plasma was long (median: 30 days), and the delay may have reduced the efficacy of the treatment. Also, the trial only reached approximately half of the planned target enrollment, and as a result, the trial lacked statistical power to determine the intended outcome. The plasma had a spike protein (S) receptor-binding domain (RBD) specific IgG titer of at least 1:640 (a titer of 1:1280 was approximately equivalent to a neutralization titer of 1:80), and the plasma dose was approximately 4 to 13 mL/kg of recipient body weight. When the analysis was restricted to those with severe but not life-threatening disease, the faster time to improvement did reach statistical significance (4.9 days; 95% CI, 9.3 to 0.54 days).
Another randomized trial in the Netherlands involving individuals who had been symptomatic for 10 days was stopped when the majority of participants were found to have existing anti-SARS-CoV-2 antibodies at trial entry [69]. This trial only reached one-fifth of the planned target enrollment.
SARS-CoV-2 variants — Convalescent plasma may be more robust than monoclonal antibodies, given their polyclonal composition, although preliminary data suggest that convalescent plasma may be less effective against certain SARS-CoV-2 variants than against the original SARS-CoV-2 virus [70,71]. Despite a possible reduction in efficacy, infection with one of these variants is not a reason to avoid using convalescent plasma if it is otherwise appropriate, especially through a clinical trial.
In contrast, convalescent plasma may confer passive immunity to some variants for which monoclonal antibodies are ineffective, since convalescent plasma is polyclonal and some of the antibodies may recognize altered versions of the spike protein. A study from mid-2022 found that some units of convalescent plasma were able to neutralize the omicron variant (50 percent of units from unvaccinated individuals with a history of COVID-19, 50 percent of units from vaccinated individuals who did not have a history of COVID-19, and nearly 100 percent of units individuals who were vaccinated and had a history of COVID-19 or individuals who received three vaccine doses) [72]. (See 'Mechanism of action' above.)
Optimal dose — The optimal dose of convalescent plasma is unknown; institutional or clinical trial protocols for dosing should be followed. Clinical trials have generally used one or two units (approximately 200 to 250 mL per unit). Multiple doses have sometimes been used in patients with immunocompromise; therapy appears to be safe but increased efficacy has not been established [73,74]. (See 'Repeat dosing (typically not used)' below.) Pediatric dosing is based on body weight.
ABO compatibility — Patients are ABO typed prior to transfusion, and ABO-compatible plasma is typically transfused [51]. Some institutions allow for out-of-group plasma transfusion in selected cases (eg, group A units might be used in group B patients, if determined to have a low titer of anti-B). Institutional policy and regulatory guidelines should be followed. (See "Clinical use of plasma components", section on 'ABO matching'.)
Premedications (typically not indicated) — Administration of convalescent plasma is no different from standard plasma transfusion, and the same cautionary measures apply. (See "Clinical use of plasma components".)
Some institutions or clinicians routinely premedicate with antihistamines and/or acetaminophen in an effort to prevent or ameliorate allergic and febrile non-hemolytic transfusion reactions (FNHTR), respectively. There is little objective evidence that this is effective, and premedications are typically not required before transfusion of convalescent plasma. Further, widespread use of premedications can have adverse effects. However, patients with a history of certain immunologic reactions may benefit from premedication. (See "Immunologic transfusion reactions", section on 'Prevention of FNHTR'.)
Repeat dosing (typically not used) — Data are not available to determine whether more than one dose or repeated doses of convalescent plasma are appropriate. The duration of efficacy is unknown.
It has been postulated, based on experience with other antibody-based therapies, that the antibodies should remain effective for several weeks to a few months. For most patients, it is likely that this duration would provide sufficient viral neutralization until the patient recovers or generates an endogenous immune response to the virus. However, repeated doses may be reasonable in selected cases, such as in individuals who appeared to be deriving benefit but continue to have evidence of active disease. Some clinical trials, particularly of critically ill patients, allow for repeated dosing. One advantage of this is compensation for the variability in donor titers.
Monitoring — There are no established guidelines to specify what clinical and laboratory monitoring is indicated in recipients of convalescent plasma. Clinical and laboratory outcomes are being evaluated in clinical trials, including recipient antibody titers in selected studies.
General aspects of monitoring (oxygenation, hemodynamic status) are discussed separately. (See "COVID-19: Management of the intubated adult", section on 'Monitoring for complications'.)
Access to therapy
United States — Convalescent plasma remains investigational.
Patients who receive convalescent plasma outside of a trial should be informed that this remains an investigational therapy; this information can be included in the consent for blood product administration. Various mechanisms have been made available to provide (or increase) access to convalescent plasma for individuals without access to a clinical trial:
●April 2020 (EAP) – In April 2020, the FDA provided an Expanded Access Program (EAP) to institutions and an emergency investigational new drug (eIND) pathway for individuals to obtain convalescent plasma. The EAP was the major mechanism for obtaining convalescent plasma in the United States. At the time of the EAP termination in late August 2020 (due to the EUA mechanism), over 94,000 patients with severe or life-threatening COVID-19 had been transfused with convalescent plasma through the program. The Mayo Clinic was the data coordinating center for the EAP [75,76]. Information about both programs was provided on the FDA website (FDA guidance) [77].
●August 2020 (EUA) – In late August of 2020, the US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for COVID-19 convalescent plasma for individuals hospitalized with COVID-19 based on the findings that it is safe and may be effective [78]. Clinical trials continue to be encouraged, and the EUA may be amended based on additional findings.
The EUA replaced the EAP as the primary mechanism for obtaining convalescent plasma outside of a clinical trial. Originally, it specified antibody levels that qualified for high-titer and low-titer units, understanding that the optimal titer remained unknown. Subsequently it was revised to specify the exclusive use of "high titer" units. (See 'Antibody measurements and definition of "high titer"' above and 'Optimal timing and titer (or antibody level)' above.)
Other differences from the EAP included greater ease of access and reduced administrative burden (no institutional review board [IRB] required) with no specific reporting requirements [79]. A grace period was allowed through February 2021, during which institutions could use existing inventories of convalescent plasma obtained before the EUA [40]; in February 2021 this was extended to June 1, 2021, with early transition to exclusively high-titer inventories encouraged. Quantification as high titer was initially based on two assays listed in the EUA and subsequently expanded to include nine assays allowable to use to quantify titer. (See 'Optimal timing and titer (or antibody level)' above.)
Resource-limited settings — Collecting and administering convalescent plasma in low- and middle-income countries may require additional considerations such as the following [30]:
●Documentation of infection and recovery by laboratory criteria (viral nucleic acid or serologic evidence of prior infection) are ideal, although self-report of infection may be considered sufficient in some cases. Most countries consider resolution of symptoms to be sufficient evidence of viral clearance; persistent positivity for viral RNA does not always correlate with active infection or infectivity.
●Standard eligibility criteria for blood donation should be enforced to prevent transfusion-transmitted infections.
●If apheresis equipment is not available, convalescent plasma can be prepared from whole blood donation. (See 'Apheresis versus whole blood collection' above.)
●Mobilization of donors may be challenging. Fixed location collection sites are likely to provide greater safety (lower risk of infection) to collection personnel than mobile collection sites. Measures to reduce infection should be followed. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)
SAFETY
Transfusion reactions — Convalescent plasma is a human blood product that can cause various transfusion reactions, including allergic and anaphylactic reactions, hemolysis, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI). (See "Clinical use of plasma components", section on 'Risks'.)
However, plasma has generally been well-tolerated, with rare transfusion reactions that can generally be controlled with supportive measures. The incidence of transfusion reactions with convalescent plasma appears to be comparable with that of standard plasma when applied to a patient population of similar acuity of illness.
An update from the COVID-19 Convalescent Plasma Project (CCPP) covering nearly 22,000 recipients of convalescent plasma determined that the risk of serious adverse events was low [80]. Complications included the following:
●Transfusion reactions in 89 (<1 percent)
●Thromboembolic complications in 87 (<1 percent)
●Cardiac events in 680 (approximately 3 percent)
The majority of thromboembolic and cardiac events were judged to be unrelated to the plasma.
Overall mortality at seven days was approximately 8.6 percent [81]. This was noted to be lower than the mortality with the first 5000 patients, for whom the mortality rate was 12 percent [82]. However, comparisons with other cohorts are challenging, since care may be improving over time, and the patient population treated with convalescent plasma has shifted to a less critically ill group.
Antibody-dependent enhancement — Antibody-dependent enhancement (ADE) was a theoretical risk of COVID-19 convalescent plasma early in the pandemic, but it has not been reported in individuals with COVID-19 (or many other viral infections), despite administration of thousands of doses [7,83].
ADE is a phenomenon by which antibodies to an infecting pathogen can paradoxically increase viral uptake by cells and exacerbate disease severity. It was observed when a specific vaccine for dengue virus led to disease worsening in a subset of individuals who had not previously been infected and received the vaccine. Monitoring is challenging, as ADE is a clinical phenomenon without specific laboratory findings, and some individuals may experience clinical deterioration unrelated to ADE [83]. (See "Dengue virus infection: Pathogenesis", section on 'Immune response and viral clearance' and "Dengue virus infection: Prevention and treatment".)
HYPERIMMUNE GLOBULIN — Hyperimmune globulin is another investigational approach to providing passive immunity to individuals exposed to SARS-CoV-2 or those early in the disease course [5]. (See 'General concepts' above and "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Hyperimmune globulins'.)
For those who have access to hyperimmune globulin through a clinical trial, this is a reasonable alternative to convalescent plasma and may carry a lower risk of adverse events.
Hyperimmune globulin is typically administered as a single dose. Some products are given intravenously and some by intramuscular injection, as discussed separately. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Intramuscular'.)
Evidence for efficacy of hyperimmune globulin in COVID-19 has not been reported.
●Advantages – Potential advantages of hyperimmune globulin include:
•Pathogen reduction is standard during manufacture
•Lower volume
•More concentrated (high titer of antibodies)
•Lower (but not eliminated) risk for transfusion reactions and other adverse events
•Potential for intramuscular administration
•Ease of storage and shipping, allowing transfer to regions of active outbreaks
●Disadvantages – Potential disadvantages include the cost of preparation, the large number of plasma units required for manufacture, and the time it takes to prepare the products.
Pathogen inactivation steps (cold ethanol fractionation, chromatography, nanofiltration, solvent/detergent treatment, and heat treatment) are expected to inactivate infectious organisms. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Purification methods'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Convalescent plasma is obtained from individuals who have recovered from an infection (or vaccination) and have generated an immune response. During the coronavirus disease 2019 (COVID-19) pandemic, over 250,000 units were administered to patients via an expanded access program, emergency use authorizations, and clinical trials. (See 'General concepts' above.)
●Criteria for donation – Most blood donation centers are no longer collecting convalescent plasma. Donation criteria are the same as other blood product donations; the individual must have fully recovered from COVID-19 for at least two weeks. Having been vaccinated for COVID-19 by itself is not sufficient for convalescent plasma donation, but vaccinated individuals can donate if they meet other criteria. (See 'Plasma donation' above.)
●Plasma collection – Plasma is generally collected by apheresis. The level of the relevant antibody can be determined on the donor or the plasma unit using a functional virus neutralization assay or a serologic binding assay. Standard infectious disease screening and ABO and RhD typing are performed. Testing for anti-human leukocyte antigen (HLA) antibodies (and exclusion if positive) is used in parous female donors to reduce the risk of transfusion-related acute lung injury (TRALI). The Emergency Use Authorization (EUA) from the FDA specifies that all units should be "high titer"; criteria for making this determination are discussed above. (See 'Preparation' above.)
●Indications for use – (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'High-titer convalescent plasma' and "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)'.)
●Administration – If used, convalescent plasma is most likely to be effective if given early (eg, within nine days of symptom onset in outpatients; within three days of hospitalization) and if the plasma is of high titer. Plasma is typically given as a single dose of one to two units, without premedication. Recipients are monitored clinically. (See 'Overview of therapeutic considerations' above and 'Optimal timing and titer (or antibody level)' above and 'Optimal dose' above and 'Premedications (typically not indicated)' above and 'Monitoring' above.)
●Safety – Convalescent plasma carries risks of transfusion reactions, similar to standard plasma. Antibody-dependent enhancement (ADE) has not been noted. Antibody-containing products such as convalescent plasma might interfere with vaccine efficacy, but this question has not been addressed clinically. (See 'Safety' above.)
●Hyperimmune globulin – Hyperimmune globulin is a concentrated product manufactured from thousands of units of convalescent plasma. Evidence for efficacy has not been reported. (See 'Hyperimmune globulin' above.)
DISCLOSURE
The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the U.S. Food and Drug Administration (FDA) Blood Products Advisory Committee of the United States government.
