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Convalescent Plasma

Last updated: August 21, 2020 

The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview 

Convalescent plasma, or blood plasma collected from patients who have recovered from an infectionhas been used to treat various infectious diseases since the early 20tcentury, although its benefit has not been consistently studied in a randomized manner (Marano, March 2016). The primary proposed protective mechanism of convalescent plasma is pathogen neutralization, via the delivery of antibody, although antibody dependent cellular cytotoxicity and phagocytosis may also play a role (Rojas, July 2020). The hypothesis is the passive administration of antibody from a person who has convalesced may be an effective therapy for those patients who have yet to develop their own antibody response. 

Interest in the use of convalescent plasma developed early in the course of the COVID-19 pandemic (Casadevall, March 2020). Numerous case series and observational studies have since been published, with variable results (Shen, March 2020; Zhang, March 2020; Duan, April 2020). Two published randomized controlled trials were halted early, one due to concern of a lack of benefit, and the other due to low enrollment (Gharbharan, July 2020; Li, June 2020). To date, one randomized controlled trial has been completed, and did not meet its composite end point of progression to severe disease  or all-cause mortality at 28 days; the median time from symptom onset to administration was 8 days, and the median antibody titer was 1:40. The results of additional randomized controlled trials are forthcoming. Questions remain about the antibody titer that should be used when treating patients with COVID-19, and if timing of administration is an important consideration.

IAugust 2020, the Food and Drug Administration announced an Emergency Use Authorization for convalescent plasma in patients with COVID-19. 

On this page: 

 

Guidelines  

IDSA guidelines recommend limiting the use of convalescent plasma for patients admitted to the hospital with COVID-19 to the context of a clinical trial.  

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Dosing

There are no standard dosing recommendations for individuals with COVID-19.  

  • The National Convalescent Plasma Expanded Access COVID-19 Protocol is studying a dose of 1 unit of plasma (at least 200 mL). 
  • The titer of antibody in plasma cannot be reliably predicted, and so when possible, it should be measured before use. 
  • FDA states a preference for the use of “high titer” convalescent plasma, as defined by a neutralizing antibody titer of ≥250 in the Broad Institute's neutralizing antibody assay or an S/C cutoff of ≥12 in the Ortho VITROS IgG assay.
    •  If high-titer plasma is not available, the use of “low titer” plasma is acceptable.

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Key Literature 

Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial)  (Agarwal, Sept 2020)

 

Study population

  • 464 hospitalized patients with moderate COVID-19 across 39 hospitals in India

Primary endpoint

  • Composite outcome of progression to severe disease or all-cause mortality at 28 days

Key findings

  • 235 patients were randomized to the intervention arm, and 229 to the control arm
  • The median time from symptom onset to enrollment was 8 days (IQR 6-11) in both arms
  • The composite primary endpoint was achieved in in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77].
  • Mortality was documented in 34 (14.5%) and 31 (13.5%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: 0.61 to 1.83].
  • The median titer of neutralizing antibody in the plasma used was 1:40 (IQR 1:30-1:80)
  • At days 3 and 5 patients in the intervention arm had a greater absolute reduction in FiO2 compared to patients in the control arm (5 (0,12) vs. 3.7 (0,9), p=0.04, and 9 (3,17) vs. 7 (0,14), p=0.04).

Limitations

  • The study was open label, which could have lead to anchoring bias among providers
  • Measurement of antibody titer prior to plasma administration was not done
  • The median titer of antibody in the plasma units used was low

Overall, in this open-label randomized controlled trial, the administration of convalescent plasma to hospitalized patients with moderate COVID-19 did not lead to improvement in a composite endpoint of disease progression or all-cause mortality. The convalescent plasma titers used in the study were low.

 

An observational, open-label Expanded Access Program for the treatment of COVID-19 patients with human convalescent plasma (Joyner, August 2020). 

Study population: 

  • 35,322 hospitalized patients with severe or life-threatening COVID-19 at 2,807 U.S. acute care facilities. 
  • 52.3% patients in the ICU; 27.5% received mechanical ventilation. 
  • Antibody levels in the units collected were not measured at the time of transfusion.  

Primary endpoint: 

  • 7-day and 30-day mortality.  

Key findings: 

  • The 7-day mortality rate was 8.7% in patients transfused within 3 days of COVID-19 diagnosis but 11.9% in patients transfused after 3 days (p<0.001).  
  • 30-day mortality was 21.6% vs. 26.7% (p<0.0001). 
  • The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days versus those transfused with low antibody level plasma units. 

Limitations: 

  • This is a non-randomized design with no comparator group—therefore, the presence of confounding factors cannot be excluded. 
  • Physicians chose whether to request plasma for their patients and the timing of plasma transfusion; selection bias cannot be examined.  
  • The cut-offs for “low” and “high” antibody titers were determined after study analysis began, rather than prior to study initiation. 
  • Participants received other SARS-CoV-2-related therapies, such as remdesivir and dexamethasone. The use of these agents varied over time. 
  • The authors sought to examine if patients who received convalescent plasma earlier in the course of disease and with higher doses of neutralizing antibodies had lower mortality.  
    • Data on the timing of receipt of convalescent plasma are presented relative to diagnosis of COVID-19, rather than symptom onset/hospitalization.  
    • The study took place between April-July.  
    • If the timing between onset of symptoms to diagnosis has differed over the course of the pandemic, this may have confounded the results.  

Overall, in this non-randomized observational study, mortality was lower in patients who received convalescent plasma within 3 days of diagnosis, as opposed to 4 days after diagnosis.  

 

Treatment of COVID-19 patients with convalescent plasma reveals a signal of significantly decreased mortality (Salazar, August 2020). 

Study population: 

  • Interim analysis of 136 patients transfused with convalescent plasma and matched to 251 non-transfused control COVID-19 patients at Houston Methodist hospitals.  

Primary endpoint: 

  • 28-day mortality.

Key findings: 

  • There was a significant reduction (p=0.047) in 28-day mortality in patients transfused with convalescent plasma, specifically in patients transfused within 72 hours of admission with plasma with an anti-spike protein receptor binding domain titer >1:1350.   

Limitations: 

  • Patients transfused with plasma and in the standard of care arm also received other agents, including steroids, azithromycin, hydroxychloroquine, remdesivir and tocilizumab, potentially confounding results. 
  • This is a non-randomized trial; however, it uses propensity-score matching to control confounding. 

Overall, in this interim propensity score-matched analysis, transfusion of high anti-receptor binding domain (RBD) IgG titer COVID-19 convalescent plasma early in hospitalization was associated with a reduction in mortality in COVID-19 patients. 

 

A randomized trial comparing convalescent plasma with standard of care in patients hospitalized for COVID-19 (Gharbharan, July 2020). 

Study population: 

  • 86 patients hospitalized with COVID-19 in the Netherlands who had been symptomatic for a median 10 days at the time of enrollment received convalescent plasma with antibody titers of  >1:80 dilution and standard of care, or standard of care alone. 
  • Standard of care included chloroquine, azithromycin, lopinavir/ritonavir, tocilizumabanakinra or other medications. 

Primary endpoint: 

  • 60-day mortality. 

Key findings: 

  • 53 of 66 patients had anti-SARS-CoV-2 antibodies at time of enrollment into the study. 
  • At the time of enrollment, the majority of participants had experienced  COVID-19 related symptoms for 10 days (IQR 6 – 15) and had been admitted to the hospital for 2 days (IQR 1 – 3 days).
  • A SARS-CoV-2 plaque reduction neutralization test revealed neutralizing antibodies in 44/56 (79%) patients tested, with median titers comparable to the 115 donors (1:160 vs. 1:160, p=0.40).  
  • No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) observed between plasma-treated patients and those on standard of care.
  • The trial was halted early due to concerns about convalescent plasma’s lack of benefit. 

Limitations: 

  • The study was stopped early and may have been underpowered to detect a benefit. 
  • The use of other medications as part of the standard COVID-19 care at the time was heterogeneous and may have confounded the results. 

Overall, patients with COVID-19 may have antibody titers and still be symptomatic. Antibody titers should be checked in patients prior to the administration of convalescent plasma. 

 

A randomized open-label clinical trial on the effect of convalescent plasma on clinical improvement in patients with severe COVID-19 (Li, June 2020). 

Study population: 

  • 103 patients hospitalized with severe or life-threatening COVID-19 at seven academic medical centers in China. 
  • Patients randomized to receive convalescent plasma with antibody titers of more than 1:640 dilution and standard of care, or standard of care alone.  
  • Standard of care included the following possible treatments: antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines or other medications. 
  • The median time between symptom onset and randomization was 30 days. 

Primary endpoint: 

  • Time to clinical improvement within 28 days. 

Key findings: 

  • Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs. 43.1% (22/51) in the control arm (OR, 1.40; p = 0.26). 
  • In patients with severe disease, clinical improvement at 28 days occurred in 21 patients (91.3%) in the convalescent plasma group vs. 15 patients (68.2%) in the control arm (OR, 2.15; p= 0.03). 
  • In patients with life-threatening disease, clinical improvement at 28 days occurred in 20.7% (6/29) of the convalescent plasma group vs. 24.1% (7/29) of the control arm (HR, 0.88; p = 0.83). 
  • There was no significant difference in 28-day mortality (15.7% vs. 24.0%; OR, 0.59; p = 0.30) or time from randomization to discharge (51% vs. 36% discharged by day 28; HR, 1.61; p = 0.12) 

Limitations: 

  • The study was terminated early due to an inability to recruit 200 patients; therefore, it may have been underpowered. 
  • The use of other medications as part of the standard COVID-19 care at the time was heterogeneous and may have confounded the results. 

Overall, in a randomized open-label trial that was stopped early, in patients with severe or life-threatening COVID-19, convalescent plasma therapy with standard of care did not significantly improve the time to clinical improvement within 28 days. In subgroup analysis of patients with severe, but not life-threatening disease, clinical improvement was seen in patients who received plasma, despite patients being symptomatic for a median of 33 days in this group (ie, one would expect they had developed their own neutralizing antibodies by then). The numbers of patients in the subgroup analyses were small.   

 

A retrospective matched control study of convalescent plasma for the treatment of hospitalized patients with severe COVID-19 (Liu, May 2020). 

Study population: 

  • 45 hospitalized patients with severe COVID-19. 
  • 39 of 45 patients were transfused with convalescent plasma with antibody titers of >1:320 dilution. 

Primary endpoint: 

  • Clinical condition at 14 days. 

Key findings:  

  • At day 14 there was no significant difference in clinical condition between patients who received plasma and controls (p=0.167). 
  • At day 14 the adjusted odds ratio for worsening oxygenation was 0.86 (95% CI: 0.75-0.98, p=0.028). 
  • In a covariates-adjusted Cox model, convalescent plasma transfusion improved survival for non-intubated patients (HR 0.19; p=0.015), but not for intubated patients (HR 1.24; p=0.752). 

Limitations: 

  • This was a small study at a single center with a non-randomized design; despite the use of matching, bias may still be present.  

Overall, in this retrospective control study, the use of convalescent plasma was associated with improved survival in non-intubated patients. 

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Safety 

In the largest safety study to date of 5,000 patients hospitalized with severe or life-threatening COVID-19 disease, 15 deaths were reported within 4 hours of transfusion (0.3%), with 4 deaths (0.08%) considered possibly or probably related to convalescent plasma transfusion (Joyner, May 2020). 

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