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Convalescent Plasma

Last reviewed: April 30, 2021 

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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 infection, has been used to treat various infectious diseases since the early 20th century, 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 antibodies, although antibody dependent cellular cytotoxicity and phagocytosis may also play a role (Rojas, July 2020). Humoral immunity, a critical part of the human immune response to the SARS-CoV-2 virus, is quite variable and matures over the 2-6 weeks following infection, with antibodies detectable at a mean of 13 days after onset of symptoms; however, neutralizing titers do not peak until a mean of 23 days post symptom onset (Seow, December 2020). The hypothesis behind the use of convalescent plasma for the treatment of COVID-19 is that the passive administration of antibodies 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 COVID-19 pandemic (Casadevall, March 2020). Numerous case series and observational studies have since been published, with variable results (Shen, March 2020Zhang, March 2020Duan, April 2020). Several published randomized controlled trials were halted early due to concern regarding a lack of benefit, low enrollment, or the finding that the majority of recipients had baseline neutralizing antibodies with similar titers to the donors (Gharbharan, July 2020Li, June 2020Avendano-Sola, September 2020). To date, several randomized controlled trials in various settings have showed mixed results concerning convalescent plasma’s ability to slow progression of COVID-19.  recent meta-analysis examining the impact of convalescent plasma on outcomes including mortality, hospital length of stay and clinical status concluded that convalescent plasma was not significantly associated with decreased mortality, decreased length of stay or need for mechanical ventilation.  

Convalescent plasma has the potential to show a differential benefit for patients with severely impaired humoral immunity, who can have a severe disease course, and this has been shown in several small case series. In a recent case series of 23 patients with prolonged COVID-19 on anti-CD20 agents who received transfusion of a high-titer unit, 87% became PCR-negative and experienced full clinical recovery (Kenig, April 2021Gharbharan, March 2021Delgado-Fernández, February 2021). 

In August 2020, the Food and Drug Administration announced an Emergency Use Authorization  for convalescent plasma in patients with COVID-19. In September 2020, FDA issued an update on convalescent plasma therapy for COVID-19 with an analysis that supported the concept of an antibody dose-response effect; FDA concluded convalescent plasma may be effective. In February 2021, FDA limited use of high-titer convalescent plasma under the EUA to hospitalized COVID-19 patients early in the course of disease and patients with impaired humoral immunity.  

Because the SARS-CoV-2 virus displays significant genomic diversitacross the globe and within regions (Thielen 2021van Dorp 2020), it is likely relevant whether the convalescent plasma a patient receives came from someone who recovered from, and has antibodies to, a similar variant of SARS-CoV-2. Analysis of FDA Expanded Access Program data showed that locally sourced convalescent plasma from donors within 150 miles was more protective against death. Geographic factors may explain part of the apparent discrepancy between encouraging results from early observational studies and less convincing efficacy data in large randomized controlled trials, which are more likely to use a centralized, non-local source of plasma. 

 

Guidelines

IDSA guidelines recommend against COVID-19 convalescent plasma among patients hospitalized with COVID-19 (conditional recommendation, low certainty of evidence). Among ambulatory patients with mild-to-moderate COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma only in the context of a clinical trial (knowledge gap). NIH guidelines state that “data are insufficient to recommend for or against” the use of convalescent plasma. 

 

Dosing

  • FDA recommends administering 1 unit of convalescent plasma (approximately 200 mL) and notes an additional unit may be considered based on prescriber clinical judgment (FDA Fact Sheet). 
  • There is a preference for administering high-titer COVID-19 convalescent plasma to hospitalized patients early in the course of disease (preferably within 3 days of diagnosis). 
  • 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 Institutes neutralizing antibody assay or an S/C cutoff of ≥12 in the Ortho VITROS IgG assay. 
  • The use of low-titer COVID-19 convalescent plasma is not authorized. 
     

Key Literature

In summary: Overall, observational studies have found both benefit and no benefit when convalescent plasma is used in hospitalized patients with COVID-19. The results of subsequent randomized controlled trials are mixed and are presented below. Several of the randomized, controlled trials of convalescent plasma were not powered to meet their primary objectives once enrollment dropped due to waning of COVID-19 cases, and interpretation was further complicated by heterogeneity with respect to titer of the convalescent plasma administered and serostatus of recipients. The largest trial showed no significant impact on 28-day mortality or clinical recovery from high-titer convalescent plasma. Data on whether, and under which circumstances, convalescent plasma is beneficial for patients hospitalized with COVID-19 are still emergingResearch is complicated by practical difficulties in measuring and accessing information on antibody titer or geographic provenance of convalescent plasmaAdditional clinical trials are underway to further examine these questions, as are trials using convalescent plasma in the outpatient setting and as post-exposure prophylaxis. Based on the published literature, the use of convalescent plasma appears to be relatively safe, and no evidence of antibody-mediated enhancement of COVID disease severity has emerged. 

 

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label platform trial (Horby, March 2021 - preprint; not peer-reviewed). 

Overall, in RECOVERY, randomized, controlled open-label platform trial of convalescent plasma versus usual care in 11,558 hospitalized U.K. COVID-19 patients, there were no significant differences in either mortality or clinical status at day 28 after transfusion. 

Patient population: 

  • Hospitalized U.K. patients of any age with confirmed or suspected SARS-CoV2 infection. 
  • Mean age was 63.5 years; 87% were receiving oxygen only and 5% were receiving mechanical ventilation. 
  • 92% were receiving steroids. 
  • Of 9,385 patients with available baseline SARS-CoV-2 antibody, 62% were seropositive. 
  • Median time from symptom onset to randomization was 9 days. 
  • Patients received plasma donations with sample: cutoff ratio of ≥6 (EUROIMMUN IgG ELISA vs. spike glycoprotein), which correlates with a neutralizing antibody titer of >1:100 (U.S. FDA considers EUROIMMUN sample: cutoff values of >3.5 to be high-titer). 

Primary endpoint: 

  • All-cause mortality at 28 days and 6 months. 

Key findings:  

  • No difference between participants who received plasma and those who received placebo with respect to mortality (24% vs. 24%; RR, 1.00; 95% CI, 0.93 to 1.07; p=0.93). 
  • An exploratory post hoc analysis of primary outcome comparing participants randomized beforand after Dec. 1, 2020 (which is when the B.1.1.7 variant emerged in the U.K.) showed similar results. 
  • The 38% of participants who were seronegative at baseline had a markedly higher 28-day mortality than seropositive participants, but this group did not get benefit from convalescent plasma. 
  • In January 2021, the data monitoring committee recommended that further recruitment would not provide convincing evidence of mortality benefit in any subgroup and that the study stop. 

Limitations: 

  • It is not clear whether there would have been benefit had participants been transfused earlier in course of illness. 
  • Fewer patients in the convalescent plasma group received IL-6 inhibitors than in the standard of care group (8% vs. 10%). 
  • The impact of corticosteroids on the immune response to convalescent plasma is unknown, but if it hampers response then it could explain the negative result, as 92% of the participants were on corticosteroids. 

 

Randomized Trial of Convalescent Plasma in COVID-19 Severe Pneumonia (Simonovich, February 2021). 

Overall, PlasmAra randomized, controlled trial of convalescent plasma versus placebo in 333 hospitalized COVID-19 patientsshowed no significant differences in either mortality or clinical status at day 30 after transfusion between those treated with convalescent plasma and placebo. 

Patient population: 

  • Hospitalized adults with severe COVID-19 pneumonia (SARS-CoV-2 PCR positive, O2 sats <93% on room air, PaO2:FiO2 <300 mm Hg or SOFA score or more points above baseline). 
  • Of the 215 patients who had a baseline anti-SARS-CoV-2 antibodymedian titer was 1:50 (IQR, 0 to 1:800); 46.0% of patients had no detectable antibody level. 
  • Median time from onset of symptoms to study entry was 8 days (IQR, 5 to 10). 
  • Median anti-SARS-CoV2 Ab titer infused 1:3200 (IQR, 1:800 to 1:300); the minimum donor titer was set at 1:400 (either single or pooled units given), measured using the COVIDAR Argentina Consortium ELISA test. 

Primary endpoint: 

  • Clinical status at day 30 on a 6-point ordinal scale. 

Key findings:  

  • There was no difference between participants who received plasma and those who received placebo with respect to clinical status (OR, 0.83; 95% CI, 0.52 to 1.35; p=0.46). 
  • There was no difference between participants who received plasma and those who received placebo with respect to mortality (10.96% in convalescent plasma group vs. 11.43% in placebo groupRD, –0.46 percentage points; 95% CI, –7.8 to 6.8). 

Limitations: 

  • It is not clear whether there would have been benefit had participants been transfused earlier in course of illness or had transfusions been given to those with milder disease. 
  • It is not clear how COVIDAR titer assay correlates to Ortho assay. 
  • Analysis of the neutralizing antibody titers was only available for 56% of the units. 
  • Prespecified subgroups (including those who received transfusion within 3 days) were all quite small, and thus likely underpowered to show differences. 

 

A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19 (O’Donnell, March 2021 preprint, not peer-reviewed). 

Overall, in this small randomized controlled trial in NYC and Brazil looking at the impact of convalescent plasma versus control plasmano significant effect on clinical status at 28 days was seen. However, there was significantly lower mortality observed among the participants who received convalescent plasma (12.6% vs. 24.6% in the control arm). 

Patient population: 

  • Adults hospitalized with SARS-CoV-2 PCR positive, infiltrates on imaging, room air oxygen saturation <94%. 
  • Excluded people with duration of mechanical ventilation or ECMO of >5 days at screening. 
  • Duration of symptoms prior to randomization: 9 days. 
  • 81% of participants received corticosteroids; 6% received remdesivir (all in NYC); even distribution across groups. 
  • Neutralizing Ab titers available for 89% of convalescent plasma units (median titer 1:160IQR, 1:80 to 1:320). 
  • Convalescent plasma for all study sites (including those in Brazil) was collected in NYC. 
  • Genomic sequencing on NP swabs was performed on a subset of Brazilian participants and found no evidence of neutralization-escape variants. 
  • Post hoc analyses performed by country of site and found no difference in outcome. 

Primary endpoint: 

  • Clinical status at 28 days from randomization (WHO 7-point ordinal scale)changed from time-to-clinical-improvement out of concern that patients could worsen again after initial improvement. 

Key findings:  

  • No significant difference in clinical status at day 28 was seen between groups. 
  • Significantly lower mortality was seen in the convalescent plasma group than in the group that received control plasma (12.4% vs. 24.6%, respectivelyaOR, 0.47; p=0.068). 
  • Non-significant trends toward clinical improvement were seen when convalescent plasma was transfused within 7 days of symptom onset and when high-titer units were given. 

Limitations: 

  • For 8 patients, the clinical/vital status at day 28 was unknown. 
  • The trial was not powered to detect mortality difference. 
  • The use of control plasma (while important for blinding) might have contributed to volume overload/thrombosis or in some way worsened outcomes. 
  • Titers in some transfused units were low. 
  • Convalescent plasma was given fairly late in progression of disease (9 days after symptom onset). 

 

Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults (Libster, January 2021).  

Overall, in this randomized, controlled trial conducted in Argentina, which was stopped early, the administration of high-titer convalescent plasma against SARS-CoV-2 to infected older adults within 72 hours after the onset of mild symptoms reduced the progression of COVID-19 to severe illness.  

Patient population:  

  • Randomized, double-blind, placebo-controlled trial of convalescent plasma with high (>1:1000) IgG titers against SARS-CoV-2 versus saline placebo, in older adult patients within 72 hours after the onset of mild COVID-19 symptoms. 
  • Conducted between June 4, 2020, and Oct. 25, 2020 (when the last patient completed follow-up), at clinical sites and geriatric units in Argentina.  
  • 80 patients received convalescent plasma and 80 patients received placebo.  
  • Patients who were >75 years old (irrespective of current comorbiditiesor between 65 and 74 years of age (with at least one comorbidity) were included.   
  • Comorbidities included: hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic renal failure, cardiovascular disease, and COPD.  
  • The mean (±SD) age of the patients was 77.2±8.6 years, and 100 patients (62%) were women. A total of 72 patients (45%) were 65-74 years of age, and 88 (55%) were >75 years old.   
  • There were no clinically significant imbalances in baseline characteristics between the convalescent plasma and placebo groups.   
  • Most patients had prespecified comorbidities at enrollment.  

Primary endpoint:  

  • To determine whether convalescent plasma with high SARS-CoV-2 antibody titers administered within 72 hours after the onset of mild symptoms would be efficacious in preventing progression to severe disease in older adult patients with COVID-19.  
  • The primary endpoint was severe respiratory disease, defined as a respiratory rate of >30 breaths/minute, an oxygen saturation of less than 93% while the patient was breathing ambient air or both.  

Key findings:  

  • Severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and in 25 of 80 patients (31%) who received placebo (RR, 0.52; 95% CI, 0.29 to 0.94p=0.03).  
  • In the time-to-event analysis, the median time to the development of severe respiratory disease in the convalescent plasma group (15 days; IQR, 15 to 15) was longer than that in the placebo group (15 days; IQR, 9 to 15; p=0.03).   
  • The relative risk reduction with convalescent plasma was 48%, and the number needed to treat to avert an episode of severe respiratory disease was 7 (95% CI, 4 to 50).  
  • A modified intention-to-treat analysis that excluded 6 patients who had a primary endpoint event before infusion of convalescent plasma or placebo showed a larger effect size (RR, 0.40; 95% CI, 0.20 to 0.81).  
  • A dose-response effect was observed with respect to antibody titers, with higher donor unit SARS-CoV-2 IgG titers (>1:3200) being associated with more benefit than those with lower titers (RR, 0.27 [0.08-0.68] vs. 0.69 [0.34-1.31], respectively). 
  • Four convalescent plasma recipients (5%) and 10 placebo recipients (12%) had life-threatening respiratory disease, and 5 (6%) and 6 (8%), respectively, had a critical systemic illness.  
  • Two patients in the convalescent plasma group and 4 patients in the placebo group died.  

Limitations:  

  • The results may not be generalizable to younger individuals, those without comorbidities, patients with vital sign abnormalities, severe symptoms or more than 2 days of symptoms.   
  • The trial was stopped early due to a decreasing number of cases in Argentina, where the study was carried out. Thus, the results need to be verified in larger trials.  
  • The trial was too small to detect differences in specific outcomes such as death or the need for invasive or noninvasive mechanical ventilation; however, the numbers favored the convalescent plasma group in all of these endpoints.  
     

Convalescent plasma in the management of moderate COVID-19 in adults in India: open label phase II multicenter randomized controlled trial (PLACID) (Agarwal, October 2020). 

Overall, in this open label, multicenter randomized controlled trial, although the use of convalescent plasma was associated with the improvement of resolution of shortness of breath and fatigue in patients with moderate COVID-19 and led to higher negative conversion of SARS-CoV-2 RNA on day 7 post-enrollment, this did not translate into a reduction in 28-day mortality or progression to severe disease. 

Study population: 

  • Open label, parallel arm, phase II, multicenter, randomized controlled trial in 39 public and private hospitals across India. 
  • 464 adults (≥18 years) admitted to hospital with confirmed moderate COVID-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg, or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air). 
  • 235 patients were assigned to convalescent plasma (2 doses of 200 mL) with standard of care; a control arm of 229 patients was assigned to standard of care only. 
  • Nearly two-thirds (n=161, 64%) of the donors had a neutralizing antibody titer of more than 1:20, with a median titer of 1:40 (IQR, 1:30-1:80). 

Primary endpoint: 

  • A composite of progression to severe disease (PaO2/FiO2 ratio <100 mm Hg) any time within 28 days of enrollment or all-cause mortality at 28 days. 
  • If progression to severe disease or all-cause mortality could be prevented in the 28 days post-enrollment, the primary outcome was classified “good”; if not, “poor.” 

Key findings: 

  • Progression to severe disease or all-cause mortality at 28 days after enrollment occurred in 44 (19%) patients in the intervention arm and 41 (18%) in the control arm (unadjusted risk difference 0.008, 95% CI, -0.062 to 0.078; RR, 1.04, 95% CI, 0.71 to 1.54). 
  • Mortality within 28 days of enrollment was recorded in 34 participants (15%) in the intervention arm and 31 participants (14%) in the control arm (RR 1.04, 0.66 to 1.63). 
  • A higher proportion of patients that received convalescent plasma showed resolution of shortness of breath and fatigue at day 7. 
  • Negative conversion of SARS-CoV-2 RNA at day 7 post-enrollment was significantly higher in patients who received convalescent plasma compared with those in the control arm. 

Limitations: 

  • Open label design, which may be susceptible to anchoring bias of the treating doctors in outcome ascertainment. 
  • Study conducted in India and may not be generalizable to other countries. 
  • No measurement of the antibody titers in convalescent plasma before transfusion because validated, reliable commercial tests for qualitative or quantitative antibody measurement were not available. 

  

Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial (Avendano-Sola, September 2020 - preprint, not peer-reviewed). 

Overall, in this open-label randomized study, the administration of convalescent plasma was associated with a reduction in the probability of clinical deterioration, ICU admission or death in hospitalized COVID-19 patients who did not require high flow oxygen devices or mechanical ventilation. However, caution must be undertaken when interpreting the results, as the study was stopped early and underpowered. 

Study population: 

  • 81 patients hospitalized for COVID-19 in 14 Spanish hospitals.  
  • The goal enrollment was 278 patients. 
  • 38 were randomized to convalescent plasma (1 unit = 250-300 mL) + standard of care; 43 were randomized to standard of care. 
  • The median age was 59 years; 54.3% of the patients were male. 

Primary endpoint: 

  • To demonstrate the efficacy and safety of convalescent plasma in preventing progression to severe disease or death in hospitalized patients with early COVID-19. 
  • Proportion of patients in categories 5, 6 or 7 of a seven-category COVID-19 ordinal scale at day 15.  
  • The ordinal scale was as follows: 1, not hospitalized, no limitations on activities; 2, not hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or high flow oxygen devices; 6, hospitalized, on invasive mechanical ventilation or ECMO; and 7, death. 

Key findings: 

  • Median time interval between symptom onset and randomization was 8 days. 
  • At baseline, 40 out of 81 patients (49.4%) tested positive for anti-SARS-CoV-2 IgG antibodies. 
  • Patients assigned to convalescent plasma had a lower rate of worsening at 15 days than patients receiving standard of care only. 
  • There were no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0%) versus 6 out of 43 patients (14%) progressing in control arm. 
  • Mortality rates were 0% vs. 9.3% at days 15 and 29 for the active and control groups, respectively. 
  • Sixteen serious or grade 3-4 adverse events were reported in 13 patients, 6 in the convalescent plasma group and 7 in the standard of care group. 

Limitations: 

  • The trial was stopped early due to low enrollment; of a planned 278 patients, only 81 were enrolled. 
  • Open-label study. 
  • Baseline characteristics of patients not provided. 
  • The patients received convalescent plasma over a week after symptom onset; this may be too late to see a significant effect. 
  • The titer of neutralizing antibodies was not obtained when the convalescent plasma units were obtained and was not used to select donors or units. 
  • Half of the patients were already IgG positive at the time of enrollment and may have benefitted less from convalescent plasma. 
  • The real-world clinical implications of the primary endpoint are not clear. 

 

Convalescent Plasma AntibodLevels and the Risk of Death from COVID-19 (Joyner, March 2021). 

Overall, in this retrospective analysis of a U.S.-based plasma registry, there was a lower occurrence of death at day 30 after transfusion among those patients who received high-titer convalescent plasma than low- or medium-titer plasma. This effect was only statistically significant among patients who had not received any invasive mechanical ventilation prior to receiving plasmano effect on mortality of high-titer versus low-titer plasma was seen among those who had progressed to require mechanical ventilation prior to transfusion.  

Study population: 

  • 3,082 hospitalized adults with high risk of progressing to severe or life-threatening COVID-19.  
  • Patients who received more than one unit of convalescent plasma were excluded. 
  • 60.6% patients in the ICU; 33.3% received mechanical ventilation.  
  • Antibody levels from remnant samples retained by blood banks from donors were measured, using the VITROS anti-SARS-CoV2 IgG chemiluminescent immunoassay (Ortho Clinical Diagnostics), and linked to patient clinical outcomes data. 

Primary endpoint: 

  • 30-day mortality. 

Key findings: 

  • There was a lower occurrence of death at day 30 after transfusion among those patients who received high-titer (22.3%) convalescent plasma than among those who received medium-titer (27.4%) or low-titer (29.6%) units. 
  • Among patients who were already receiving mechanical ventilation at the time of their convalescent plasma transfusion, no mortality benefit from high-titer plasma (as compared to low- or medium-titer plasma) was seen. 
  • Among patients who were not yet on mechanical ventilation at the time of transfusion, there was a significant reduction in the risk of death from high-titer antibody transfusion (RR, 0.6695% CI, 0.48-0.91). 

Limitations: 

  • Retrospective analysis and possible bias/confounding. 
  • Only single unit transfusions were studied. 
  • Measured qualitative antibody levels, not neutralizing antibody titers (though there is some correlation between the two).  
  • Percentage of hypoxemia and of concomitant hydroxychloroquine were lower in the high-titer group than the low- and medium-titer groups. 

 

An observational, open-label Expanded Access Program for the treatment of COVID-19 patients with human convalescent plasma (Joyner, August 2020 - preprint, not peer-reviewed). 

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. 

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.     

  

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

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

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.  

  

A randomized trial comparing convalescent plasma with standard of care in patients hospitalized for COVID-19 (Gharbharan, July 2020 - preprint, not peer-reviewed).  

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. 

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, tocilizumab, anakinra 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.  

  

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

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 (i.e., one would expect they had developed their own neutralizing antibodies by then). The numbers of patients in the subgroup analyses were small.  

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.  

 

A retrospective, propensity score-matched cohort study of convalescent plasma for the treatment of hospitalized patients with severe COVID-19 (Liu, May 2020 - preprint, not peer-reviewed) 

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

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 and oxygen requirements 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.    

  

Additional Literature 

Convalescent plasma for patients with severe COVID-19: a matched cohort study (Rogers, October 2020). In this matched cohort analysis of hospitalized patients with severe COVID-19, 64 patients receiving convalescent plasma a median of 7 days after symptom onset were compared to a matched control group of 177 patients. The incidence of in-hospital mortality was 12.5% in the convalescent plasma group versus 15.8% in the control group (p=0.52). There was no significant difference in the risk of in-hospital mortality between the two groups (aHR, 0.93; 95% CI, 0.39-2.20). 

Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma (Maor, September 2020). In this prospective cohort study, outcomes were assessed in 49 patients with moderate to severe COVID-19 who received convalescent plasma. At day 14, 24 (49.0%) patients improved, 9 (18.4%) died and 13 (26.5%) were ventilated. IgG level and neutralizing antibody titer were correlated (0.85 p<0.001). In patients receiving ≤4.0 antibody levels, 11/30 improved (36.7%) vs. 13/19 (68.4%) in patients receiving >4.0 odds ratio (OR,0.267; p=0.030). In patients diagnosed >10 days prior to treatment, 4/14 (22.4%) improved in the ≤4.0 antibody group, versus 6/7 (85.7%) in the >4.0 antibody group (OR, 0.048; p=0.007). 

  

Safety 

In the first 5,000 patients hospitalized with severe or life-threatening COVID-19 who were given convalescent plasma through FDA’s pre-EUA Expanded Access Program, 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). A subsequent analysis of the first 20,000 plasma recipients found that 7-day mortality rates after transfusion were 9.8% among those not requiring mechanical ventilation and 18.33% among those requiring mechanical ventilation; rates of serious adverse events related to transfusion continued to be <1% (Joyner, September 2020). Of those serious adverse events reported within 4 hours of transfusion, there were 36 transfusion-associated circulatory overload events, 21 transfusion-related acute lung injuries, 21 severe allergic transfusion reactions and 63 deaths (10 deemed possibly related to transfusion; 0.05% of all transfusions). Cardiac adverse events occurred in 3% of transfused patients, 88% of which were deemed unrelated to transfusion by the treating physician. 

 

Resources

Multimedia 

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