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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.
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 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.
In August 2020, the Food and Drug Administration (FDA) announced an Emergency Use Authorization (EUA) for convalescent plasma in patients with COVID-19. On September 23, 2020, the FDA issued an update on convalescent plasma therapy for COVID-19. The update included an analysis that supported the concept of an antibody dose response effect; the FDA concluded convalescent plasma 'may be effective.'
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.
- The 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).
- 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.
In summary: Overall, observational studies have found both benefit and no benefit when convalescent plasma is used in hospitalized patients with COVID-19. To date, of the several randomized controlled trials examining the use of convalescent plasma in patients hospitalized with COVID-19, only one was able to fully enroll; others were under-powered due to low enrollment and not meeting their target sample size. It is therefore unknown if convalescent plasma is beneficial for patients hospitalized with COVID-19. This question is further complicated by a lack of knowledge regarding what titer of antibody should be administered; many of published studies to date did not measure donor plasma antibody titers prior to use. Additional 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.
Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults (Libster, January 2021).
- Randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers SARS-CoV-2 in older adult patients within 72 hours after the onset of mild COVID-19 symptoms conducted between June 4, 2020, and October 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 coexisting conditions) or between 65 and 74 years of age (with at least one coexisting condition) were included.
- Coexisting conditions 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 coexisting conditions at enrollment.
- 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 end point 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.
- Severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and in 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=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; interquartile range, 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 end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81).
- 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.
- 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.
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.
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).
- 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 (interquartile range 1:30-1:80).
- 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.”
- 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% confidence interval [CI] -0.062 to 0.078; risk ratio [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.
- 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.
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.
Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial (Avendano-Sola, September 2020).
- 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.
- 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.
- 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 AE were reported in 13 patients, 6 in the CP group and 7 in the standard of care group.
- 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 were not used to select donors or units.
- Half of the patients were already IgG positive art the time of enrollment, and may have had less of a benefit from convalescent plasma.
- The real-world clinical implications of the primary endpoint is not clear.
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 highflow oxygen devices or mechanical ventilation. However, caution must be undertaken when interpreting the results, as the study was stopped early and under-powered.
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, September 2020).
- 464 hospitalized patients with moderate COVID-19 across 39 hospitals in India.
- Composite outcome of progression to severe disease or all-cause mortality at 28 days.
- 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).
- 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).
- 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.
- 7-day and 30-day mortality.
- 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.
- 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).
- Interim analysis of 136 patients transfused with convalescent plasma and matched to 251 non-transfused control COVID-19 patients at Houston Methodist hospitals.
- 28-day mortality.
- 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.
- 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).
- 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.
- 60-day mortality.
- 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.
- 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).
- 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.
- Time to clinical improvement within 28 days.
- 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)
- 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).
- 45 hospitalized patients with severe COVID-19.
- 39 of 45 patients were transfused with convalescent plasma with antibody titers of >1:320 dilution.
- Clinical condition at 14 days.
- 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).
- 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.
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 (adjusted hazard ratio [aHR] 0.93, 95% CI, 0.39-2.20).
A Propensity Score-Matched Control Study of Convalescent Plasma in Severe COVID-19 (Liu, September 2020). In this retrospective study, the effectiveness of convalescent plasma was assessed in 39 patients with severe or life-threatening COVID-19 hospitalized at a single center. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score–matched controls (aOR, 0.86; 95% CI 0.75–0.98; chi-square P value = 0.025). Survival also improved in plasma recipients (aHR 0.34; 95% CI 0.13–0.89; chi-square P = 0.027).
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).
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).