Convalescent Plasma

 SARS-CoV2 Meta-Analysis:

1.  Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review - Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul 10;7(7):CD013600. PMID 32648959
   
   Meta-Analysis details: Included 20 studies (1 RCT, 3 controlled non-randomized studies of interventions (NRSIs) and 16 non‐controlled NRSIs) with 5443 participants, of whom 5211 received CCP. Also identified 98 ongoing studies evaluating CCP or hyperimmune immunoglobulin, of which 50 are randomised. 
   
   Findings: 
   Effectiveness - Very uncertain whether CCP has any effect on:
   • all‐cause mortality at hospital discharge (RR 0.89, 95% CI 0.61 to 1.31),
   • time to death (RCT: HR 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96)
   • or improvement of clinical symptoms:
     • at 7 days (RCT: RR 0.98, 95% CI 0.30 to 3.19),
     • 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77;
     • controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29),
     • and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81).
   All considered very low certainty evidence.
   
   Safety - Very uncertain whether or not CCP affects the risk of moderate to severe and serious adverse events (very low‐certainty evidence).

 Peer Reviewed SARS-CoV2 Randomized Controlled Trial

1.  Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial - Ling Li, MD, PhD1,2; Wei Zhang, MD3,4; Yu Hu, MD, PhD5; et al
   JAMA . 2020 Jun 3;324(5):1-11. PMID: 32492084
   
   Study details: RCT in Wuhan, China comparing CCP with COVID-19 standard of care to standard of care alone. Included patients with severe or life-threatening disease. Excluded patients with SARS-CoV2 spike protein–receptor binding domain-specific IgG antibody titer ≥1:640. Primary outcome was time to clinical improvement within 28 days.
   
   103 participants were enrolled before the trial was stopped due to significant decrease in COVID-19 cases in Wuhan (the study was powered for enrollment of 200 participants). 
   
   Results: Clinical improvement occurred within 28 days in 51.9%(27/52) of the CCP group vs 43.1% (22/51) in the control group (difference, 8.8% [95%CI,−10.4%to 28.0%]; HR 1.40 [95%CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the CCP group vs 68.2% (15/22) of the control group (HR, 2.15 [95%CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7%(6/29) of the CCP group vs 24.1%(7/29) of the control group (HR, 0.88 [95%CI, 0.30-2.63]; P = .83). CCP use was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of CCP group vs 37.5% of control group (P<0.001). 2 patients in the CPP group experienced adverse events within hours of transfusion but recovered with supportive care. 
   
   Summary: Among patients with severe or life-threatening COVID-19, CCP added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference.
    
2.  Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).  Anup Agarwal ¹, Aparna Mukherjee ², Gunjan Kumar ¹, Pranab Chatterjee ¹, Tarun Bhatnagar ³, Pankaj Malhotra ⁴, PLACID Trial Collaborators. PMID 33093056
   
   Study details: An open label, parallel arm, phase II, multicenter, randomized controlled trial designed to investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India
   
   464 adults (≥18 years) admitted to hospital with confirmed moderate covid-19: 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 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm).  
   
   Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralizing antibodies were not measured a priori; stored samples were assayed at the end of the study.  The main outcome measure was a composite of progression to severe disease (PaO₂/FiO₂ <100 mm Hg) or all-cause mortality at 28 days post-enrollment.
   
   Results: Progression to severe disease or all-cause mortality at 28 days after enrollment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval -0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54).  Small beneficial effects were found for resolution of shortness of breath and fatigue. However, these results should be interpreted with caution, because the trial was not blinded, so knowledge of treatment status could have influenced the reporting of subjective symptoms by patients who survived to day 7.
   
   A statistically significant 20% higher rate of conversion to a negative result for SARS-CoV-2 RNA occurred on day 7 among patients in the intervention arm, however, this was not associated with clinical benefit.  It has been hypothesized that the CCP causes endothelial damage and that this effect negated or outweighed the benefit from antibody neutralization, but this remains unproven.
   
   Summary: Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all-cause mortality.
    
3.  Early High – Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults. Libster Et Al. NEJM  Jan 6, 2021
   
   Study Details: Randomized, double-blind, placebo-controlled trial of high IgG titer convalescent plasma vs. placebo in adults (75 y/o or older) within 72 hours of COVID-19 symptom onset. Participants with severe disease, severe respiratory disease were excluded from the study. 
   
   Study Drug: 250 ml of CP with IgG titer greater than 1:1000 against the spike protein or 250 m; of placebo (0.9% normal saline). 
   
   Primary end-point: The development of severe respiratory disease as defined as a respiratory rate of 30 breaths per minute or more, oxygen saturation of less than 93% on room air. 
   
   Results: In an intention to treat analysis, 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). A modified intention-to-treat analysis; severe respiratory disease developed in 9 of 76 patients (12%) in the convalescent plasma group and 23 of 78 patients (29%) in the placebo group (relative risk, 0.40; 95% CI, 0.20 to 0.81). 
   
   Summary: Administration of high titter convalescent plasma to adults 75 y/o and older within 72 hours of their COVID-19 symptom onset reduced the progression to severe respiratory disease. 
   
   Limitations: The trial was stopped at 76% of their enrollment target because of a decline in COVID-19 cases and inability to reach pre-specified enrollment numbers. 
   Provides supportive evidence for the use of high titer COVID-19 convalescent plasma early in the disease course in older adults who present with mild disease.

 Key Peer Reviewed SARS-CoV2 Observational Trials:

1.  Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: Results of a multicenter clinical study - Abolghasemi H, et al. Transfus Apher Sci. 2020 Jul 15;102875. PMID 32694043
   
   Study Details: Case control study conducted in multiple hospitals in Iran. Participants were enrolled within 7 days of illness onset. All were hospitalized and had SpO2<93% on RA but were not intubated. Primary outcomes were survival and length of stay. 
   
   189 patients (115 CCP, 74 control) were enrolled. Groups were matched based on gender, age, comorbidities (HTN/DM), and chest imaging at admission. All participants received similar non-CCP COVID-19 therapeutics. 
   
   Results: All-cause mortality was 17/115 (14.8%) in the CCP arm versus 18/74 (24.3%) in the control arm [p=0.09]. The mean hospital length of stay was 9.5 days in CCP arm versus 12.9 in the control [p=0.002]. 107 (93%) CCP patients were discharged versus 59 (79.7%) in the control [p=0.006]. No AEs other than mild, self limited fever and chills in one participant receiving CCP. 
   
   Summary:  In this non-randomized case control study, there was no statistically significant difference in all-cause mortality between CCP and control groups. However, hospital length of stay was significantly shorter in patients treated with CCP.  
    
2.  Treatment of COVID-19 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality - Salazar E, et al. Am J Pathol. 2020 Aug 11;S0002-9440(20)30370-9. PMID 32795424
   
   Study Details: Interim analysis of a prospective, propensity score-matched study to assess the efficacy of CCP vs standard of care as treatment for severe and/or critical COVID-19. Primary endpoint was mortality within 28 days. 
   
   Results: 316 patients received CCP of which 136 and were matched to 251 control patients. There was no statistically significant difference in 28 day mortality between between these two groups. However, there was a significant difference in 28 day mortality between patients who received CCP with an anti-RBD IgG titer of ≥1:1350 within 72 h of admission vs controls (1.2% vs 7%, P=0.047).
   
   Summary: This prospective, propensity score-matched study demonstrated no difference in mortality between CCP treated patients and controls. However, the administration of high titer CCP within 72 hours of admission was associated with decreased 28 day mortality compared to patients not receiving CCP. 
   
   Provides support only for the use of high titer CCP early in the course of COVID-19
    
3.  Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti–Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG.  Eric Salazar, Paul A. Christensen, Edward A. Graviss, Duc T. Nguyen, Brian Castillo, Jian Chen, Bevin V. Lopez, Todd N. Eagar, Xin Yi, Picheng Zhao, John Rogers, Ahmed Shehabeldin,David Joseph,Faisal Masud,Christopher Leveque,Randall J. Olsen,David W. Bernard,Jimmy Gollihar,and James M. Musser.   Am J Pathol. 2020 Nov 4.  PMID: 33157066.
   
   Study Details:  This paper describes a continued effort to track a cohort of 351 patients treated with CCP and compare their outcomes with a propensity matched cohort that did not receive CCP (see #2 above for earlier paper).  The CCP used was high-titer: retrospective analysis by the Ortho VITROS IgG assay revealed a median signal/cutoff ratio of 24.0 for transfused units, a value far exceeding the recently US Food and Drug Administration–required cutoff of 12.0 for designation of high-titer convalescent plasma. 
   
   The study found that patients who received CCP within 44 hours after hospitalization showed a significant mortality benefit. In the aggregate, the analysis confirms and extends our previous preliminary finding that transfusion of COVID-19 patients soon after hospitalization with high-titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.
   
   Results
   Safety: Among 351 transfused patients included in the study, only 7 (2.0%) had adverse events deemed related to plasma transfusion. 
   
   Efficacy: Kaplan-Meier curves showed significantly decreased mortality in the transfused cohort relative to propensity score–matched controls (P = 0.02). Statistical significance increased to P = 0.003 when the matching algorithm and analysis were restricted to patients transfused with plasma with an anti-RBD IgG titer of ≥1:1350. Mortality was not significantly different between cases and controls in patients who were intubated at day 0 or in patients who were transfused >72 hours after admission, even when the analysis was restricted to patients who received plasma with an anti-RBD IgG titer of ≥1:1350. 
   
   There was no significant difference in mortality between cases and controls when the analysis was restricted to patients who received plasma with an anti-RBD IgG titer of <1:1350. In contrast, mortality was significantly decreased in patients who received plasma with an anti-RBD IgG titer of ≥1:1350 within 72 hours of admission. Receiver operating characteristic curve analysis with Youden index revealed an optimal cut point of transfusion within 44 hours of hospital admission for discriminating mortality within 60 days after transfusion in all patients transfused with COVID-19 convalescent plasma
   
   Summary:  In the aggregate, the data confirm and extend findings from their earlier analysis suggesting that transfusion of CCP with high-titer anti-RBD IgG is safe and significantly decreases COVID-19 mortality. Transfusion later in hospitalization or later in the disease course (eg, after intubation) had no significant benefit on mortality, regardless of plasma titer.
    

4.  Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in Patients With Coronavirus Disease 2019. Zeng Q, et al. J Infect Dis. 2020 Jun 16;222(1):38-43. PMID 32348485

   Study Details: Retrospective observational study in Zhenzhou City, China comparing patients who did and did not receive CCP. Primary endpoint was death or recovery and secondary endpoint was SARS-CoV2 viral clearance. 

   Results: 21 critically ill patients with COVID-19 were enrolled; 6 received CCP. Death occurred in 5 of 6 patients in the treatment group and 14 of 15 in the control group (P = .18); each group had just 1 recovered patient. Viral clearance was achieved in all CCP treated patients; among patients who died, all 5 (100%) in the CCP group and 3 of 14 (21.4%) in the control group had undetectable SARS-CoV2 by PCR before death (P=0.005). 

   Summary: There was no mortality benefit of CCP in this small, critically ill cohort of patients with COVID-19, although CCP use was associated with increased rates of viral clearance.

5.  Convalescent Plasma Antibody Levels and the Risk of Death From COVID-19. Michael Joyner et. al. 
   
   Study Details: Retrospective study to determine whether convalescent plasma with high antibody titer vs. low antibody titer is associated with a lower risk of death in hospitalized patients with COVID-19.
   
   Main Study Results: 3082 patients were included in this analysis. Patients in the high-titer group had a lower relative risk of death within 30 days after transfusion than patients in the low-titer group (relative risk, 0.75; 95% CI, 0.61 to 0.93). In a subgroup analysis, there was a lower risk of death within 30 days after plasma transfusion in the high-titer group than in the low-titer group in person who were not receiving mechanical ventilation before transfusion (relative risk, 0.66; 95% CI, 0.48 to 0.91). No effect on mortality was observed among patients who received mechanical ventilation before transfusion (relative risk, 1.02; 95% CI, 0.78 to 1.32). 
   
   Summary: In patients with Covid-19 who were not receiving mechanical ventilation, the transfusion of plasma with high antibody levels was associated with a lower risk of death than the transfusion of plasma with low antibody levels. No reduction in the risk of death was and antibody level was observed in COVID-19 patients who were receiving mechanical ventilation. 
   
   Limitations: Retrospective study, open-label design, lack of a randomization, and no placebo (control) group.
   
   Provides supportive evidence for the administration of high titer convalescent plasma in hospitalized patients who are not receiving mechanical ventilation.

Pre clinical (SARS-CoV2)

1. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development - Imai M, et al
   Proc Natl Acad Sci U S A. 2020 Jul 14;117(28):16587-16595. PMID 32571934
   
   In this study, passive transfer of convalescent serum from SARS CoV-2-infected hamsters to naïve hamsters efficiently suppressed viral replication in the lungs. 
    
2. Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment - Sun J, et al
   Cell. 2020 Aug 6;182(3):734-743.e5. PMID 32643603
   
   In this study, CCP was administered to mice 1 day prior to SARs-CoV2 infection and was found to prevent weight loss and lung histological changes and accelerate the rate of viral clearance. 

Clinical (SARS-CoV1)

1. Use of convalescent plasma therapy in SARS patients in Hong Kong - Cheng Y, et al
   Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46.
   
   Summary: Observational study of 80 patients with SARS in Hong Kong who received convalescent plasma. Higher discharge rate at day 22 was observed in patients who received convalescent plasma before day 14 of illness (58.3%vs 15.6%;P<0.001) and among those who were PCR positive and seronegative for coronavirus at the time of plasma infusion (66.7% vs 20%;P=0.001).
    
2. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients - Soo Y, et al.
   Clin Microbiol Infect. 2004 Jul;10(7):676-8. PMID 15214887
   
   Summary: Retrospective study of 40 SARS patients with progressive disease after ribavirin + methylprednisolone given either convalescent plasma (n=19) or ongoing steroids (n=21). Patients in the plasma group had a shorter hospital stay (p 0.001) and Lower mortality (P=0.049) than the comparator group. 

Pre-Peer Reviewed SARS-CoV2 Randomized Controlled Trial

1. Convalescent Plasma for COVID-19. A randomized clinical trial - Gharbaharan A, et al
   
   Study Details: Randomized controlled trial comparing CCP with neutralizing Ab titers >1:80 with standard of care in hospitalized patients with COVID-19 in the Netherlands. Primary endpoint was 60 day mortality. 
   
   Results: The trial was stopped early after 86 patients were enrolled. Although patients were symptomatic for only 10 days (IQR 6-15) at time of enrollment, 53 of 66 patients tested had anti-SARS-CoV2 antibodies at baseline. A SARS-CoV2 plaque reduction neutralization test demonstrated neutralizing Ab in 44 of 56 (79%) patients tested and median Ab titers in these patients were comparable to titers in CCP donors. Due to concern about the potential benefit of CCP in the study population, the trial was halted. 
   
   Of note, no difference in mortality, hospital stay, or day 15 disease severity was seen between CCP and control patients at time of study discontinuation.
   
   Provides equivocal support for CCP

Pre-Peer Reviewed SARS-CoV2 Uncontrolled Observational Study

1. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience - Joyner M, et al 
   
   Study Details: Multicenter, open-label study of adult patients enrolled in the US Convalescent Plasma Expanded Access Program (EAP). All patients were hospitalized with (or at risk of) severe or life threatening acute COVID-19. Primary outcomes were 7 and 30 day mortality. 
   
   Results: This cohort included a high proportion of critically-ill patients, with 52% in the intensive care unit (ICU) and 28% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% in patients transfused within 3 days of COVID-19 diagnosis but 11.9% in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). A gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma, seven-day mortality was 8.9%; for recipients of medium IgG plasma mortality was 11.6%; and for recipients of low IgG plasma mortality was 13.7% (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 for 7 days and 0.77 for 30 days compared to low antibody level plasma units.
   
   Conclusions and Relevance: Relationships observed between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma.

List of current clinical trials for convalescent plasma therapy.