COVID-19: Convalescent plasma does not reduce their chances of getting seriously ill or dying

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Plasma taken from the blood of people who have recovered from COVID-19 and given to people sick with the disease does not reduce their chances of getting seriously ill or dying, new research has found.

The findings are from one of the first clinical trials to report the effects of convalescent plasma, which has been given emergency approval in countries including India and the United States.

As a potential treatment for patients with moderate COVID-19, particularly in places where laboratory capacity is limited, the study conducted across India and published in the medical journal BMJ Friday concluded that “convalescent plasma showed limited effectiveness”.

But the researchers said future studies could explore using only plasma with high levels of neutralising antibodies to see if this might be more effective.

With few useful treatments and no cure or vaccine, nations are scrambling to find ways to blunt the severity of the new coronavirus.

One idea has been to harvest recovered patients’ antibodies, which float in plasma – the liquid component of blood—and then inject this into the blood of someone fighting infection.

The technique was first tried against diphtheria in 1892 and was shown to help speed recovery from Ebola and SARS, which is caused by the same family of pathogens as the novel coronavirus.

Observational studies recently carried out suggested convalescent plasma could be beneficial.

But in a randomised clinical trial at dozens of public and private hospitals across India, researchers found that it failed to reduce mortality or stop progression to severe COVID-19 in moderately ill patients.

Antibody concentration

The study, funded by the Indian Council of Medical Research, enrolled 464 adult patients, with an average age of 52, between April and July and split them randomly into two groups.

A control group of 229 was given the normal best standard of hospital care, while 235 people received two transfusions of convalescent plasma and were then given the best standard of hospital care.

After 28 days, 44 (19 percent) of the participants in the plasma group and 41 (18 percent) in the control group progressed to severe disease or died from any cause.

When they restricted the comparison to patients who received plasma with detectable levels of antibodies, the results were the same, the authors said.

They did however find that the use of convalescent plasma seemed to improve resolution of shortness of breath and fatigue and led to higher conversion to a negative result for the virus – a sign of it being neutralised by antibodies – after 7 days.

The trial “was a rigorous randomised controlled study on a topic of enormous global importance” said public health scientist Elizabeth Pathak in a separate commentary also published in the BMJ.

But the results were greeted with caution by a spokesman from Britain’s National Health Service, which is also in the process of carrying out large, randomised control trials of convalescent plasma.

A spokesman from the NHS blood and transplant department said that the Indian trial had used donations with antibody levels around six to 10 times lower than in Britain.

“There is other promising evidence that convalescent plasma transfusions with high antibody levels could improve patient outcomes,” the spokesman said, adding that results from trials with these higher levels of antibodies “should provide clear answers”.


Convalescent plasma therapy

Passive immunization has been utilized for preventing and treating human infectious disorders since the 20th century when specific antibodies were acquired from the serum of stimulated animals.

Convalescent blood products are obtained by collecting whole blood or plasma from a patient who has survived infection and developed consequent humoral immunity against the virus. This acts as a source of various antibodies whose transfusion can neutralize the pathogen which eventually leads to its eradication from the blood circulation (Marano et al., 2016).

Alternatively, non-neutralizing antibodies can get bound to the virus thus, contributing to prophylaxis as well as recovery. On the other hand, administering a passive antibody can be another option to provide quick immunity.

A pilot study was done in ten patients with a severe form of COVID-19 infection in which they were transfused with convalescent plasma with neutralizing antibodies. All the patients showed an improvement in fever, cough, chest pain, and shortness of breath within three days of transfusion. A radiology improvement in pulmonary lesions was also seen (Bloch et al., 2020).

Several studies also show a shorter duration in the hospital and reduced mortality rate in patients given convalescent plasma than those not given the same treatment (Chen et al., 2020). Another study was done to determine the benefits of convalescent plasma transfusion in patients who were gravely at the infectious disease department located in the Shenzhen Third People’s Hospital in China. It was conducted in 5 patients who received antiviral therapy along with methylprednisolone.

After plasma transfusion, it was observed that the body temperature normalized and the viral load had reduced which became negative within 12 days after the transfusion (Shen et al., 2020). 

Table 8 outlines some of the clinical studies for the evaluation of Convalescent plasma therapy.

Table 8 – Clinical studies for evaluation of Convalescent Plasma Therapy (https://clinicaltrials.gov/ct2/results).

Clinical Trial NumberStudy DescriptionPhaseDoseLocation
NCT04345679Anti COVID-19 Convalescent Plasma TherapyEarly Phase 1~200 ml over 4 hNot yet recruiting
NCT04346446Evaluating the Efficacy of Convalescent Plasma Therapy2Not SpecifiedIndia
NCT04345523Evaluation of Convalescent Plasma Therapy against the Standard care for the Treatment2fresh plasma from donor immunized against COVID-19Spain
NCT04356534Convalescent Plasma Therapy Clinical Trial in COVID -19 PatientsNot Applicable400 ml given as 200 ml over 2 h in 2 consecutive daysBahrain
NCT04342182Utilizing Convalescent Plasma as Therapy for Covid-192,3300 mlNetherlands
NCT04359810Convalescent Plasma utilization for in Critically Ill Patients21 unit; ~200–250 mlUnited States
NCT04358783The use of Convalescent Plasma comparing with Best available Therapeutic for the Treatment2single 200 ml doseMexico
NCT04343261Convalescent Plasma utilization in the Treatment22 UnitsUnited States
NCT04343755Utilization of Convalescent Plasma in Hospitalized Subjects2Not SpecifiedUnited States
NCT04340050COVID-19 Convalescent PlasmaEarly Phase 1~300 ml over 4 hUnited States
NCT04345289Evaluating Efficacy and Safety of Novel Treatment- Convalescent Plasma for Adults3Single Infusion 2 × 300 mlDenmark
NCT04345991Evaluation of the Efficacy of Convalescent Plasma2Two units of 200–220 ml each transfused i.v.France
NCT04333355Safety in Convalescent Plasma Transfusion to COVID-191Not SpecifiedMexico
NCT04347681Evaluating the Potential Efficacy of Convalescent Plasma210–15 ml/kg body weight of the recipientSaudi Arabia
NCT04346446Evaluating the Efficacy of Convalescent Plasma Therapy for Severely Sick Patients2200–600 ml of convalescent plasma will be transfused to patients.New Delhi, India

Rationale for Recommendation

Currently, there are insufficient data from well-controlled, adequately powered, randomized clinical trials to evaluate the efficacy and safety of convalescent plasma for the treatment of COVID-19. However, >70,000 patients in the United States have received COVID-19 convalescent plasma through the Mayo Clinic’s Expanded Access Program (EAP), which was designed primarily to provide broad access to investigational convalescent plasma and thus did not include an untreated control arm. Both the Food and Drug Administration (FDA) and the Mayo Clinic performed retrospective, indirect evaluations of efficacy by using the Mayo Clinic EAP data, hypothesizing that patients who received plasma units with higher titers of SARS-CoV-2 neutralizing antibodies would have better clinical outcomes than those who received plasma units with lower antibody titers. The results of their analyses suggest that convalescent plasma with high antibody titers may be more beneficial than low-titer plasma in nonintubated patients, particularly when administered within 72 hours of COVID-19 diagnosis.

The FDA determined that these findings—along with additional data from small randomized and nonrandomized studies, observational cohorts, and animal experiments—met the criteria for Emergency Use Authorization (EUA) issuance.2,3 Despite meeting the “may be effective” criterion for EUA issuance, the EAP analyses are not sufficient to establish the efficacy or safety of convalescent plasma due to the lack of a randomized, untreated control group and potential confounding. There is no widely available and generally agreed-upon best test for measuring neutralizing antibodies, and the antibody titers of plasma from patients who have recovered from COVID-19 are highly variable. Furthermore, hospitalized patients with COVID-19 may already have SARS-CoV-2 neutralizing antibody titers that are comparable to those of plasma donors, potentially limiting the benefit of convalescent plasma in this patient population.4,5 Several randomized, placebo-controlled trials of COVID-19 convalescent plasma are ongoing.

The Panel’s assessment of the EAP data is consistent with the FDA statements in the convalescent plasma EUA documents.3,6,7

Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19

Adverse Effects

Before administering convalescent plasma to patients with a history of severe allergic or anaphylactic transfusion reactions, the Panel recommends consulting a transfusion medicine specialist who is associated with the hospital blood bank.

The available data suggest that serious adverse reactions following the administration of COVID-19 convalescent plasma are infrequent and consistent with the risks associated with plasma infusions for other indications. These risks include transfusion-transmitted infections (e.g., human immunodeficiency virus [HIV], hepatitis B, hepatitis C), allergic reactions, anaphylactic reactions, febrile nonhemolytic reactions, transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and hemolytic reactions. Hypothermia, metabolic complications, and post-transfusion purpura have also been described.7

Additional risks include a theoretical risk of antibody-dependent enhancement and a theoretical risk of suppressed long-term immunity.

Considerations in Pregnancy

The safety and effectiveness of COVID-19 convalescent plasma during pregnancy have not been evaluated. Several ongoing clinical trials that are evaluating COVID-19 convalescent plasma include pregnant individuals.

Considerations in Children

The safety and effectiveness of COVID-19 convalescent plasma have not been evaluated in pediatric patients. Clinical trials of COVID-19 convalescent plasma in children are ongoing.

Product Availability

On August 23, 2020, the FDA authorized the use of convalescent plasma for the treatment of hospitalized patients with COVID-19.3 Both High Titer (i.e., Ortho VITROS SARS-CoV-2 IgG tested with signal-to-cutoff ratio ≥12) and Low Titer COVID-19 Convalescent Plasma are authorized for use.6,7 Access to convalescent plasma is no longer available through the Mayo Clinic EAP, which was discontinued on August 28, 2020. Please refer to the FDA’s Recommendations for Investigational COVID-19 Convalescent Plasma website for guidance on the transfusion of investigational convalescent plasma while blood establishments develop the necessary operating procedures to manufacture COVID-19 convalescent plasma in accordance with the Conditions of Authorization set forth in the EUA.

People who have been fully recovered from COVID-19 for ≥2 weeks and who are interested in donating plasma can contact their local blood donation or plasma collection center or refer to the FDA’s Donate COVID-19 Plasma website.

Clinical Trials

Randomized clinical trials that are evaluating convalescent plasma for the treatment of COVID-19 are underway; a list is available at ClinicalTrials.gov.

Clinical Data to Date

Open-Label Randomized Clinical Trial of Convalescent Plasma in Hospitalized Patients With Severe or Life-Threatening COVID-19

An open-label randomized clinical trial of convalescent plasma versus standard of care for patients with severe or life-threatening laboratory-confirmed COVID-19 was conducted in Wuhan, China, from February 14 to April 1, 2020. The primary outcome was time to clinical improvement within 28 days. Only plasma units with a SARS-CoV-2 viral spike-receptor binding domain-specific IgG titer of at least 1:640 were transfused. The median time from symptom onset to study randomization was 27 days in the treatment group and 30 days in the control group.8

Due to the decreasing incidence of COVID-19 in Wuhan, the trial was terminated early after 103 of the planned 200 patients were enrolled. There was no significant difference between the treatment and control groups in time to clinical improvement within 28 days (HR 1.40; 95% CI, 0.79–2.49; P = 0.26). Among those with severe disease, 91% of the convalescent plasma recipients and 68% of the control patients improved by Day 28 (difference of 23%; OR 1.34; 95% CI, 0. 98–1.83; P = 0.07). Among those with life-threatening disease, the proportion of patients who showed clinical improvement was similar between the treatment (21%) and control (24%) groups. There was no significant difference in mortality (16% vs. 24% of patients in the treatment and control groups, respectively; P = 0.30). At 24 hours, the rates of negative SARS-CoV-2 viral polymerase chain reaction were significantly higher in the convalescent plasma group (45%) than in the control group (15%; P = 0.003), and differences persisted at 72 hours.

Limitations

The study was not blinded, and, on average, convalescent plasma was administered approximately 1 month into the disease course. Also, the study was terminated early, and thus lacked sufficient power to detect differences in clinical outcomes between the study groups.

Open-Label Randomized, Multicenter Clinical Trial of Convalescent Plasma in Hospitalized Patients with COVID-19 (ConCOVID Study)

This study has not been peer reviewed.

An open-label randomized clinical trial of convalescent plasma versus standard of care for hospitalized patients with COVID-19 was conducted in 14 hospitals in the Netherlands from April 8 to July 1, 2020. Only plasma confirmed to have anti-SARS-CoV-2 neutralizing antibodies by a SARS-CoV-2 plaque reduction neutralization test (PRNT) and a PRNT50 titer ≥1:80 was transfused. The primary endpoint was in-hospital mortality up to 60 days after admission.

The trial was halted prematurely by the investigators and the study’s data safety monitoring board when the baseline SARS-CoV-2 neutralizing antibody titers of participant and convalescent plasma were found to be comparable, challenging the potential benefit of convalescent plasma for the study patient population. Fifty-three of 66 participants had anti-SARS-CoV-2 antibodies at baseline despite being symptomatic for a median time of only 10 days. Among 56 participants whose blood was tested using SARS-CoV-2 plaque reduction neutralization testing, 44 (79%) had neutralizing antibody levels that were comparable to those of 115 donors (median titers of 1:160 vs. 1:160, respectively, P = 0.40).When the trial was halted, 86 participants had been enrolled. No differences in mortality (= 0.95), length of hospital stay (P = 0.68), or disease severity at Day 15 (P = 0.58) were observed between the study arms.4

Limitations

The study was terminated early, and thus lacked sufficient power to detect differences in clinical outcomes between the study groups.

Open-Label Randomized, Multicenter Clinical Trial of Convalescent Plasma in Hospitalized Patients with COVID-19 (PLACID Trial)

This study has not been peer reviewed.

An open-label, randomized clinical trial of convalescent plasma versus standard of care for hospitalized patients with COVID-19 was conducted in 39 tertiary care centers in India from April 22 to July 14, 2020. Patients with confirmed COVID-19 and signs of severe disease with hypoxia were eligible if matched donor plasma was available at the time of enrollment. Critically ill patients (those with a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2] <200 mmHg or shock) were excluded. The primary outcome was time to disease progression through 28 days (i.e., to PaO2/FiO2 <100 mmHg) or all-cause mortality at 28 days. Participants in the intervention arm received two doses of 200 mL plasma, transfused 24 hours apart. Antibody testing to assess titers of donated plasma was not available when the trial started.

Four-hundred and sixty-four participants were randomized; 235 were randomized into the convalescent plasma arm and 229 were randomized into the standard of care arm. The arms were well-balanced with regard to age (median of 52 years in both arms) and days from symptom onset to enrollment (median of 8 days in both arms). There was no difference in the primary outcome (time to disease progression and 28-day mortality) across the trial arms. The composite outcome occurred in 44 patients (18.7%) in the convalescent plasma arm and 41 (17.9%) in the control arm. Thirty-four participants (14.5%) in the convalescent plasma arm and 31 patients in the control arm (13.6%) died. In each arm, 17 participants progressed to severe disease (7.2% in the convalescent plasma arm vs. 7.4% in the standard of care arm).5

Limitations

SARS-CoV-2 antibody testing was not used to select donated convalescent plasma units; therefore, many participants may have received units with low titers of SARS-CoV-2 neutralizing antibodies. Additionally, the study was not blinded.

Prospective Safety Analyses and Retrospective Exploratory Analyses of Outcomes Among Tens of Thousands of Patients Receiving Open-Label COVID-19 Convalescent Plasma Through the Mayo Clinic Expanded Access Program

The Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19 program was an open-label, nonrandomized EAP that was primarily designed to provide adult patients who have severe or life-threatening (critical) COVID-19 with access to convalescent plasma. Secondary objectives were to obtain data on the safety of the intervention. Exploratory objectives included assessment of 7-day and 28-day mortality. The program was sponsored by the Mayo Clinic and included a diverse range of clinical sites. SARS-CoV-2 antibody testing of plasma donors and assessment of SARS-CoV-2 neutralization potential were not mandated. Patients were transfused with 1 or 2 units (200–500 mL) of convalescent plasma. The main outcomes for the safety analysis were serious adverse events (SAEs), including death; SAEs were reported at 4 hours and at 7 days after transfusion, or as they occurred.3,6,9,10

A peer-reviewed publication described the safety outcomes for the first 20,000 EAP plasma recipients, enrolled between April 3 and June 2, 2020.9 One-third of the participants were aged ≥70 years, 60% were men, and 71% had severe or life-threatening COVID-19. Twenty percent of the participants were African American, 35% were Hispanic/Latino, and 5% were Asian. Thirteen deaths were assessed as possibly or probably related to the convalescent plasma treatment. The 83 nonfatal SAEs that were assessed as possibly or probably related to the convalescent plasma treatment included 37 TACO events, 20 TRALI events, and 26 severe allergic reactions. The life-threatening events that were reported up to 7 days after transfusion included 87 thrombotic/thromboembolic complications, 406 sustained hypotension events, and 643 cardiac events. The overall mortality rate was 8.6% at 7 days.

Both the FDA and the Mayo Clinic performed retrospective, indirect evaluations of the efficacy of COVID-19 convalescent plasma by using subsets of EAP data, hypothesizing that patients who received plasma units with higher titers of neutralizing antibodies would have better clinical outcomes than those who received plasma units with lower titers of antibodies. This analytic approach was not prespecified in the Mayo Clinic EAP protocol.

The FDA analysis included 4,330 patients, and donor neutralizing antibody titers were measured by the Broad Institute using a pseudovirus assay.6 The analysis revealed no difference in 7-day mortality between the patients who received high-titer plasma and those who received low-titer plasma, in the patient population overall, or in the subset of patients who were intubated. However, among nonintubated patients (approximately two-thirds of those analyzed), mortality within 7 days of transfusion was 11% for those who received high-titer plasma and 14% for those who received low-titer plasma (P = 0.03).In a post hoc analysis of patients aged <80 years who were not intubated and who were treated within 72 hours of COVID-19 diagnosis, 7-day mortality was lower among the patients who received high-titer plasma than among those who received low-titer plasma (6.3% vs. 11.3%, respectively; P = 0.0008).6

A similar efficacy analysis by the Mayo Clinic, which has not been peer reviewed, included 3,082 participants who received a single unit of plasma out of the 35,322 participants who had received plasma through the EAP by July 4, 2020. Antibody titers were measured by using the Ortho Clinical Diagnostics COVID-19 IgG assay, and outcomes in patients transfused with low- (lowest 18%), medium-, and high- (highest 17%) titer plasma were compared. After adjusting for baseline characteristics, the 30-day mortality in the low-titer group was 29% and 25% in the high-titer group. This difference did not reach statistical significance. Similar to the FDA analyses, post hoc subgroup analyses suggested a benefit of high-titer plasma in patients aged <80 years who received plasma within 3 days of COVID-19 diagnosis and who were not intubated.10

Limitations

  • The lack of an untreated control arm limits interpretation of the safety and efficacy data. For example, the possibility that differences in outcomes are attributable to harm from low-titer plasma rather than benefit from high-titer plasma cannot be excluded.
  • The EAP data may be subject to multiple confounders, including regional differences and temporal trends in the management of COVID-19.
  • There is no widely available and generally agreed-upon best test for measuring neutralizing antibodies, and the antibody titers in convalescent plasma from patients who have recovered from COVID-19 are highly variable.
  • The efficacy analyses rely on a subset of EAP patients who only represent a fraction of the patients who received convalescent plasma through the EAP.
  • The subgroup that demonstrated the largest estimated effect between high-titer and low-titer convalescent plasma—patients aged <80 years who were not intubated and who were transfused within 3 days of COVID-19 diagnosis—was selected post hoc by combining several subset rules which favored subgroups that showed a trend toward benefit of high-titer plasma. This approach tends to overestimate the treatment effect.
  • The FDA analysis relied on 7-day mortality, which may not be clinically meaningful in the context of the prolonged disease course of COVID-19. Because participants in this observational study were not rigorously followed after they were discharged from the hospital, the 30-day mortality estimates are uncertain.

Other Clinical Studies of COVID-19 Convalescent Plasma

The results of retrospective case-controlled studies that evaluated outcomes among COVID-19 convalescent plasma recipients have been published.11 In one such study of patients who were hospitalized between March 24 and April 8, 2020, at Mount Sinai Hospital in New York City, outcomes among 39 consecutive patients who received convalescent plasma with a SARS-CoV-2 anti-spike antibody titer of 1:320 were compared to outcomes among 156 propensity-score-matched controls. As of May 1, 2020, 13% of the plasma recipients and 24% of the matched control patients had died (P = 0.04, log-rank test), and 72% and 67% of the transfused patients and control patients, respectively, had been discharged from the hospital. Subgroup analyses suggested a benefit of convalescent plasma among patients who were not intubated, had a shorter duration of symptoms, and received therapeutic anticoagulation.

Another study compared convalescent plasma with standard of care in patients with COVID-19 who were hospitalized between March 28 and July 6, 2020, at eight Houston Methodist hospitals. Outcomes for the first 136 convalescent plasma recipients who reached Day 28 post-transfusion were compared with the outcomes for two sets of propensity-score matched controls at 28 days after admission. The analyses suggested a trend towards benefit of convalescent plasma, with larger differences in mortality seen primarily among subgroups of patients who were transfused early (i.e., within 72 hours of admission) with high-titer plasma (i.e., anti-spike protein receptor binding domain titer ≥1:1350).12

Other smaller, uncontrolled case series that describe clinical outcomes in patients with COVID-19 have been reported and also suggest that SAEs are uncommon following COVID-19 convalescent plasma treatment.1,13-18

Clinical Data for Other Viral Infections

The use of convalescent plasma has been evaluated for other viral diseases, such as SARS, with some suggestion of potential benefit.19-21 The only randomized controlled trial that demonstrated efficacy of convalescent plasma for an infectious disease was conducted more than 40 years ago, for treating Argentine hemorrhagic fever.22 No convalescent plasma products are currently approved by the FDA for the treatment of COVID-19.

References

  1. Wang X, Guo X, Xin Q, et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32497196.
  2. Food and Drug Administration. Convalescent plasma letter of authorization. 2020. Available at: https://www.fda.gov/media/141477/download. Accessed August 31, 2020.
  3. Food and Drug Administration. EUA 26382: Emergency Use Authorization (EUA) decision memo. 2020 Available at: https://www.fda.gov/media/141480/download. Accessed August 31, 2020.
  4. Gharbharan A, Jordans CCE, GeurtsvanKessel C, et al. Convalescent plasma for COVID-19: a randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1.
  5. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial). medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.09.03.20187252v2.
  6. Food and Drug Administration. EUA 26382: emergency use authorization (EUA) request. 2020. Available at: https://www.fda.gov/media/141481/download.
  7. Food and Drug Administration. EUA of COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients: fact sheet for health care providers. 2020. Available at: https://www.fda.gov/media/141478/download. Accessed September 22, 2020.
  8. Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492084.
  9. Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clinical Proceedings. 2020. Available at: https://mayoclinicproceedings.org/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_6_8.pdf. Accessed June 26, 2020.
  10. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. medRxiv. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32817978.
  11. Liu STH, Lin HM, Baine I, et al. Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study. Nat Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32934372.
  12. Salazar E, Christensen PA, Graviss EA, et al. Treatment of coronavirus disease 2019 patients with convalescent plasma reveals a signal of significantly decreased mortality. Am J Pathol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32795424.
  13. Salazar E, Perez KK, Ashraf M, et al. Treatment of COVID-19 patients with convalescent plasma in Houston, Texas. medRxiv. 2020;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511574.
  14. Ahn JY, Sohn Y, Lee SH, et al. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020;35(14):e149. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281317.
  15. Pei S, Yuan X, Zhang Z, et al. Convalescent plasma to treat COVID-19: Chinese strategy and experiences. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.07.20056440v1.
  16. Ye M, Fu D, Ren Y, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32293713.
  17. Zeng Q, Yu Z, Gou J, et al. Effect of convalescent plasma therapy on viral shedding and survival in COVID-19 patients. The Journal of Infectious Diseases. 2020;In press. Available at: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa228/5826985.
  18. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci US. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32253318.
  19. Burnouf T, Radosevich M. Treatment of severe acute respiratory syndrome with convalescent plasma. Hong Kong Med J. 2003;9(4):309; author reply 310. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12904626.
  20. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15616839.
  21. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211(1):80-90. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25030060.
  22. Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2(8154):1216-1217. Available at: https://www.ncbi.nlm.nih.gov/pubmed/92624.

Journal information: British Medical Journal (BMJ)

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