Author: Federica La Russa; Revision and Translation: Irene Di Ceglie
Convalescent plasma therapy is attracting increasing attention as a potential strategy for the treatment of COVID-19 patients. Here, we provide an overview of clinical data available to date, pro and cons of such an approach, and discuss opportunities to overcome limitations.
● As of today, there are no available treatments for coronavirus disease (COVID-19), a global yet unmet clinical challenge. Given the virological and clinical similarities with severe infectious disease like SARS and MERS, the scientific community is considering therapeutic approaches previously used in such contexts e.g. convalescent plasma (CP) therapy .
● CP therapy consists in a passive immunotherapy whereby plasma collected from individuals following resolution of infection, hence rich in antibodies, is transfused to recipients with the goal of preventing or reducing clinical manifestations of the infection, and potentially conferring immediate protection.
Overview of clinical studies
- To date, there are reports indicating the use of convalescent plasma to treat COVID-19 patients [2-6]. Here, we provide an overview of relevant criteria offering a comparison among successful studies with the highest number of recruited patients (Table 1). Favorable results were also suggested by Ahn et al. reporting results of early transfusion (9-10d) of 500mL (250×2) CP, selected for compatibility and Ig titer, in 2 COVID-19 patients with ARDS, which induced rapid improvement and recovery . Of note, a retrospective study on 6 COVID-16 patients treated with CP, and compared to 11 COVID-19 controls, shows that such a therapy might not limit fatality, but only discontinue viral shedding, especially when initiated at later stages of disease (21.5d after first viral detection, 300ml CP) .
|Study 1 ||Study 2 ||Study 3 |
|Treatment||200 ml – single dose||400 ml – two doses||200 ml – single/multiple|
|Donor Ab titer||1:640||1:1000||N.A.|
|Time frame||10-20d from symptom onset||10-22d after admission||Later stage from symptom onset|
|Viral Load||Undetectable within 2d (3/10), 3d (3/10) and 6d (1/10)||↓ and became negative within 12d (5/5)||N.A.|
|Clinical symptoms||↓ Fever, cough, shortness of breath, chest pain within 1-3d; ↑ SaO2||↓ fever within 3d (4/5); ↓ sequential organ failure assessment within 12d; ↑ PAO2/FlO2 within 12d||↓ shortness of breath (2/6); ↑ PAO2/FlO2 (1/6); N.A. (3/6)|
|Lab tests||↓ C-reactive protein, alanine aminotransferase, aspartate aminotransferase, total bilirubin ↓ lymphocytopenia (7/10)||↓ C-reactive protein, procalcitonin (5/5); ↓ IL6 (4/5)||No or minor alterations at admission|
|Radiological lung exams||↓ lesions by 7d||improvement (1/5) or resolution (4/5) of lesion by 3d||↓ lesions (5/6); N.A. (1/6)|
|Ventilation||Weaned mechanical ventilation (2/3); discontinued high-flow nasal cannula (1/3); from continuous oxygenation to intermittent (1/2)||Weaned mechanical ventilation within 9 days (3/5)||Discontinued high-flow nasal cannula (1/6); N.A. (5/6)|
|Neutralizing abs||↑ (5/10) or ~ (4/10)||↑||↑ (2/6); ~ (2/6); N.A. (1/6)|
Despite, these encouraging results, limitations of these studies are worth being reported:
- Small sample size with a wide range of clinical features especially in Study 3; no controls except in Study 1, for which a historic control group was formed by random selection of 10 patients from the cohort treated in the same hospital and matched by age, gender, and severity of diseases
- All patients involved received another set of treatment (e.g. antivirals) previously or during CP therapy, thus limiting evaluation of improvements specifically due to this approach
- Comparable inclusion criteria for donors and recipients, but lack of consistency among each other
Key factors for success – open questions: workflow, clinical trials and FDA recommendations
- Composition and titer of neutralizing antibodies as well as a time frame of treatment are suggested as key factors for a successful CP therapy [2,3]. Yet, no consensus has been reached about the optimal plasma composition and dosage, best time points for treatment, and on what outcomes might be specifically improved by CP therapy.
- Bloch et al. recently provided a workflow overview, describing limitations of CP therapy and its implementation as well as providing a framework for generating practical as well as clinical consensus . Other commentaries have also been reasoning around these concepts  and we report a summary in Table 2.
|Subject||Criteria||Limitations (L) / Proposal (P)|
|Donor||Recruitment||L: ratio of recovered patients to ill individual causes shortage of CP P: Community outreach; advertising and communication through media; recruitment through health care providers|
|Screening for CP quality||P: two-step process > clinical provider donor assessment followed by referral to collection facility|
|Ab testing||L1: uncertainty on which Abs are effective in COVID-19 L1.1: uncertainty on the optimal correlate for efficacy (total vs neutralizing Abs; specific isotype) L2: limited availability of high throughput screening for neutralizing Abs (likely to better correlate with therapy efficacy) L2.1: quantitative assays (e.g. ELISA) commercially available, but not rigorously validated P: collection time point ≥ 14d after resolution is reported to be sufficient for high titers of Abs with caveat of limited availability of data|
|Collection and testing||P: apheresis is recommended over whole blood donation due to higher efficiency (2-4 units of CP for transfusion)|
|Distribution||L: not all blood centers have ability to recruit and allocate units equitably P: follow FDA proposal of an expanded access program to regionalize or centralize recruitment, collections and inventory|
|Recipient||Dosing and Transfusion||L: Abs duration of efficacy is unknown although postulated to be weeks to months P: titer ≥ 1:160 (or lower for prophylaxis) P: one unit is proposed for post-exposure prophylaxis; one to two units for treatment|
|Timing of administration||L: CP therapy has the latent risk of aggravating hyperimmune attacks (i.e. cytokine storm, which usually happen in the second week of symptom onset) P: CP therapy should be administered in earlier stage of disease|
- In response to the above-mentioned unmet questions, at least five clinical trials have been registered with the goal to assess safety and efficacy of CP therapy in COVID-19 patients, as summarized in Table 3 .
|Post-exposure prophylaxis in adults who have been closely exposed to COVID-19, but without manifested symptoms||Intervention for vulnerable populations following exposure e.g healthcare workers, individual with pre-existing, at risk, conditions|
|Patients with mild disease||Resolution of symptoms, prevention of worsening of respiratory symptoms and/or clinical complications|
|Moderately ill patients (not in ICU)||Limiting disease progression to avoid overburdening of critical care resources|
|Severely ill patients (ICU admitted)||Rescuing from mechanical ventilation|
|High risk pediatric patients||Counterbalance underscored risk assessment|
- Similarly, FDA has provided guidelines for investigation of CP in COVID-19 in clinical trials as well as in severely ill patients who cannot be recruited in one (i.e. under investigation of a new drug extension FDA pathway), which should support increased consistency among studies . The most relevant information are reported in Table 4.
|Donor eligibility||Evidence of documented COVID-19 by either a diagnostic test or positive serological tests after recoveryComplete resolution of symptoms at least 14d prior donation (negative result for COVID-19 by diagnostic test is not necessary to qualify) SARS-CoV-2 neutralizing antibody titers: at least 1:160 (1:80 considered acceptable if alternative matched unit is unavailable)|
|Patient eligibility (new drug extension FDA pathway)||COVID-19 confirmed by laboratory diagnostic testSevere or life-threatening COVID-19:severe: shortness of breath; respiratory frequency ≥ 30/min; blood oxygen saturation ≤ 93%; partial pressure of arterial oxygen to fraction of inspired oxygen ration <300; lung infiltrates > 50% within 24 to 48 hrslife-threatening: respiratory failure; septic shock; multiple organ dysfunction or failure|
Evidence collected so far supports CP therapy as a safe and potentially beneficial therapy as well prophylactic approach in COVID-19. Notwithstanding, controlled clinical trials are required to confirm efficacy and form a consensus around a more structured strategy for testing and use on a large scale.
 Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, van Buskirk C, Grossman BJ, Joyner M, Henderson JP, Pekosz A, Lau B, Wesolowski A, Katz L, Shan H, Auwaerter PG, Thomas D, Sullivan DJ, Paneth N, Gehrie E, Spitalnik S, Hod E, Pollack L, Nicholson WT, Pirofski LA, Bailey JA, Tobian AA. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020 Apr 7. pii: 138745.
 Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9490-9496.
 Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar 27.
 Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, Xia X, Lv T. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020 Apr 15.
 Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, Jeong SJ, Kim JH, Ku NS, Yeom JS, Roh J, Ahn MY, Chin BS, Kim YS, Lee H, Yong D, Kim HO, Kim S, Choi JY. Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea. J Korean Med Sci. 2020 Apr 13;35(14):e149.
 Zeng QL, Yu ZJ, Gou JJ, Li GM, Ma SH, Zhang GF, Xu JH, Lin WB, Cui GL, Zhang MM, Li C, Wang ZS, Zhang ZH, Liu ZS. Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in COVID-19 Patients. J Infect Dis. 2020 Apr 29. pii: jiaa228.
 Zhao Q, He Y. Challenges of Convalescent Plasma Therapy on COVID-19. J Clin Virol. 2020 Apr 10;127:104358.
 US Food and Drug Administration (FDA), Recommendations for Investigational COVID-19 Convalescent Plasma, May 1, 2020