Table 1.

Summary of included studies (RCTs, controlled NRSIs, and non-controlled NRSIs) on CP for COVID-19 patients.

Author	Country	Study design	No. of participants	Patients Condition	CPT dose	Time of Administration	Antibody titer(s)	Concomitant therapy	Conclusion of authors	AEs
Gharbharan et al. [21]	Netherlands	Open-label RCT,MC	Intervention 43;control 43	Mild moderately ill	300 ml	9 days(IQR7-13)	Nabs titers＞1:80	CHQ;LPVr; AZM;tocilizumab, anakinra as appropriate.	No statistically significant differences in mortality or improvement in the day-15 disease severity	No serious AEs.
Li et al [22]	China	Open-label RCT,MC	Intervention 52; control 51	Critically ill	4–13 ml/kg. 200 ml(IQR 200–300 ml)	27 days(IQR 22–39)	IgG ＞1:640	antivirals, steroid, immunoglobulin, antibiotics and Chinese herbal medicines,as appropriate	Compared with standard treatment alone,CPT did not statistically reduce mortality or the time to clinical improvement within 28 days.	N = 3(in 2 patients)0.1 possible severe transfusion-associated dyspnoea.1 non-severe allergic transfusion reaction and 1 probable non-severe febrile
C Avendaño-Solà et al [23]	Spanish	RCT,MC	Intervention 38; control 43	Less severe	250–300 ml	Median time was 8 days.	Nabs titers＞1:80	–	No significant differences were found in mortality, but CPT could be superior to SOC in avoiding disease progression.	16 serious or grade 3–4 AEs were reported in 13 patients, 6 in the CP group and 7 in the SOC group.
Anup Agarwal et al [24]	Indian	Open-label RCT,MC	Intervention 235; control 229	Moderately ill	2 doses of 200 ml	–	Nabs titers 1:90 (1:30 to 1:240).	Antivirals, antibiotics, immunomodulators and supportive management	CP was not associated with reduction in mortality or progression to severe COVID-19.	Minor AEs of pain in local infusion site, chills, nausea, bradycardia and dizziness was reported in one patient each. Fever and tachycardia were reported in three patients each.
Duan et al [25]	China	Pilot prospective cohort with a historiacal control group, MC	Intervention 10; control 10.	Severely ill.	200 ml single dose	Median time from onset of illness to CPT was 16.5 days (IQR 11–19)	Nabs titers＞1:640	Antivirals, antimicrobials	CPT was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases.	Self-limited facial erythema in 2/10 patients. No major AEs.
Liu et al [26]	USA	Matched control study,SC	Intervention 39;control 156	Moderate-critically ill	2 units. Each unit of 250 ml	Median time 4 days(IQR 1–7)	antispike antibody titer of ≥ 1:320	antivirals, antibiotics, steroid and immunoglobulin, as appropriate	CPT is a potentially efficacious treatment option for inpatients, and non-intubated patients may benefit more.	No serious AEs.
Zeng et al [27]	China	Retrospective conntrolled study,MC	Intervention 6, control 15	Critically ill	300 ml(IQR 200–600 ml)	21.5 days(IQR 17.8–23)	–	Antivirals, steroid and immunoglobulin, as appropriate	CPT can discontinue SARS-CoV-2 shedding but cannot reduce mortality in critically end stage patients.	No serious AEs.
Donato et al [28]	USA	Prospective controlled study, SC	Intervention 47; control 1340	Moderate-critically ill	500 ml(n = 36); 400 ml(n = 10); 200 ml(n = 1)	Median time 8–15 days	IgG Spike RBD > 1:500	HCQ,AZM,Steroids,Tocilizumab,Remdesivir	CPT was safe and conferred effective transfer of immunity while preserving endogenous immune response	Mild rash(n = 1)
Ralph Rogers et al. [29]	USA	A matched cohort analysis,SC	Intervention 64,control 177	Severe ill	One or two units	7 days after symptom onset	SARS-CoV-2 IgG antibody index ＞1.4	Remdesivir, corticosteroids	No overall significant reduction of in-hospital mortality or increased rate of hospital discharge associated with the use of CP in this study, although there was a signal for improved outcomes among the elderly.	Two patients who received CP were judged to have a TRALI reaction. ONE have transfusion-associated circulatory overload (TACO)
Martin R Salazar et al [30]	Argentina	Retrospective cohort,MC	Intervention 868, control 2298	–	200–250 ml	–	Ig-G antibody titer ≥ 1:400	–	CP might be beneficial in COVID-19 and independently associated with decreased mortality.	No major adverse effects occurred.
Eric Salazar et al [31]	USA	Prospective, propensity score-matched study,MC	Intervention 321, control 582	Severe and/or critically ill	One or two units	≤72 h(n = 321)	Anti-RBD IgG titer ≥ 1:1350(n = 321)	Steroids, AZM, and tocilizumab	Transfusion of COVID-19 patients soon after hospitalization with high titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.	7 CP-related AEs, 2 of which were serious AEs
Livia Hegerova et al [32]	Swedish	Matched study,MC	Intervention 20, control 20	Severe or life-threatening	1 unit	Median time from hospitalization to CP was early at 2 days	–	Remdesivir	CP use in severe and critically ill patients with COVID-19 may improve survival if given early in the course of disease.	No AEs with CP were reported.
Abolghasemi et al [33]	Iran	Non-randomized study, MC	Intervention 115, control 74	Moderate to severely ill	1 unit(500 cc)	less than 3 days of hospital admission	Antibody titer cut off index＞1.1	LPVr and HCQ	CPT substantially improved patients’ survival, significantly reduced hospitalization period and needs for intubation in COVID-19 patients in comparison with control group.	No AEs
Rasheed et al [34]	Iraq	Matched study,MC	Intervention 21,control 28	Critically-ill	400 ml	–	IgG index equal or more than 1.25	HCQ + AZM	CP therapy is an effective therapy if donors with high level of SARS-Cov2 antibodies are selected and if recipients are at their early stage of critical illness, being no more than three days in RCUs.	A single case developed mild skin redness. No serious AEs
Xia et al [35]	China	Retrospective cohorts, SC	Intervention 138, control 1430	Severe or critical	200–1200 ml	More than 14 days	Antibody titers ≥ 1:160	antivirus therapy, traditional Chinese medicine, and respiratory support	CP transfused even after 2 weeks of symptom onset, could improve the symptoms and mortality in patients with severe or critical cases.	3 patients had minor allergic reactions, no serious AEs
Joyner et al(a)[36]	USA	Open-label, EAP, MC	Intervention 35,322	High proportion of critically-ill patients	One unit(approximately 200 ml)	0 days (n = 1364), 1–3 days(n = 14043), 4–10 days(n = 14358), and 11 + days(n = 5557)	Antibody levels over 18.45 S/Co or less than 4.62 S/Co	HCQ,CHQ,AZM, remdesivir and steroids	Earlier time to transfusion and CP with high antibody titers may reduce patient mortality	–
Perotti et al [37]	Italy	Single-arm, open-label,MC	Intervention 46	Severe	Approximate 330 ml	–	NAbs titer > 1:160	antibiotics, HCQ and anticoagulants	Hyperimmune plasma in Covid-19 shows promising benefits.	5 serious AEs occurred in 4 patients (2 likely, 2 possible treatment related).
Joyner et al(b)[38]	USA	Open-label, EAP, MC	Intervention 20,000	Critically illness.	200–500 ml	–	–	–	CPT is safe in hospitalized patients with COVID-19, and earlier administration is more likely to reduce mortality.	The incidence of all serious AEs was low; these included transfusion reactions (n = 78; <1%), thromboembolic or thrombotic events (n = 113; <1%), and cardiac events (n = 677,~3%).
Valentini et al [39]	Argentina	Open label trial, MC	Intervention 87	Severe or critical	300–600 ml.	Median of three days after hospital admission	Index values ranged between 0 and 10 (mean 5.7)	LPVr	CPT are feasible, safe, and potentially effective, especially before requiring MV.	No serious AEs attributed to plasma.
Olivares-Gazca et al [40]	Mexico	Prospective, longitudinal, single arm, and quasi experimental, MC	Intervention 10	Critically-ill	200 ml	Median time 6 days	–	HCQ,AZM,Steroids,Tocilizumab, LPVr	The addition of CP to other therapies improved pulmonary function	–
Bradfute et al [41]	USA	Single arm trial	Intervention 12	Severe or life-threatening	200 ml	Median time: 8.5 days	Median Nabs titer is 1:40	–	CP infusion did not alter recipient NAb titers. Pre-screening of CP may be necessary for selecting donors with high levels of neutralizing activity for infusion into patients with COVID-19.	No study-related serious AEs
Madariaga MD et al [42]	USA	Open label clinical study	Intervention 10	Severe or life-threatening	~300 ml	Within 21 days	RBD range from 0 to 1:3289	Remdesivir, tocilizumab, anakinra and HCQ.	Despite variability in donor titer, 80% of recipients showed significant increase in antibody levels post-transfusion.	–

Abbreviations: M, male; F, female. CPT:convalescent plasma transfusion; ICU:Intensive care Unit; IQR:Inter quartile range; MC:multi center; SC:single center; RCT:randomized controlled trial; OR: odds ratio; CHQ:Chloroquine; HCQ: hydroxychloroquine; LPVr: lopinavir/ritonavir; AZM: azithromycin; MV:mechanical ventilation; TACO:transfusion-associated circulatory overload; TRALI:transfusion-related acute lung injury. NAbs, Neutralizing antibodies; SOC: standard of care; AEs:adverse events; EAP, Expanded Access Program