. 2021 Apr 7;7(4):e25500. doi: 10.2196/25500

Table 1.

Summary of literature.

Article type^a and group		Articles, n	Summary	References
Clinical studies		64
	Case reports		A single severe or critically ill COVID-19 patient of different ages (6-100 years), either previously healthy or with comorbidities (cancers, organ transplantation, immunodeficiency, hypertension, diabetes, cerebral hemorrhage, cardiopulmary disease, or pregnancy), was successfully treated with one or two doses of CP^b (150-250 mL per dose; anti–SARS-CoV-2 IgG titer 1:13.3-1:700) in combination with antiviral or anti-inflammatory drugs (favipiravir and hydroxychloroquine, enoxaparin, methylprednisolone, remdesivir, lopinavir or ritonavir, prednisone), antibiotic therapy (azithromycin, ceftriaxone moxifloxacin, piperacillin, tienam), antifungal medication (fluconazole), or prophylactic low-molecular-weight heparin	Al Helali et al 2020 [65] Anderson et al 2020 [66] Bao et al 2020 [67] Cinar et al 2020 [68] Clark et al 2020 [69] Figlerowicz et al 2020 [70] Grisolia et al 2020 [71] Hahn et al 2020 [72] Hartman 2020 [73] Im et al 2020 [74] Jafari et al 2020 [75] Jiang et al 2020 [76] Karataş et al 2020 [77] Khan et al 2020 [78] Kong et al 2020 [79] Mira et al 2020 [80] Rodriguez et al 2020 [81] Soleimani and Soleimani 2020 [82] Xu et al 2020 [83] Zhang et al 2020 [84]
	Case series		31 clinical studies involving two or more COVID-19 patients of different ages (14-91 years) and disease severity (eg, hospitalized, moderate, severe, or life-threatening), either previously healthy or with comorbidities (cancer, hypertension, immunosuppression, organ transplantation) that were treated with various doses of CP (200 mL to 3 × 200 mL) in addition to supportive care, antiviral therapy, antibiotics, steroids, or anticoagulation treatment.	Ahn et al 2020 [85] Abdullah et al 2020 [86] Bradfute et al 2020 [87] Diorio et al 2020 [88] Enzmann et al 2020 [89] Erkurt et al 2020 [90] Fung et al 2020 [56] Gemici et al 2020 [91] Hartman et al 2020 [63] Ibrahim et al 2020 [92] Bobek et al 2020 [93] Jin et al 2020 [94] Joyner et al 2020 [95-97] Liu et al 2020 [98] Maor et al 2020 [99] Naeem et al 2020 [100] Olivares-Gazca et al 2020 [101] Pal et al 2020 [102] Rahman et al 2020 [103] Salazar et al 2020 [104] Shen et al 2020 [105] Tremblay et al 2020 [106] Wei et al 2020 [107] Wang et al 2020 [108] Wu et al 2020 [109] Xi et al 2020 [110] Ye et al 2020 [111] Zhang et al 2020 [112] Zeng et al 2020 [113]
	Observational (cohort, case-control studies)		11 cohort, case-control studies of a CP treatment group (6-316 patients) and a matched control (12-1430 patients) of severe or life-threatening COVID-19 patients to compare clinical and laboratory outcomes including all-cause mortality, total hospitalization days, and patients’ need for intubation between the two groups.	Abolghasemi et al 2020 [114] Duan et al 2020 [115] Hegerova et al 2020 [116] Liu et al 2020 [117] Perotti et al 2020 [118] Rasheed et al 2020 [119] Roger et al 2020 [120] Salazar et al 2020 [121] Xia et al 2020 [122] Xiao et al 2020 [123] Zeng et al 2020 [124]
	RCT^c		Two RCTs of 86 hospitalized and 103 severe or life-threatening COVID-19 patients randomized at 1:1 ratio for standard of care therapy with and without CP. The primary outcome was mortality and time to clinical improvement.	Gharbharan et al 2020 [125] Li et al 2020 [126]
Commentary (correspondence, editorial, letter to the editor, opinions, perspectives, viewpoints)		79
	Positive		These are commentaries that supported clinical use and evaluation of CP for COVID-19 treatment based on the unique immunomodulatory properties of CP and historical and current data for its safety and efficacy against coronaviruses including SARS-CoV-2 but suggested limitations, future clinical investigations, and a variety of aspects to be considered for the optimal use of CP for COVID-19 including CP donor selection, CP collection and testing, manufacturing turnaround time, cost and the logistics of storage, distribution, treatment population, and administration timing and dosing.	Alghamdi and Abdel-Moneim 2020 [127] Alzoughool and Alanagreh 2020 [128] Borlongan and Sanberg 2020 [129] Cantore and Valente 2020 [130] Casadevall and Pirofski 2020 [34] Casadevall et al 2020 [131] Chen et al 2020 [28] Cheraghali et al 2020 [132] Gazzaruso et al 2020 [133] Farhat et al 2020 [134] Focosi et al 2020 [135] Franchini 2020 [136] Franchini et al 2020 [137-139] Islam et al 2020 [140] Kesici et al 2020 [141] Knudson and Jackson 2020 [142] Kumar et al 2020 [143] McAllister et al 2020 [144] Montelongo-Jauregui et al 2020 [36] Morabito and Gangadharan 2020 [29] Nnaji et al 2020 [145] Pau et al 2020 [146] Perez-Cameo and Marin-Lahoz 2020 [41] Rabelo-da-Ponte et al 2020 [147] Roback and Guarner 2020 [148] Roberts et al 2020 [149] Rubin 2020 [47] Sabando Velez et al 2020 [150] Sahu et al 2020 [151] Sheikh and Baig 2020 [152] Sheridan 2020 [43] Syal 2020 [153] Teixeira da Silva 2020 [154] The Lancet Haematology 2020 [155] Tonn et al 2020 [156] Wong and Lee 2020 [157] Yoo 2020 [158] Zhao and He 2020 [159] Zhu et al 2020 [160]
	Neutral		This group of articles highlighted both pros and cons of CP therapy and alternative therapeutic options (eg, equine polyclonal antibodies) for COVID-19, and raised questions regarding neutralizing antibodies, donor selection, collection, testing and qualification of CP, time frame for transfusing CP to recipients, transfusion volume, quality of evidence for the safety, efficacy, and ethics of clinical trials of CP therapy.	Tamburello and Marando 2020 [161] Begum and Ray 2020 [162] Bloch 2020 [163] Brown 2020 [164] Casadevall et al 2020 [165,166] Cunningham et al 2020 [167] Dhanasekaran et al 2020 [168] Dzik 2020 [169] Estcourt and Roberts 2020 [170] Farrugia 2020 [171] Fleming and Raabe 2020 [172] Focosi 2020 [173] Garraud 2020 [174] Gniadek and Donnersberger 2020 [175] Han and Zhou 2020 [176] Langhi et al 2020 [177] Lanza and Seghatchian 2020 [178] Mahase 2020 [179] Mahase 2020 [180] Malani et al 2020 [58] Adiwinata Pawitan 2020 [181] Prajapati 2020 [182] Saverino 2020 [183] Stevens et al 2020 [184] Tedder and Semple 2020 [185] Van den Berg et al 2020 [186] Verkerke and Maier 2020 [187] Xi 2020 [188] Zeng et al 2020 [189] Zylberman et al 2020 [190]
	Negative		This group of commentaries suggested that the risks associated with CP use (eg, adverse effects and blood-borne pathogen transmission) outweighed its benefits or other therapeutics for COVID-19.	Caccamo et al 2020 [191] Ferreira and Mostajo-Radji 2020 [192] Joob and Wiwanitkit 2020 [193] Sanfilippo et al 2020 [194,195] Wiwanitkit 2020 [196]
Review		46	46 different types of reviews (a total of 10 review types with unique features in terms of prescribed and explicit methodologies) on CP for treatment of virus infectious diseases (eg, SARS^d, MERS^e, EBOV^f, and H1N1) and COVID-19 with safety and efficacy as main outcomes and recommendations. Some reviews also covered other aspects related to CP use, such as SARS-CoV-2 immunology, mechanism of action, CP donor selection, CP collection, pooling technologies, pathogen inactivation systems, banking of CP, timing and dose of CP treatment, patient selection, risk-benefit analysis, and list of ongoing registered clinical trials.
	Rapid review			Barone and DeSimone 2020 [197] Majbour and El-Agnaf 2020 [198]
	State-of-the-art review			Brown and McCullough 2020 [199] Focosi et al 2020 [27]
	Scoping review			Cao and Shi 2020 [200] Zheng et al 2020 [201]
	Review of the evidence			de Alwis et al 2020 [202] Fischer et al 2020 [203] Mucha and Quraishy 2020 [204]
	Systematic review and meta-analysis			Chai et al 2020 [205] Devasenapathy et al 2020 [206] Piechotta et al 2020 [207] Sarkar et al 2020 [208] Sun et al 2020 [209]
	Overview			Abdollahi et al 2020 [210] Annamaria et al 2020 [211] Anudeep et al 2020 [212] Bloch et al 2020 [55] Venkat Kumar et al 2020 [213] Gasparyan et al 2020 [214] Iftikhar et al 2020 [215] Li et al 2020 [216] Lindholm et al 2020 [217] Murphy et al 2020 [218] Sayinalp et al 2020 [219] Subbarao et al 2020 [220]
	Mixed studies review			Pawar et al 2020 [221]
	Systematic review			Bakhtawar et al 2020 [222] Chen and Xia 2020 [223] Rajendran et al 2020 [224] Valk et al 2020 [225] Wooding and Bach 2020 [57]
	Critical review			Focosi and Farrugia 2020 [226] Nagoba et al 2020 [227] Psaltopoulou et al 2020 [228] Tiberghien et al 2020 [59]
	Literature review			Choi 2020 [52] Khulood et al 2020 [229] Chua Vi Long et al 2020 [230] Ouyang et al 2020 [231] Piyush et al 2020 [232] Rojas et al 2020 [233] Selvi 2020 [234] Sharun et al 2020 [235] Sullivan and Roback 2020 [236] Yigenoglu et al 2020 [237]
Protocol/guidance		19	These are protocols for clinical trials to evaluate the safety and efficacy of CP in treating COVID-19 patients, guidelines or programs for CP donor selection, CP preparation, laboratory examination, storage, distribution, dose, frequency and timing of CP administration, targeted patients, parameters to assess response to the treatment and long‐term outcome, adverse events, and CP application in resource-limited countries and in pediatrics and neonates.
	Preparation/production of CP			Accorsi et al 2020 [238]
	Protocol for a nonrandomized trial			Albalawi et al 2020 [239]
	Clinical study and application of CP			Al-Riyami et al 2020 [240]
	Conceptual framework			Albahri et al 2020 [241]
	Expert opinion, survey of group members, and review of available evidence			Bloch et al 2020 [242]
	COVID-19 CP program			Blackall et al 2020 [243] Budhai et al 2020 [244]
	Study protocol for RCTs			Chowdhury et al 2020 [245] Eckhardt et al 2020 [246] Janssen et al 2020 [247]
	Perspective document of the Working Party on Global Blood Safety of the International Society of Blood Transfusion			Epstein and Burnouf 2020 [248]
	Commentary			Epstein et al 2020 [249]
	Guidance for treating early to moderate COVID-19 patients with CP			Hassan et al 2020 [250]
	Initiative for provision of CP			Ipe et al 2020 [251]
	A pilot program of CP collection			Li et al 2020 [252]
	Strategy and experience			Pei et al 2020 [253]
	One arm proof-of-concept clinical trial protocol			Perotti et al 2020 [254]
	An apheresis research project proposal			Seghatchian and Lanza 2020 [255]
	Authority guide by Turkish Ministry of Health			Yilmaz et al 2020 [256]
In vitro testing of convalescent plasma		35
	ELISA^g with virus antigens (eg, spike and NP^h protein sequences) or recombinant ACE-2ⁱ as substrates		An ELISA could be a high-throughput competitive assay to detect different antibody types against SARS-CoV-2 in serum and plasma from convalescent patients; to estimate the neutralizing capacity of antispike protein antibodies to block interaction with the human ACE-2 required for viral entry; and to identify candidate sera for therapeutic use. A combination of antigenic targets (NP, spike protein, S-RBD^j) may improve the accuracy of IgG detection in CP donors.	Amanat et al 2020 [257] Byrnes et al 2020 [258] Gattinger et al 2020 [259] Zhang et al 2020 [84] DomBourian et al 2020 [260]
	Pseudovirus capture assay, VN^k assay using SARS-CoV-2 strains and Vero-E6 cells		In vitro evaluation of CP potency for COVID-19 treatment could be measured by its binding capacity to the SARS-CoV-2 spike protein and neutralizing activity against pseudotyped and chimeric viruses and authentic SARS-CoV-2, which is useful to identify donors with high titers for CP for COVID-19 therapy. There were individual differences in the antibody level (neutralizing antibody titers <1:16 to >1:1024) and its changes over 12-60 days since onset of symptoms among representative convalescent patients.	Ding et al 2020 [261] Ianevski et al 2020 [262] Schmidt et al 2020 [263] Wang et al 2020 [264] Muruato et al 2020 [265]
	Immunoassays for anti–SARS-CoV-2 IgM, IgG, and IgA based on SARS-CoV-2 SP		CP collected from adults who met all criteria for donating blood had confirmed COVID-19 by positive SARS-CoV-2 PCR^m test and completed resolution of symptoms at least 14 days prior to donation showed a wide range of antibody levels. Total anti–SARS-CoV-2 NP antibody strength correlated with time from symptom resolution to sample collection and symptom duration. There was a decline in the IgG level over a short duration of 10 days. RBDⁿ-specific serum IgG, IgM, and IgA COVID-19 convalescent patients continued to decline from 28 to 99 days after hospital discharge. Anti–SARS-CoV-2 spike protein IgG antibody strength correlated with age and hospitalization for COVID-19.	Ragnesola et al 2020 [266] Yang et al 2020 [267] de Assis et al 2020 [268] Dulipsingh et al 2020 [269] Ikegami et al 2020 [270] Ma et al 2020 [271]
	PCR-based tests		SARS-CoV-2 neutralizing antibodies were detectable as early as 10 days after onset of symptoms and continue to rise, plateauing after 18 days and were not altered by amotosalen and UV-A radiation to inactivate potentially contaminating infectious pathogens in CP. Detectable viral RNA in older COVID-19 patients screened for CP donation even 12-24 days after symptom resolution.	Danh et al 2020 [272] Hartman et al 2020 [273]
	VN assays based on pseudotyped and live SARS-CoV-2 virus, and anti–SARS-CoV-2 IgM, IgG, and IgA ELISA based on virus antigens and ACE-2		The levels of anti–SARS-CoV-2 IgM, IgG, and IgA and the neutralization capacity of CP showed a wide range and changed over time after the onset of COVID-19 symptoms and declined within the first 3 months following diagnosis, suggesting an optimal time period for CP collection. Both could be associated with donor’s age, sex, weight, COVID-19 severity, days between disease onset and plasma collection. There were various degrees of positive correlations (coefficients 0.21-0.87) between the VN and ELISA results. Some commercial ELISA can perform effectively as surrogate assays for predicting neutralizing antibody titres.	Abe et al 2020 [274] Beaudoin-Bussières et al 2020 [275] Benner et al 2020 [276] Boonyaratanakornkit et al 2020 [277] Gniadek et al 2020 [278] Patel et al 2020 [279] Harvala et al 2020 [280] Wendel et al 2020 [281] Zeng et al 2020 [282] Dogan et al 2020 [283] Jungbauer et al 2020 [284] Li et al 2020 [285] Ni et al 2020 [286] Robbiani et al 2020 [287] Salazar et al 2020 [288] Weidner et al 2020 [289]
	Biophysical antibody profiling		CP antibodies can elicit Fc-dependent functions beyond viral neutralization such as complement activation, phagocytosis, and antibody-dependent cellular cytotoxicity against SARS-CoV-2.	Natarajan et al 2020 [290]

^aThe articles were classified into five types: 64 clinical studies (20 case reports, 31 case series, 11 case-controlled and two RCTs), 79 commentary articles, 46 reviews, 19 guidance and protocols, and 35 in vitro testing of CP antibodies. The details are shown in Table S1 in Multimedia Appendix 1.

^bCP: convalescent plasma.

^cRCT: randomized controlled trial.

^dSARS: severe acute respiratory syndrome.

^eMERS: Middle East respiratory syndrome.

^fEBOV: Ebola virus.

^gELISA: enzyme-linked immunosorbent assay.

^hNP: nucleocapsid protein.

ⁱACE2: angiotensin converting enzyme 2.

^jS-RBD: spike protein receptor-binding domain.

^kVN: virus neutralization.

^lSP: spike protein.

^mPCR: polymerase chain reaction.

ⁿRBD: receptor-binding domain.