Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases avançadas dos ensaios clínicos e seus resultados preliminares

Lionel Fernel Gamarra Autor correspondente: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi CEP: 05652-000 – São Paulo, SP, Brasil. Tel.: (11) 3747-0243 E-mail: lionelgamarra7@gmail.com

Hospital Israelita Albert Einstein, São Paulo, SP, Brasil.

http://orcid.org/0000-0002-3910-0047

Autor correspondente: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi CEP: 05652-000 – São Paulo, SP, Brasil. Tel.: (11) 3747-0243 E-mail: lionelgamarra7@gmail.com

Contribuições dos autores

A extração e coleta de dados e a avaliação do risco de viés foram realizadas por seis autores (Fernando Anselmo de Oliveira, Mariana Penteado Nucci, Gabriel Nery de Albuquerque Rego, Arielly da Hora Alves, Leopoldo Penteado Nucci e Javier Bustamante Mamani) organizados em pares, que revisaram e avaliaram, de forma independente e aleatória, as informações registradas nos protocolos de ensaios clínicos e estudos identificados pela estratégia de busca nas bases de dados mencionadas. As discrepâncias entre os autores na seleção de estudos e na extração de dados foram discutidas com dois autores (Luciana Cavalheiro Marti e Lionel Fernel Gamarra) e resolvidas. A inclusão final dos estudos desta revisão foi acordada entre todos os autores.

Número de identidade	Fase	Características do paciente	Intervenção por braço	Dose PC (dia)	Faixa etária (anos)	Data de início	Data de conclusão	Progresso (%)	Situação de recrutamento
NCT02735707⁽¹⁰10. ClinicalTrials.gov. Randomized, embedded, multifactorial adaptive platform trial for community- acquired pneumonia (REMAP-CAP). Bethesda: National Library of Medicine; 2016 [cited 2020 Oct 28]. [First posted Apr 13, 2016; Last update posted Oct 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT02735707 https://ClinicalTrials.gov/show/NCT02735... ⁾	IV	Doença respiratória aguda grave e pneumonia adquirida na comunidade grave	Corticosteroides versus antibióticos versus macrolídeo versus antiviral para gripe versus LPV/Rit versus HCQ versus IFN-β1a versus Anak versus Tmab versus Smab versus Vit C versus heparina versus sinvastatina versus PC versus TP	1 ou 2 unidades em 48 horas	>18	11/4/2016	1/12/2023	58	Recrutamento
NCT04391101⁽¹¹11. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a pilot study. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 2, 2020; Last update posted Aug 17, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04332380 https://ClinicalTrials.gov/show/NCT04332... ⁾	III	Pacientes graves tratados na UTI	PC associado a TP versus TP	400-500mL	>18	1/6/2020	1/12/2021	19,2	Ainda sem recrutamento
NCT04372979⁽¹²12. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in the early care of COVID-19 patients (PLASCOSSA). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 4, 2020; Last update posted Oct 26, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04372979 https://ClinicalTrials.gov/show/NCT04372... ⁾	III	Atendimento precoce de pacientes hospitalizados	PC associado a TP versus PP associado a TP	200-230mL	18-80	1/5/2020	1/5/2021	37,3	Ainda sem recrutamento
NCT04418518⁽¹³13. ClinicalTrials.gov. A trial of CONvalescent plasma for hospitalized adults with acute COVID-19 respiratory illness (CONCOR-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 5, 2020; Last update posted July 7, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04418518 https://ClinicalTrials.gov/show/NCT04418... ⁾	III	Atendimento precoce a pacientes hospitalizados	PC associado a TP versus TP	500mL de doador único ou 2 unidades de 250mL de 1-2 doações	18-70	24/6/2020	1/12/2021	15,6	Recrutamento
NCT04355767⁽¹⁴14. ClinicalTrials.gov. Convalescent plasma in outpatients with COVID-19 (C3PO). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 21, 2020; Last update posted Sep 29, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04355767 https://ClinicalTrials.gov/show/NCT04355... ⁾	III	Pacientes graves/críticos hospitalizados	PC (títulos de anticorpos ≥1:160) versus placebo	PC: 1 unidade versus placebo: solução fisiológica com multivitamínico	>18	11/8/2020	1/12/2022	4,0	Ainda sem recrutamento
NCT04432103⁽¹⁵15. ClinicalTrials.gov. Treatment of severe and critical COVID-19 pneumonia with convalescent plasma. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 16, 2020; Last update posted June 17, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04432103 https://ClinicalTrials.gov/show/NCT04432... ⁾	III	Pacientes graves/críticos hospitalizados	PC de IgG (pacientes graves versus pacientes críticos) associado a TP	NR	>19	19/6/2020	30/9/2020	84,5	Ainda sem recrutamento
NCT04348656⁽¹⁶16. ClinicalTrials.gov. CONvalescent plasma for hospitalized adults with COVID-19 respiratory illness (CONCOR-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 16, 2020; Last update posted Oct 20, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04348656 https://ClinicalTrials.gov/show/NCT04348... ⁾	III	Atendimento precoce a pacientes hospitalizados	PC versus TP	500mL de doador único ou 2 unidades de 250mL de 1-2 doações	>20	14/5/2020	31/12/2020	53,2	Recrutando
NCT04425915⁽¹⁷17. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in patients with COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 11, 2020; Last update posted Sep 3, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04425915 https://ClinicalTrials.gov/show/NCT04425... ⁾	III	Pacientes graves/críticos hospitalizados	PC associado a TP versus TP	2 doses de 250mL em dias consecutivos iniciadas no dia 3 do início dos sintomas	>21	14/6/2020	30/5/2021	26,3	Recrutando
NCT04362176⁽¹⁸18. ClinicalTrials.gov. Passive immunity trial of the nation for COVID-19 (PassItOnII). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 24, 2020; Last update posted Aug 27, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04362176 https://ClinicalTrials.gov/show/NCT04362... ⁾	III	Pacientes hospitalizados ou em UTI	Patógeno reduzido PC versus placebo	PC: 500mL em 12 horas (dia 0) versus placebo: 250mL de Ringer lactato associado a multivitaminas (dia 1)	>22	24/4/2020	1/4/2021	41,8	Recrutando
NCT04381858⁽¹⁹19. ClinicalTrials.gov. Convalescent plasma vs human immunoglobulin to treat COVID-19 pneumonia. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 11, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04381858 https://ClinicalTrials.gov/show/NCT04381... ⁾	III	Insuficiência respiratória grave com ventilação mecânica invasiva	PC (títulos de anticorpos > 1:164) versus HIg	PC: 400mL (2 unidades) versus HIg 0,3g/kg/dia (5 doses)	16-18	6/5/2020	30/9/2020	89,1	Recrutando
NCT04361253⁽²⁰20. ClinicalTrials.gov. Evaluation of SARS-CoV-2 (COVID-19) antibody-containing plasma therapy (ESCAPE). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 24, 2020; Last update posted May 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04361253 https://ClinicalTrials.gov/show/NCT04361... ⁾	III	Pacientes hospitalizados	PC (título alto) versus PP (PFC ou PC 24)	PC-AT 2 doses de 250mL de doador único em 24 horas; PFC: 2 unidades de 200-275mL	>1	30/4/2020	1/12/2021	23,6	Recrutando
NCT04376034⁽²¹21. ClinicalTrials.gov. Convalescent plasma collection and treatment in pediatrics and adults. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 6, 2020; Last update posted May 6, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04376034 https://ClinicalTrials.gov/show/NCT04376... ⁾	III	Gravidade leve, moderada e grave/crítica	PC associado a TP versus TP	Adultos: 200 a 250mL; crianças: 10mL/kg; 2 unidades de pacientes graves ou em condição crítica	>30 dias	16/4/2020	30/3/2021	43,4	Recrutando
NCT04483960⁽²²22. ClinicalTrials.gov. Australasian COVID-19 trial (ASCOT) [Internet]. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted July 23, 2020; Last update posted July 23, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04483960 https://ClinicalTrials.gov/show/NCT04483... ⁾	III	Sem pacientes graves	LPV/Rit versus HCQ versus PC	1 unidade no dia 1 e no dia 2	>18	21/7/2020	12/6/2022	8,0	Recrutando
NCT04345289⁽²³23. ClinicalTrials.gov. Efficacy and safety of novel treatment options for adults with COVID-19 pneumonia. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 14, 2020; Last update posted July 31, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04345289 https://ClinicalTrials.gov/show/NCT04345... ⁾	III	Pacientes hospitalizados com doença leve, moderada e grave/crítica	PC associado a TP (Smab versus baricitinibe versus HCQ) versus TP associado a placebo injetável	PC: (2 vezes de 300mL) e dose única de 600mL; placebo: (2 vezes de 300mL) e dose única de 600mL de solução fisiológica IV por placebo: 3 vezes ao dia (7 dias)	>18	1/5/2020	15/6/2021	33,2	Recrutando
NCT04342182⁽²⁴24. ClinicalTrials.gov. Convalescent plasma as therapy for Covid-19 severe SARS-CoV-2 disease (CONCOVID Study). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 10, 2020; Last update posted May 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04342182 https://ClinicalTrials.gov/show/NCT04342... ⁾	II-III	Pacientes hospitalizados	PC associado a TP versus TP	300mL (de acordo com o protocolo Erasmus MC KIS)	>18	8/4/2020	1/7/2020	100	Recrutando
NCT04388410⁽²⁵25. ClinicalTrials.gov. Safety and efficacy of convalescent plasma transfusion for patients with COVID-19 (EPCOvid-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 14, 2020; Last update posted Aug 26, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04388410 https://ClinicalTrials.gov/show/NCT04388... ⁾	II-III	Pacientes hospitalizados com doença grave ou risco de doença grave	PC versus placebo	PC: 2 unidades de 200mL dentro de 24-72 horas; placebo: 200mL de soro fisiológico	>18	25/8/2020	31/12/2020	15,6	Ainda sem recrutamento
NCT04374526⁽²⁶26. ClinicalTrials.gov. Early transfusIon of convalescent plasma in elderly COVID-19 patients. to prevent disease progression. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 5, 2020; Last update posted Oct 6, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04374526 https://ClinicalTrials.gov/show/NCT04374... ⁾	II-III	Pacientes hospitalizados	PC associado a TP versus TP	200mL/dia por 3 dias	>65	27/5/2020	30/6/2021	27,6	Recrutando
NCT04384588⁽²⁷27. ClinicalTrials.gov. COVID19-convalescent plasma for treating patients with active symptomatic COVID 19 infection (FALP-COVID). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 12, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04384588 https://ClinicalTrials.gov/show/NCT04384... ⁾	II-III	Pacientes oncológicos e não oncológicos com doença grave	PC associado a TP versus TP	1 ou mais unidades	>15	7/4/2020	6/4/2021	44,0	Recrutando
NCT04425837⁽²⁸28. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma in patients with high-risk COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 11, 2020; Last update posted June 11, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04425837 https://ClinicalTrials.gov/show/NCT04425... ⁾	II-III	Pacientes hospitalizados com alto risco de doença grave ou em UTI	PC (títulos de anticorpos ≥1:160) associado a TP versus TP	2 doses de 200mL por dia	>18	1/7/2020	1/2/2021	34,9	Ainda sem recrutamento
NCT04395170⁽²⁹29. ClinicalTrials.gov. Convalescent plasma (PC) and human intravenous anti-COVID-19 immunoglobulin (IV anti COVID-19 IgG) in patients hospitalized for COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 20, 2020; Last update posted July 10, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04395170 https://ClinicalTrials.gov/show/NCT04395... ⁾	II-III	Atendimento precoce a pacientes hospitalizados	PC associado a TP versus anti-COVID-19 HIg versus TP	PC: 200-250mL (dias 1 e 3); Solução IgG a 10%: 50mL (paciente ≥50kg); 1mL/kg (paciente <50Kg), nos dias 1 e 3	>18	1/9/2020	1/6/2021	4,8	Ainda sem recrutamento
NCT04380935⁽³⁰30. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma therapy on COVID-19 patients with acute respiratory distress syndrome. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 8, 2020; Last update posted Aug 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04380935 https://ClinicalTrials.gov/show/NCT04380... ⁾	II-III	Pacientes hospitalizados na UTI (usando ventilação mecânica)	PC associado a TP versus TP	NR	>18	18/5/2020	31/10/2020	71,7	Ainda sem recrutamento
NCT04332835⁽³¹31. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a randomized, open label, parallel, controlled clinical study. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 3, 2020; Last update posted Sep 2, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04332835 https://ClinicalTrials.gov/show/NCT04332... ⁾	II-III	Gravidade moderada e grave/crítica	PC associado a TP versus HCQ associado a TP	250mL nos dias 1 e 2	18-60	8/8/2020	31/10/2020	44,0	Ainda sem recrutamento
NCT04385043⁽³²32. ClinicalTrials.gov. Hyperimmune plasma in patients with COVID-19 severe infection. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 12, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04385043 https://ClinicalTrials.gov/show/NCT04385... ⁾	II-III	Pacientes graves/críticos hospitalizados	PC associado a TP versus TP	NR	18-60	1/5/2020	15/5/2021	35,9	Recrutando
NCT04381936⁽³³33. ClinicalTrials.gov. Randomised evaluation of COVID-19 therapy. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 11, 2020; Last update posted Sep 29, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04381936 https://ClinicalTrials.gov/show/NCT04381... ⁾	II-III	Pacientes hospitalizados com alto risco de doença grave	LPV/Rit versus corticosteroide versus HCQ versus Azi versus Tmab associado a TP versus PC associado a TP	275mL±75mL nos dias 1 e 2	Todos	19/3/2020	1/12/2031	4,2	Recrutamento

Referências	Amostra n/PC	Título de anticorpos	Dose PC (mL)	Carga viral (x10 ^/dL)	Tratamentos anteriores	Hospitalização (variação)	Eventos adversos (n)	Redução da taxa de mortalidade
Abolghasemi et al.⁽³⁶36. Abolghasemi H, Eshghi P, Cheraghali AM, Imani Fooladi AA, Bolouki Moghaddam F, Imanizadeh S, et al. Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: results of a multicenter clinical study. Transfus Apheresis Sci. 2020;59(5):102875.⁾	189/115 PC versus 74 TP	Índice de corte de título de anticorpos plasmáticos >1,1	2×500mL	NI	TP + antiviral (LPV/Rit), HCQ e agente anti-inflamatório	9,54 dias PC versus 12,88 dias TP PC reduziu o tempo de hospitalização em aproximadamente 26%	Aproximadamente 1% PC Febre leve transitória e calafrios após infusão do plasma (n=1)	14,8% PC versus 24,3% TP Aproximadamente 40%
Li et al.⁽³⁷37. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, 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;324(5):460-70. Erratum in: JAMA. 2020;324(5):519.⁾	103/52 PC (23 graves + 29 com risco de vida) versus 51 TP (22 graves + 29 com risco de vida)	1:350 (6 doadores)	4-13mL/kg	Redução em pacientes graves: 44,7% (24 horas), 68,1% (48 horas) e 87,2% (72 horas) livre de vírus Pacientes com risco de vida: 53,8% (24 horas); 73,1 (48 horas) e 84,6% (72 horas) livre de vírus	Antiviral (41/46; 89,1%); antibacteriano (38/46; 82,6%); fitoterapia chinesa (26/46; 56,5%); corticoides 21/46; 45,7%); antifúngico (15/46; 32,6%); HIg (13/46; 28,3%); Interferon (12/46; 26,1%)	Graves: 32,00 (26,00-40,00); com risco de vida: indeterminado (46,00 - indeterminado)	Aproximadamente 4% PC Calafrios e erupções cutâneas em 2 horas (n=1); falta de ar, cianose e dispneia intensa em 6 horas (n=1)	15,7% PC versus 24,0% TP Aproximadamente 35%
Xia et al.⁽³⁸38. Xia X, Li K, Wu L, Wang Z, Zhu M, Huang B, et al. Improved clinical symptoms and mortality among patients with severe or critical COVID-19 after convalescent plasma transfusion. Blood. 2020;136(6):755-9.⁾	1.568/138	Não significativamente maior nos que responderam de forma rápida ao tratamento do que nos que responderam de forma moderada	200-1.200mL	20/25 (80%) ficaram livres de vírus após 14 dias	NI	2,4% PC versus 5,1% TP PC reduziu o número de internados na UTI em aproximadamente 53%	Aproximadamente 2% PC Prurido ou eritema durante a transfusão (n=3)	2,2% PC versus 4,1% TP Aproximadamente 50%

[1] Autor correspondente: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi CEP: 05652-000 – São Paulo, SP, Brasil. Tel.: (11) 3747-0243 E-mail: lionelgamarra7@gmail.com

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Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases avançadas dos ensaios clínicos e seus resultados preliminares

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