Einsteinapps.einstein.br/.../6186-6186-870-artigo-76120201125.docx · Web view(1) Até setembro de 2020, essa pandemia havia afetado cerca de 28 milhões pessoas, com cerca de 920

COLOCADO NO SISTEMARW-6186_REVISÃO DO ORIGINAL EM INGLÊS – SUZANA GONTIJOPREPRINT FRAN

Convalescent plasma therapy in COVID-19 critically ill patients during

advanced phases of clinical trials and their preliminary results

Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases

avançadas dos ensaios clínicos e seus resultados preliminares

Short title: Convalescent plasma therapy in COVID-19 critically ill patients during

advanced phases of clinical trials

Fernando Anselmo de Oliveira1, Mariana Penteado Nucci2, Gabriel Nery de

Albuquerque Rego1, Arielly da Hora Alves1, Luciana Cavalheiro Marti1, Leopoldo

Penteado Nucci3, Javier Bustamante Mamani1, Lionel Fernel Gamarra1

1 Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.

2 Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São

Paulo, SP, Brazil.

3 Centro Universitário do Planalto Central Apparecido dos Santos, Gama, DF, Brazil.

DOI: 10.31744/einstein_journal/2020RW6186

How to cite this article:

Oliveira FA, Nucci MP, Rego GN, Alves AH, Marti LC, Nucci LP, et al., Convalescent

plasma therapy in COVID-19 critically ill patients during advanced phases of clinical

Francislaine Cristina da Silva Soriani, 29/10/20,

NOTA:RW – 6186 / CHECK LIST – RENAN (2.076 palavras / 48 referências / 3 figuras / 2 tabelas)2.701 palavras49 referências3 figuras2 tabelasO artigo é atribuído para a instituição Hospital Israelita Albert Einstein – HIAETurnitin obrigatorio

trials and their preliminary results. einstein (São Paulo). 2020;18:eRW6186.

http://dx.doi.org/10.31744/einstein_journal/2020RW6186

Corresponding author:

Lionel Fernel Gamarra

Avenida Albert Einstein, 627/701 – Morumbi

Zip code: 05652-900 – São Paulo, SP, Brazil

Phone: (55 11) 3747- 0243

E-mail: [email protected]

Received on:

Set 21, 2020

Accepted on:

Oct 29, 2020

ABSTRACT

Objective: To highlight the global scientific effort to fight the severe acute respiratory

syndrome coronavirus 2, addressing the preliminary results of passive immunization

through convalescent plasma. Methods: We performed a search at the major

databases of interventional clinical trial protocols about the transfusion of

convalescent plasma in patients with coronavirus disease 2019, as well as, published

articles (n≥25), using the following search strategy: [(COVID-19 OR SARS-CoV-2 OR

nCoV-2019) AND (Convalescent plasma OR Plasma exchange) AND (Treatment OR

Therapy)]. Results: A total of 24 interventional clinical trial protocols (advanced in

phases II-III, III, and IV) were included in this review, as well as three studies that had

mailto:[email protected]

enough outcomes to evaluate the efficacy of convalescent plasma therapy for

patients with coronavirus disease 2019. All interventional clinical trial protocols

applied approximately 500 mL of convalescent plasma (from single or more

donations) in hospitalized patients, mainly in patients with severe disease associated

with standard therapy for coronavirus disease 2019, and compared to placebo or

standard therapy plus specific drugs. Most of interventional clinical trial protocols are

multicenter, and the phase IV studies are recruiting at intercontinental centers of

North America, Oceania, Europe, but most are recruiting center inside their own

county. The three studies published reported similar approach of convalescent

plasma intervention with decrease in length of stay, mortality, with less than 4% of

adverse events, mainly for treating critical cases with life-threatening disease.

Conclusion: All advanced clinical trials focused on convalescent plasma therapy in

patients with coronavirus disease 2019 hospitalized in severe conditions, and the

preliminary results provide strong evidence for therapy for the coronavirus disease

2019 patients.

Keywords: Covid-19; Coronavirus infections; SARS-CoV-2; Betacoronavirus;

Immunization; Immunization, passive; Plasma; Convalescent plasma

RESUMO

Objetivo: Destacar o esforço científico global para combater o coronavírus 2 da

síndrome respiratória aguda grave, abordando os resultados preliminares da

imunização passiva por plasma convalescente. Métodos: Foi realizada uma busca

nas principais bases de dados dos protocolos de ensaios clínicos intervencionistas

sobre transfusão de plasma convalescente em pacientes com doença pelo

coronavírus 2019, bem como artigos publicados (n≥25), utilizando a seguinte

estratégia de busca: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND

Edna Terezinha Rother, 10/29/20,

Manter edna

(Convalescent plasma OR Plasma exchange) AND (Treatment OR Therapy)].

Resultados: Um total de 24 protocolos de ensaios clínicos intervencionistas

(avançados nas fases II-III, III e IV) foram incluídos nesta revisão, assim como três

estudos que tiveram resultados suficientes para avaliar a eficácia da terapia com

plasma convalescente para pacientes com doença pelo coronavírus 2019. Todos os

protocolos de ensaios clínicos intervencionistas aplicaram cerca de 500 mL de

plasma convalescente (de uma ou mais doações) em pacientes hospitalizados,

principalmente em pacientes com grau grave de doença associada à terapia padrão

para doença pelo coronavírus 2019 em comparação com placebo ou terapia padrão

mais medicamentos específicos. A maioria dos protocolos de ensaios clínicos

intervencionistas são multicêntricos, e os estudos de fase IV [N.T.] estão recrutando

em centros intercontinentais da América do Norte, Oceania, Europa, mas na maioria

os centros de recrutamento estão dentro de seu próprio país. Os três estudos

publicados relataram abordagem semelhante de intervenção para plasma

convalescente com redução do tempo de internação, mortalidade, com menos de

4% de eventos adversos, principalmente para o tratamento de casos críticos com

risco de vida. Conclusão: Todos os ensaios clínicos avançados focaram a terapia

com plasma convalescente em pacientes com doença pelo coronavírus 2019

hospitalizados em condições graves, e os resultados preliminares fornecem fortes

evidências para a terapia para esses pacientes com doença pelo coronavírus 2019.

Descritores: Covid-19; Infecções por coronavírus; SARS-CoV-2; Betacoronavírus;

Imunização; Imunização passiva; Plasma; Plasma convalescente

INTRODUCTION


Foram citadas 34 referências apenas na introdução.


Manter edna

At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-

CoV-2) emerged, resulting in the coronavirus disease 2019 (COVID-19), which

caused an unprecedented health emergency and declared a pandemic by the World

Health Organization (WHO) on March 11, 2020.(1) Up to September 2020, this

pandemic had affected approximately 28 million and killed roughly 920 thousand

people worldwide.(2) In Brazil, more than 5 million cases and more than 130 thousand

deaths have occurred so far.(3)

New approaches to the development of immunity transfer were quickly

implemented in preclinical studies, and currently interesting results of clinical trials

are beginning to emerge, aiming to improve the symptoms of COVID-19, a disease of

heterogeneous symptoms caused by SARS-CoV-2.(2) Simultaneously, different

vaccines are being developed and tested for effective disease prevention.(4)

Before SARS-CoV-2, the use of convalescent plasma (CP) had been

investigated, with positive outcomes, in outbreaks of other viral infections,(5) such as

the pandemic influenza A (H1N1), in 2009,(6) avian influenza A (H5N1),(7) among

others. Furthermore, some studies have demonstrated that CP antibodies can limit

virus proliferation during the infection and support viral clearance, which is favorable

for fast recovery of the disease.(8)

A recent review on plasma therapy in COVID-19 patients reported low

frequency of severe adverse event, and improvement in clinical symptoms in some

participants after plasma therapy, but the authors judged the risk of reporting bias.(9)

The high or low titers of neutralizing antibodies against COVD-19 can be

managed to reduce patient’s symptoms and mortality. There are 24 advanced clinical

trials in phases II-III, III, and IV reported in several countries using CP to treat these

patients, and answer this question.(10-33) Although passive immunization has been

used for over a century to treat infectious diseases, the recent results pose

challenges to set the best time of plasma extraction and donor choice, in addition to

the cost of this whole procedure. This lack of information empowers the movements

of antivaccine and antiplasma groups.(34)

OBJECTIVE

To highlight the global scientific effort in the fight against severe acute respiratory

syndrome coronavirus 2, addressing passive immunization through convalescent

plasma and their preliminary results.

METHODS

A search was performed until 14 September 2020 at ClinicalTrials.gov

(https://clinicaltrials.gov/), Chinese Clinical Trial Registry, and EU Clinical Trials

Register for interventional clinical trials on CP transfusion, in patients with COVID-19,

using the following search strategy: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019)

AND (Convalescent Plasma OR Plasma Exchange) AND (Treatment OR Therapy)].

Then, the same strategy was used to search for studies in PubMed and Scopus

databases about the efficacy of CP therapy to treat patients with COVID-19.

Inclusion and exclusion criteria

This review included clinical trial protocols (CTPs) (phases III and IV) that addressed

the development of therapies based on CP to treat COVID-19 patients by passive

immunization, and studies that showed the efficacy of CP therapy applied in more

than 25 COVID-19 patients. The reasons for excluding studies were as follows: -

Lionel Fernel Gamarra Contreras, 11/25/20,

Confirmo


Autor,Confirma o link de acesso da página EUCTR?https://www.clinicaltrialsregister.eu/


Confirmo


Autor,Confirma o link de acesso da página CHICTR?http://www.chictr.org.cn/abouten.aspx


DIAGRAMADORInserir o link.

CTPs for observational studies, -CTPs involving vaccines, and - CTPs canceled, or

not approved, until the searching date in the databases.

Study eligibility, data extraction, data collection, and risk of bias assessment

The study eligibility followed the preferred reporting items for systematic reviews and

meta-analyses (PRISMA) guidelines.(35) The data extraction, collection, and risk of

bias assessment was performed by six authors (F.A.O.; M.P.N.; G.N.A.R.; A.H.A.;

L.P.N.; and J.B.M.) organized in pairs, independently and randomly reviewed and

evaluated the information recorded from the CTPs and studies identified by the

search strategy in the databases mentioned above. Discrepancies in study selection

and data extraction between the authors were discussed with two authors (L.C.M.

and L.F.G.) and resolved. The final inclusion of studies in this review was agreed

among all authors.

Data analysis

All results were described and presented using the percentage distribution for all

variables analyzed in the tables.

RESULTS

Study selection

After applying the search strategies in the databases, 170 CTPs were identified (153

protocols at ClinicalTrials.gov, 14 at Chinese Clinical Trial Registry, and 3 at the EU

Clinical Trials Register). The search strategy used the PRISMA.(35)

Based on established inclusion and exclusion criteria, of 170 protocols

identified, 146 clinical trials were excluded after screening (130 protocols were

phases I and II and 16 were observational), remaining 24 protocols selected from

these databases. In total, 24 CTPs were included in the present work for passive

immunization for COVID-19 through CP therapy.(10-13, 15-33)

Of the selected studies published in the databases mentioned above, only

three studies had enough data that allow statistical analysis of the outcomes, to

evaluate the CP therapy efficacy due to the number of patients with COVID-19

(n≥25).(36-38)

Overview of clinical trial protocols for passive immunization for COVID-19

Of 24 more advanced clinical trials on CP therapy for COVID-19 inpatients, only one

(4.2%) was in phase IV, with 58% of study progress rate (SPR), recruiting individuals

in different countries by Netherlands sponsor (green bar of Figure 1).(10) The phase III

studies (54.2%),(11-13, 15-19) almost half of CTPs had more than 40% of SPR, mainly in

Mexico(15, 19) and the USA (blue bars of Figure 1),(18, 21) and the phase II-III studies

(41.7%),(24-33) one CTP has 100% of SPR in the Netherlands,(24) and almost half of

CTPs have more than 40% of SPR (red bars of Figure 1), as shown in Figure 1 and

Table 1.

NCT: number clinical trial.

Figure 1. Analysis of the study progress rate percentile of clinical trial protocols on

convalescent plasma therapy for hospitalized patients of COVID-19 distributed by

their phases (green bar: phase IV; blue bars: phase III; and red bars: phase II-III) and

the corresponding sponsor country.


A imagem está OK

Table 1. Study design, arms, interventions, and study time progress

ID Number Phase Patient features Intervention by arm CP dose (day)Age range(years)

Start dateCompletion date

NCT02735707(10) IVSevere acute respiratory illness and severe community acquired pneumonia

Corticosteroid vs. Antibiotics vs. Macrolide vs. Influenza antiviral vs. LPV/Rit vs. HydChl vs. IFN-β1a vs. Anak vs. Tmab vs. Smab vs. VitC vs. Heparin vs. Simvastatin vs. CP vs. ST

1 or 2 units within 48 hours >18 04/11/16 12/01/23

NCT04391101(11) III Severe patients treated in ICU CP + ST vs. ST 400-500 mL >18 06/01/20 12/01/21

NCT04372979(12) IIIEarly care of hospitalized patients

CP + ST vs. SP + ST 200-230 mL 18-80 05/01/20 05/01/21

NCT04418518 (13) IIIEarly care for patients hospitalized

CP + ST vs. ST500 mL of single-donor or 2 units of 250 mL from 1-2 donations

18-70 06/24/20 12/01/21

NCT04355767(14) IIISevere/critical hospitalized patients

CP (antibodies titers ≥1:160) vs. placeboCP: 1-unit vs. placebo: saline with multivitamin

>18 08/11/20 12/01/22

NCT04432103(15) IIISevere/ critical hospitalized patients

CP from IgG (severe patients vs. critical patients) + ST NR >19 06/19/20 09/30/20

NCT04348656(16) IIIEarly care for patients hospitalized

CP vs. ST500 mL of single-donor or 2 units of 250 mL from 1-2 donations

>20 05/14/20 12/31/20

NCT04425915(17) IIISevere/critical hospitalized patients

CP + ST vs. ST2 doses of 250 mL on consecutive day started by day 3 of symptom onset

>21 06/14/20 05/30/21

NCT04362176(18) III Patients hospitalized or in ICU Pathogen reduced CP vs. placeboCP: 500mL within 12 hours (day 0) x placebo: 250mL of Lactate Ringers + multivitamins (day 1)

>22 04/24/20 04/01/21

NCT04381858(19) IIISevere respiratory failure with invasive mechanical ventilation

CP (antibodies titers > 1:164) vs. HIgCP: 400 mL (2 units) vs. HIg: 0.3 g/kg/day (5 doses)

16-18 05/06/20 09/30/20

NCT04361253(20) III Patients hospitalized CP (High-Titer) vs. SP (FFP or FP24) HT-CP: 2 doses of 250 mL of single donor within 24 hours; FFP: 2 units of 200-275 mL

>1 04/30/20 12/012/21

NCT04376034(21) III Mild, moderate and severe/critical severity

CP +ST vs. ST Adult: 200 to 250 mL; children: 10 mL/kg; 2 units severe patients

>30 d 04/16/20 03/30/21


Edna,Deixei com as linhas apenas visualização.Diagramar sem.

or critical conditionNCT04483960(22) III No severe patients LPV/Rit vs. HydChl vs. CP 1 unit on day 1 and day 2 >18 07/21/20 06/12/22

NCT0434528 9(23) IIIMild, moderate and severe/critical hospitalized patients

CP + ST (Smab vs. Baricitinib vs. HydChl) vs. ST + injective placebo

CP: (2x 300 mL) and single dose of 600 mL; placebo: (2x300 mL) and single dose of 600 mL IV saline oral placebo: 3x/day (7 days)

>18 05/01/20 06/15/21

NCT04342182(24) II-III Hospitalized patients CP + ST vs. ST300 mL (according to the Erasmus MC KIS protocol)

>18 04/08/20 07/01/20

NCT04388410(25) II-IIIHospitalized patients with severe disease or at risk for severe disease.

CP vs. placeboCP: 2 units of 200 mL within 24-72 hours); placebo: 200 mL of saline

>18 08/25/20 12/31/20

NCT04374526(26) II-III Hospitalized patients CP + ST vs. ST 200 mL/day for 3 days >65 05/27/20 06/30/21

NCT04384588(27) II-IIIOncological and non-oncological patients with severe disease

CP + ST vs. ST 1 or more units >15 04/07/20 04/06/21

NCT04425837(28) II-IIIHospitalized patients at high risk of severe disease or in ICU

CP (antibodies titers of ≥1:160) + ST x ST 2 doses of 200 mL in a day >18 07/01/20 02/01/21

NCT04395170(29) II-IIIEarly care for patients hospitalized

CP + ST vs. Anti-COVID-19 HIg vs. ST

CP: 200-250 mL (day 1 and 3); 10% IgG solution: 50 mL (patient ≥ 50 Kg); 1 mL/Kg (patient < 50Kg), on days 1 and 3

>18 09/01/20 06/01/21

NCT04380935(30) II-IIIHospitalized patients in ICU (using mechanical ventilation)

CP + ST vs. ST NR >18 05/18/20 10/31/20

NCT04332835(31) II-IIIModerate and severe/critical severity

CP + ST vs. HyChl + ST 250 mL on days 1 and 2 18-60 08/08/20 10/31/20

NCT04385043(32) II-IIISevere/ critical hospitalized patients

CP + ST vs. ST NR 18-60 05/01/20 05/15/21

NCT04381936(33) II-IIIHospitalized patients at high-risk of severe disease

(LPV/Rit vs. Corticosteroid vs. HyChl vs. Azi vs. Tmab) + ST vs. CP + ST

275 mL± 75 mL on days 1 and 2 all 03/19/20 12/01/31

Note: The passive immunotherapy through plasma infusion of convalescent subjects – convalescent plasma, also known as hyperimmune plasma or ABO compatible

convalescent plasma. ICU: intensive care unit; Cort.: corticosteroid; LPV/Rit: lopinavir/ritonavir; HydChl: hydroxychloroquine; IFN-β1a: interferon- β1a; Anak: anakinra;

Tmab: tocilizumab; Smab: sarilumab; Vit C: Vitamin C; CP: convalescent plasma; ST: standard therapy; SP: standard plasma; IgG: immunoglobulin G; HIg: human

immunoglobulin; FFP: fresh frozen plasma; FP24: plasma frozen within 24 hours after phlebotomy; Azi: azithromycin; NR: not report; HT-CP: high-titer convalescent plasma.

Convalescent plasma intervention

The CP intervention applied in all CTPs was for inpatients with different degrees of

disease impairment, especially for severe cases admitted to the ICU (58.3%) with or

without invasive mechanical ventilation, and all patients received the ST for COVID-

19. The intervention arms applied in these inpatients normally compared the CTP of

plasma therapy plus ST versus only ST associated or not with some selected drugs,

such as corticosteroid, antibiotics, antimalarials (HydChl:), anticoagulants, HIg,

antiviral drugs, among others.(10, 22, 23, 29, 31, 33) The CP therapy was applied mainly as

single dose, with different volume of transfusion (45.8%), and the volume more

frequently used was 500 mL, in 20.8%,(13, 16, 18, 39) following by doses of 200-250 mL in

8.3%,(12, 21) 400 mL in 8.3%,(19, 39) 300 mL in 4.2%,(24) and 600 mL in 4.2%.(23) In the

cases using more than one dose, the volume was two doses of 250 mL,(13, 16, 17, 20, 29, 31,

33) used in most of CTPs, following by 2 x 200 mL(19, 25, 28, 29, 33) and 2 x 300 mL. (23, 33)

Plasma doses were derived from a single donor,(13, 16, 20, 23) or until 2 different donors in

some CTPs.(13, 16) Almost all CTPs test the intervention in individuals aged over 18

years, with exception of two CTPs (Table 1).

Regarding study design characteristics of these CTPs, Figure 2 shows the

intervention was mostly (87.5%) randomized and few CTPs used some type of

masking (33.3%), such as: 4.2% single blinding (participant), 12.5% double-blinding

(participant, outcome evaluator), 8.3% triple-blinding (participant, care provider,

outcome evaluator), and 8.3% quadruple-blinding (participant, care provider,

investigator, outcome evaluator). Although 12.5% of CTPs have not adopted any

technique used to minimize the bias in allocations and blinding, keeping it open-label.

The estimated enrollment of clinical trial in phase IV is 7,100 individuals,(10) in phase

III from 36 to 2,400 individuals,(11-23) and phase II-III from 60 to 15,000.(24-33) The

number of volunteers estimated in each protocol was represented by the color scale

bar in Figure 2.

UK: United Kingdom; USA: United States of America.

Figure 2. Study design of clinical trials of passive immunization against COVID-19

(plasma therapy), distributed inside out by the different types of allocation

(randomized or not), masking (none, single, double, triple, and quadruple blinding),

estimated enrollment (varied from 36 to 15,000 individuals), and study countries. The

color scale bar represents the number of volunteers estimated in each protocol


A imagem está OK

Global research network in clinical trial protocol

Among the CP multicenter CTPs,(10, 12, 13, 16, 17, 22-24, 26, 30, 32) the CTP phase IV(10) is the

only one with intercontinental collaborations represented by the dashed black lines

on the world map (Figure 3), with 87 recruitment centers (green cylinders) distributed

in North America, Europe, and Oceania. The CTPs phase III also have collaborations

among countries and involve 48 recruitment centers (yellow cylinders) in the USA

and Canada.(16) The other multicenter CTPs involve a varied number of recruitment

centers within the same country, such as: Australia with 79 centers (purple cylinders),

(22) the Netherlands with 18 centers (blue cylinders),(24) Denmark with 12 centers (dark

gray cylinders),(23) Italy with 6 centers (orange cylinders),(32) highlighted in Figure 3,

with the enlarged image for better visualization of the collaboration centers, and

others with approximately 3 centers.(12, 17, 26, 30) The single center CTPs concentrate

mainly in North America(15, 18-21) and South America.(11, 27-29, 31)

Figure 3. The global distribution of clinical trials by phase (circles) and the centers

carrying out research on COVID-19 plasma therapy (red bar) and their recruitment

centers (cylinders). The main centers of each continent are highlighted in the

enlarged image around the central map. Phase IV (green circle), phase III (blue

circle), phases II-III (red circle). The intercontinental collaborations of the clinical trial

protocols at phase IV are represented by the dashed black lines on the world map.


A imagem está OK

Plasma therapy outcome in COVID-19 patients

The three studies that evaluate the efficacy of plasma therapy also prioritize the

evaluation of COVID-19 in severely ill patients or those in life-threatening situation,

such as the advanced clinical trials mentioned above. The CP therapy intervention

varied a lot among studies, without a consensus about the best CP pattern of

application. Regarding the results, the studies showed a reduction by 53% in disease

severity (not needing intensive care),(38) 26% in length of hospital stay,(36) and from 35

to 50% in mortality rate,(36-38) reporting adverse effects in less than 4% of patients

after treatment with CP in different doses and volumes associated with standard

therapy for COVID-19,(36-38) as shown in Table 2.

Table 2. Studies that evaluation the efficacy of plasma therapy in COVID-19 patients

References N/CP sample Antibody titer CP dose (mL) Viral charge (x10^/dL)Previous

treatments

Hospitalization

(variation)Adverse events (N)

Xia et al.,(38) 1568/138

Not significantly higher in rapid

responders than in moderate

responders

200-1200 mL20/25 (80%) became virus-free

after 14 daysNI

2.4% CP vs. 5.1% ST

CP reduced admitted to the

ICU by ~53%

~2% CP

Pruritus or erythema

during transfusion (n=3)

Li et al.,(37) 103 /52 CP (23

severe + 29 life-

threatening) vs. 51

ST (22 severe + 29

life-threatening)

1:350 (6 donors) 4 to 13 mL/kg Reduction in severe patients:

44.7% (24 h), 68.1% (48 h) and

87.2% (72 h) virus-free;

Life-threatening patients: 53.8%

(24 h); 73.1 (48 h) and 84.6%

(72 h) virus-free

Antiviral [41/46

(89.1%)];

Antibacterial [38/46

(82.6%)]; Chinese

herbal medicine

[26/46 (56.5%)];

Steroids [21/46

(45.7%)]; Antifungal

[15/46 (32.6%)]; HIg

[13/46 (28.3%);

Severe: 32.00 (26.00-

40.00); Life-threatening:

Indeterminate (46.00-

Indeterminate)

~4% CP

Chills and rashes within 2 h

(n=1); Shortness of breath,

cyanosis and severe

dyspnea within 6 h (n=1).


Edna,Deixei com as linhas apenas visualização.Diagramar sem.Citações devem estar na ordem sequencial

Interferon [12/46

(26.1%)

Abolghasemi

et al.,(36)

189 /115 CP vs.

74 ST).

Plasma antibody titer cut off

index >1.12x 500 mL NI

ST + antiviral

(LPV/Rit), HydChl

and anti-

inflammatory

agent

9.54 days CP vs. 12.88

days ST

CP reduced length of stay

by ~26%

~1% CP

Transient mild fever and

chills following infusion of

the plasma (n=1);

n: number; CP: convalescent plasma; ST: standard treatment; NI: not informed; HIg: human immunoglobulin; LPV/Rit: lopinavir/ritonavir; HydChl: hydroxychloroquine; ICU: Intensive care

unit; h: hour.

DISCUSSION

In the absence of effective treatment for patients with COVID-19, many studies have sought alternatives to treat patients and

enhance patient's immune defense, such as the use of CP therapy. The recovery trial(40) provides evidence to support some

treatments (for instance, dexamethasone) and improve immunity in critical condition cases, and this trial uses CP therapy as one

therapeutic arm. However, many aspects of this therapy are still being explored, such as a timeout/collection interval for COVID-19,

or immunoglobulin G (IgG) / immunoglobulin M (IgG / IgM) titers from donors, the therapy clinical improvement and efficacy in

critical or non-critical patients and adverse effects. Among 170 CTPs identified, only 24 CTPs were in advanced phase (III/IV) with

33,000 individuals, concentrated in the regions of America, showing the pivotal questions on efficient use of the CP still uncertain or

fragile to justify an increased use in critical or non-critical hospital care. In addition, no country, including the USA, has licensed CP

as a treatment for COVID-19. The Food and Drug Administration (FDA) judged eligible for wider use under an emergency use

authorization,(41) although other countries have granted approval for use on an individual patient basis.

One of the first CP clinical trials that analyzed 103 patients with severe and life-threatening COVID-19 (median age 70

years),(37) showed no statistically significance in clinical improvement after 28 days or reduced mortality. However, there was

evidence of notable therapeutic effects and possible antiviral activity in group of 60 to 80-year-old patients, at the final stage of the

disease course, after 14 days of symptoms, using only units with a very high antibody titers (IgG over 1:50) specific for S-RBD.

Another study on CP therapy in severe COVID-19 patients(42) showed significant improvement of clinical symptoms, with an


Conforme solicitado, foi incluído a definição da sigla no texto


Autor,Inserir o termo da sigla.

increase in oxyhemoglobin saturation after the third day of transfusion, reduction of pulmonary lesions, amelioration of routine

laboratory criteria, and pulmonary function accompanied by rapid neutralization of viremia, using 200 mL of CP derived from

recently recovered donors with the neutralizing antibody titers between 1:160 – 640, approximately 16.5 days after onset of

symptoms, associated to standard care and antiviral agents. Only three CTPs(14, 19, 28) mentioned the antibody titers used in the CP

therapy (over 1:160), and the studies by Abolghasemi et al.,(36) and Li et al.,(37) also reported the use of antibody titers above 1.1 in

CP therapy associated with clinical improvement and reduction in mortality.

To reduce the variability in therapeutic response of patients, the WHO recommends some care and standardization in the

selection of CP donors.(43) Eligibility criterion in relation to donor age does not vary widely: 18-67 years.(36, 44) The donors were

patients who recovered from COVID-19 and showed no detection of SARS-CoV-2 by qRT-PCR or any related symptoms after a

period that varied among studies. In one study, donors could have recovered after one week, and the short recovery period might

have contributed to the death of 5 out of 6 patients.(45) Longer recovery period allowed reports of therapeutic efficacy. This period

could be 10 days, with collection performed twice, with a difference of 24 hours,(46) at least 14 days,(36, 47) and more than two weeks.

(36, 42, 44) In some cases, qPCR from nasopharyngeal swabs must be tested negative twice, and an interval of 24 hours between tests.

(36, 42)

Regarding the quantification of antibodies, spike (S)- and receptor-binding domain (RBD)-specific IgG titers vary from donor

to donor. One study demonstrated that 10 out of 25 collected plasma displayed the titer of 1:450, 6/25 1:350, while in the others

vary from 1:1 to 1:150.(44) Most of studies employed a CP volume of roughly 500 mL, in a single dose or divided into two doses,

derived from a single donor,(12, 16, 20, 23) or 2 different donors.(12, 16) Therefore, this lack of standardization regarding donor selection,

quality control of the CP, and recipient patients could explain the varied therapeutic effects.

Some possible adverse effects with the use of CP can be avoided, such as CP free of antigens, which could cause

transfusion-related acute lung injury (TRALI), such as human leukocyte antigens (HLA) that protect the embryo.(36) In a multicenter

clinical trial, the use of CP was not allowed in pregnant women, aiming to prevent TRALI.(36)

The severity of patient’s disease transfused with CP varied from mild, moderate, severe to critical. A CTP with severe

patients divided the study groups in severe acute respiratory illness and severe community acquired pneumonia. (10) Another CTP

compared the effects of the treatment in oncological and non-oncological COVID-19 patients. (27) Admission in the intensive care unit

is related in some CTP,(11, 18, 28, 30) although it is presumed that it is applied to all severe patients. In some CTPs, the CP treatment

was compared to other treatments, such as corticoids, antibiotics, monoclonal antibodies, and anti-viral drugs. (10, 22, 23, 33)

Some published results allowed evaluation of different parameters concerning the efficacy of treatment. In a study in which

CP was applied, 6 out of 17 patients required mechanical ventilation, mainly elderly patients.(47) In a multicenter study, the mortality

rate was 14.8% of the patients (n=115).(36) Similar results were found in another multicenter study (15.7%).(36) Another investigation

reported a mortality rate of only 2.2%.(38) A study employed this therapy in patients with hypertension, diabetes or cardiovascular

disease, but it was not clear the effect of these comorbidities in the CP treatment effect.(36)

The transfusion of CP therapy for COVID-19 must follow some pre-established conditions, such as availability of a population

of donors who have recovered from the disease and can donate convalescent serum; blood banks to process serum donations;

availability of assays, including serological tests, to detect SARS-CoV-2 in serum and virological assays to measure viral

neutralization; laboratory support for virology to carry out these tests; and standardization of phase and condition of COVID-19

patient.(48)

The main limitations of the multicenter studies were the reduced number of patients in the control groups compared to the

treatment group, usually due to lack of blood group CP match, and concomitant or previous use of another treatment. (36) Another

limitation is the lack of standard protocols and training for the study staff, as well as diversity in patients monitoring. (49) In turn, the

main limitation of our study is the impossibility of carrying out a meta-analysis, due to the lack of a robust number of studies

reporting conclusive therapeutic effects of this modality, such as decrease in SARS-CoV-2 titers. However, few articles published

on multicenter studies demonstrated that CP could be a promising therapeutic modality.

CONCLUSION

Currently, there are no reliable therapeutic options for critically-ill COVID‐19 patients. Based on the few consolidated multicenter

clinical data results available, we concluded the convalescent plasma therapy studies provided relevant results in severe/critical

cases of COVID-19 patients, reducing length of hospital stay, disease severity, and mortality, with low frequency of adverse events

in a considerable number of patients. However, it is not possible to state, in a conclusive fashion, about the real relevance of this

treatment, considering the lack of data that enable a robust statistics analysis, such as a meta-analysis.

AUTHOR’S INFORMATION

Oliveira FA: http://orcid.org/0000-0002-7226-1694

Nucci MP: http://orcid.org/0000-0002-1502-9215

Rego GN: http://orcid.org/0000-0003-2011-0373

Alves AH: http://orcid.org/0000-0003-3570-0827

Marti LC: http://orcid.org/0000-0002-3890-0827

Nucci LP: http://orcid.org/0000-0002-1234-5845

Mamani JB: http://orcid.org/0000-0001-5038-0070

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

REFERENCES


Edna,Referência 2 é um site que atualizado todos os dias com dados dos países referente aos números de COVID-19. Mantive a data da última postagem.Referência 3: é igual a referência 2.As referências da Clinical Trial mantevi as informações da primeira e da última postagem.OBS.: não traduzir Available from

1. Ge H, Wang X, Yuan X, Xiao G, Wang C, Deng T, et al. The epidemiology and clinical information about COVID-19. Eur J

Clin Microbiol Infect Dis. 2020;39(6):1011-9.

2. Worldometer. COVID-19 Pandemic Data Update 2020 [Internet]. Worlfometer; 2020 [cited 2020 Oct 26]. [Last update posted

Oct 26, 2020].Available from: https://www.worldometers.info/coronavirus/.

3. Worldometer. COVID-19 Pandemic Data Update. 2020.

4. Rego GN, Nucci MP, Alves AH, Oliveira FA, Marti LC, Nucci LP, et al. Current clinical trials protocols and the global effort for

immunization against SARS-CoV-2. Vaccines. 2020;8(3). pii: E474. Review.

5. Wong HK, Lee CK. Pivotal role of convalescent plasma in managing emerging infectious diseases. Vox Sang.

2020;115(7):545-7.

6. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with

severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.

7. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med.

2007;357(14):1450-1.

8. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in

Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.

https://www.worldometers.info/coronavirus/

9. Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, Wood EM, et al. Convalescent plasma or hyperimmune immunoglobulin

for people with COVID‐19: a rapid review. Cochrane Database Syst Rev. 2020;5:CD013600. Update

in: Cochrane Database Syst Rev. 2020;7:CD013600.

10. ClinicalTrials.gov. Randomized, embedded, multifactorial adaptive platform trial for community- acquired pneumonia (REMAP-

CAP) [Internet]. Bethesda (MD): U.S. 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

11. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a pilot study [Internet]. Bethesda (MD): U.S. 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

12. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in the early care of COVID-19 patients (PLASCOSSA) [Internet].

Bethesda (MD): U. S.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

13 ClinicalTrials.gov. A trial of CONvalescent plasma for hospitalized adults with acute COVID-19 respiratory illness (CONCOR-1)

[Internet]. Bethesda (MD):U.S. 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


14. ClinicalTrials.gov. Convalescent plasma in outpatients with COVID-19 (C3PO) [Internet]. Bethesda (MD): U.S. National Library

of Medicine; 2020 [cited 2020 Oct 28] [First posted Apr 21, 2020; Last update posted Sep 29, 2020]. Available from:


15. ClinicalTrials.gov. Treatment of severe and critical COVID-19 pneumonia with convalescent plasma [Internet]. Bethesda

(MD): U.S. 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

16. ClinicalTrials.gov. CONvalescent plasma for hospitalized adults with COVID-19 respiratory illness (CONCOR-1) [Internet].

Bethesda (MD): U.S. 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

17. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in patients with COVID-19 [Internet]. Bethesda (MD): U.S.

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

18. ClinicalTrials.gov. Passive immunity trial of the nation for COVID-19 (PassItOnII) [Internet]. Bethesda (MD): U.S. National

Library of Medicine; 2020 [cited 2020 Oct 28] [First posted Apr 24, 2020; Last update posted Aug 27, 2020]. Available from:




19. ClinicalTrials.gov. Convalescent plasma vs human immunoglobulin to treat COVID-19 pneumonia [Internet]. Bethesda (MD):

U.S.National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 11, 2020; Last update posted May 12, 2020].


20. ClinicalTrials.gov. Evaluation of SARS-CoV-2 (COVID-19) antibody-containing plasma therapy ((ESCAPE)) [Internet]. Bethesda

(MD): U.S.National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted Apr 24, 2020; Last update posted May 18, 2020].


21. ClinicalTrials.gov. Convalescent plasma collection and treatment in pediatrics and adults [Internet]. Bethesda (MD): U.S.

National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 6, 2020; Last update posted May 6, 2020]. Available from:


22. ClinicalTrials.gov. Australasian COVID-19 trial (ASCOT) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2020

[cited 2020 Oct 28] [First posted July 23, 2020; Last update posted July 23, 2020]. Available from:


23. ClinicalTrials.gov. Efficacy and safety of novel treatment options for adults with COVID-19 pneumonia [Internet]. Bethesda (MD):

U.S. National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted Apr 14, 2020; Last update posted July 31, 2020].


24. ClinicalTrials.gov. Convalescent plasma as therapy for Covid-19 severe SARS-CoV-2 disease (CONCOVID Study) [Internet].

Bethesda (MD): U.S. 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

25. ClinicalTrials.gov. Safety and efficacy of convalescent plasma transfusion for patients with COVID-19 (EPCOvid-1) [Internet].

Bethesda (MD): U.S. 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

26. ClinicalTrials.gov. Early transfusIon of convalescent plasma in elderly COVID-19 patients. to prevent disease progression

[Internet]. Bethesda (MD): U.S. 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

27. ClinicalTrials.gov. COVID19-convalescent plasma for treating patients with active symptomatic COVID 19 infection (FALP-

COVID) [Internet]. Bethesda (MD): U.S. 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

28. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma in patients with high-risk COVID-19 [Internet]. Bethesda

(MD): U.S. National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted June 11, 2020; Last update posted June 11, 2020].


29. ClinicalTrials.gov. Convalescent plasma (PC) and human intravenous anti-COVID-19 immunoglobulin (IV anti COVID-19

IgG) in patients hospitalized for COVID-19 [Internet]. Bethesda (MD): U.S. 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

30. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma therapy on COVID-19 patients with acute respiratory

distress syndrome [Internet]. Bethesda (MD): U.S. 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

31. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a randomized, open label, parallel, controlled clinical study

[Internet]. Bethesda (MD): U.S.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

32. ClinicalTrials.gov. Hyperimmune plasma in patients with COVID-19 severe infection [Internet]. Bethesda (MD): U.S. National

Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 12, 2020; Last update posted May 12, 2020]. Available from:


33. ClinicalTrials.gov. Randomised evaluation of COVID-19 therapy [Internet]. Bethesda (MD): U.S. National Library of Medicine;

2020 [cited 2020 Oct 28] [First posted May 11, 2020; Last update posted Sep 29, 2020]. Available from:


34. Wadman M. Antivaccine forces gaining online. Science. 2020;368(6492):699.



35. Moher D, Liberati A, Tetzlaff J, Altman DG ; PRISMA Group. Preferred reporting items for systematic reviews and meta-

analyses: the PRISMA statement. BMJ. 2009;339:b2535.

36. 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 Apher Sci. 2020:102875.

doi: 10.1016/j.transci.2020.102875. [Epub ahead of

print].

37. 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.

38. 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.

39. ClinicalTrials.gov. .Convalescent plasma for the treatment of severe SARS-CoV-2 (COVID-19) [Internet]. Bethesda (MD): U.S.

National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 18, 2020; Last update posted May 20, 2020]. Available

from: https://ClinicalTrials.gov/show/NCT04391101


40. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C,

Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K,

Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ.

Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl

J Med. 2020 Jul 17. doi: 10.1056/NEJMoa2021436. [Epub ahead of print].

41. Estcourt LJ, Roberts DJ. Convalescent plasma for covid-19. BMJ. 2020;370:m3516.

42. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients.

Proc Natl Acad Sci U S A. 2020;117(17):9490-6.

43. World Health Organization (WHO). Blood products and related biologicals. Blood Regulators Network (BRN). Position paper

on use of convalescent plasma, serum or immune globulin concentrates as an element in response to an emerging virus[Internet].

Geneva: WHO; 2017[cited 2020 Oct 26]. Available from:

https://www.who.int/bloodproducts/brn/2017_BRN_PositionPaper_ConvalescentPlasma.pdf.

44. Salazar E, Perez KK, Ashraf M, Chen J, Castillo B, Christensen PA, et al. Treatment of coronavirus disease 2019 (COVID-

19) patients with convalescent plasma. Am J Pathol. 2020;190(8):1680-90.

45. Zeng QL, Yu ZJ, Gou JJ, Li GM, Ma SH, Zhang GF, et al. Effect of convalescent plasma therapy on viral shedding and

survival in patients with coronavirus disease 2019. J Infect Dis. 2020;222(1):38-43.

https://www.who.int/bloodproducts/brn/2017_BRN_PositionPaper_ConvalescentPlasma.pdf

46. Olivares-Gazca JC, Priesca-Marín JM, Ojeda-Laguna M, Garces-Eisele J, Soto-Olvera S, Palacios-Alonso A, et al. Infusion

of convalescent plasma is associated with clinical improvement in critically ill patients with covid-19: a pilot study. Rev Invest Clin.

2020;72(3):159-64.

47. Erkurt MA, Sarici A, Berber İ, Kuku İ, Kaya E, Özgül M. Life-saving effect of convalescent plasma treatment in covid-19

disease: clinical trial from eastern Anatolia. Transfus Apher Sci. 2020:102867. doi:10.1016/j.transci.2020.102867. [Epub ahead of

print].

48. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545-8.

49. Joyner M, Wright RS, Fairweather D, Senefeld J, Bruno K, Klassen S, et al. Early safety indicators of COVID-19

convalescent plasma in 5,000 patients. medRxiv. 2020. pii: 2020.05.12.20099879. Update in: J Clin Invest. 2020 Aug 10;:.

RW-6186_TRADUÇÃO PARA PORTUGUÊS – SUZANA GONTIJOPREPRINT FRAN

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

resultados preliminares

Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

Título curto: Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases avançadas dos ensaios clínicos

Fernando Anselmo de Oliveira1, Mariana Penteado Nucci2, Gabriel Nery de Albuquerque Rego1, Arielly da Hora Alves1, Luciana

Cavalheiro Marti1, Leopoldo Penteado Nucci3, Javier Bustamante Mamani1, Lionel Fernel Gamarra1

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

2 Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.

3 Centro Universitário do Planalto Central Apparecido dos Santos, Gama, DF, Brasil.


NOTA:RW – 6186 / CHECK LIST – RENAN (2.076 palavras / 48 referências / 3 figuras / 2 tabelas)2.701 palavras49 referências3 figuras2 tabelasO artigo é atribuído para a instituição Hospital Israelita Albert Einstein – HIAETurnitin obrigatorio

DOI: 10.31744/einstein_journal/2020RW6186

Como citar este artigo:

Oliveira FA, Nucci MP, Rego GN, Alves AH, Marti LC, Nucci LP, et al., Convalescent plasma therapy in COVID-19 critically ill

patients during advanced phases of clinical trials and their preliminary results. einstein (São Paulo). 2020;18:eRW6186.

http://dx.doi.org/10.31744/einstein_journal/2020RW6186

Autor correspondente:

Lionel Fernel Gamarra

Avenida Albert Einstein, 627/701 – Morumbi

CEP: 05652-900 – São Paulo, SP, Brasil

Tel.: (55 11) 3747- 0243

E-mail: [email protected]

Data de submissão:

21/09/2020

mailto:[email protected]

Data de aceite:

29/10/2020

ABSTRACT

Objective: To highlight the global scientific effort to fight the severe acute respiratory syndrome coronavirus 2, addressing the

preliminary results of passive immunization through convalescent plasma. Methods: We performed a search at the major

databases of interventional clinical trial protocols about the transfusion of convalescent plasma in patients with coronavirus disease

2019, as well as, published articles (n≥25), using the following search strategy: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND

(Convalescent plasma OR Plasma exchange) AND (Treatment OR Therapy)]. Results: A total of 24 interventional clinical trial

protocols (advanced in phases II-III, III, and IV) were included in this review, as well as three studies that had enough outcomes to

evaluate the efficacy of convalescent plasma therapy for patients with coronavirus disease 2019. All interventional clinical trial

protocols applied approximately 500 mL of convalescent plasma (from single or more donations) in hospitalized patients, mainly in

patients with severe disease associated with standard therapy for coronavirus disease 2019, and compared to placebo or standard

therapy plus specific drugs. Most of interventional clinical trial protocols are multicenter, and the phase IV studies are recruiting at

intercontinental centers of North America, Oceania, Europe, but most are recruiting center inside their own county. The three

studies published reported similar approach of convalescent plasma intervention with decrease in length of stay, mortality, with less

than 4% of adverse events, mainly for treating critical cases with life-threatening disease. Conclusion: All advanced clinical trials

focused on convalescent plasma therapy in patients with coronavirus disease 2019 hospitalized in severe conditions, and the

preliminary results provide strong evidence for therapy for the coronavirus disease 2019 patients.

Keywords: Covid-19; Coronavirus infections; SARS-CoV-2; Betacoronavirus; Immunization; Immunization, passive; Plasma;

Convalescent plasma

RESUMO

Objetivo: Destacar o esforço científico global para combater o coronavírus 2 da síndrome respiratória aguda grave, abordando os

resultados preliminares da imunização passiva por plasma convalescente. Métodos: Foi realizada uma busca nas principais bases

de dados dos protocolos de ensaios clínicos intervencionistas sobre transfusão de plasma convalescente em pacientes com

doença pelo coronavírus 2019, bem como artigos publicados (n≥25), utilizando a seguinte estratégia de busca: [(COVID-19 OR

SARS-CoV-2 OR nCoV-2019) AND (Convalescent plasma OR Plasma exchange) AND (Treatment OR Therapy)]. Resultados: Um

total de 24 protocolos de ensaios clínicos intervencionistas (avançados nas fases II-III, III e IV) foram incluídos nesta revisão, assim

como três estudos que tiveram resultados suficientes para avaliar a eficácia da terapia com plasma convalescente para pacientes

com doença pelo coronavírus 2019. Todos os protocolos de ensaios clínicos intervencionistas aplicaram cerca de 500 mL de

plasma convalescente (de uma ou mais doações) em pacientes hospitalizados, principalmente em pacientes com grau grave de


Manter edna

doença associada à terapia padrão para doença pelo coronavírus 2019 em comparação com placebo ou terapia padrão mais

medicamentos específicos. A maioria dos protocolos de ensaios clínicos intervencionistas são multicêntricos, e os estudos de fase

IV [N.T.] estão recrutando em centros intercontinentais da América do Norte, Oceania, Europa, mas na maioria os centros de

recrutamento estão dentro de seu próprio país. Os três estudos publicados relataram abordagem semelhante de intervenção para

plasma convalescente com redução do tempo de internação, mortalidade, com menos de 4% de eventos adversos, principalmente

para o tratamento de casos críticos com risco de vida. Conclusão: Todos os ensaios clínicos avançados focaram a terapia com

plasma convalescente em pacientes com doença pelo coronavírus 2019 hospitalizados em condições graves, e os resultados

preliminares fornecem fortes evidências para a terapia para esses pacientes com doença pelo coronavírus 2019.

Descritores: Covid-19; Infecções por coronavírus; SARS-CoV-2; Betacoronavírus; Imunização; Imunização passiva; Plasma;

Plasma convalescente

INTRODUÇÃO

No final de 2019 surgiu o coronavírus 2 da síndrome respiratória aguda grave (SARS-CoV-2), resultando na doença do coronavírus

2019 (COVID-19), que causou uma emergência sanitária sem precedentes, sendo declarada pandemia pela Organização Mundial


Manter edna

de Saúde (OMS) em 11 de março de 2020.(1) Até setembro de 2020, essa pandemia havia afetado cerca de 28 milhões pessoas,

com cerca de 920 mil mortes em todo o mundo.(2) No Brasil, até agora já ocorreram mais de 5 milhões de casos com mais de 130

mil mortes.(3)

Novas abordagens para o desenvolvimento de transferência de imunidade foram rapidamente implementadas em estudos

pré-clínicos, e atualmente estão começando a surgir resultados interessantes de ensaios clínicos, com o objetivo de melhorar os

sintomas da COVID-19, uma doença de sintomas heterogêneos causada pelo SARS-CoV-2 SARS-CoV-2. (2) Ao mesmo tempo,

diversas vacinas estão sendo desenvolvidas e testadas para a prevenção efetiva da doença.(4)

Antes da SARS-CoV-2, já havia sido investigado o uso de plasma convalescente (PC), com desfechos positivos, em surtos

de outras infecções virais,(5) como a pandemia de gripe A (H1N1), em 2009,(6) e a gripe aviária A (H5N1)(7), entre outras. Além

disso, há estudos que demonstram que os anticorpos do PC podem limitar a proliferação do vírus durante a infecção e promover a

eliminação viral, favorecendo uma recuperação rápida da doença.(8)

Uma revisão recente sobre a terapia com plasma em pacientes com COVID-19 relatou baixa frequência de eventos

adversos graves, e melhora nos sintomas clínicos em alguns participantes após a terapia com plasma, mas os autores julgaram

haver risco de viés de relatório.(9)

Os títulos altos ou baixos de anticorpos neutralizantes contra a COVID-19 podem ser manejados para reduzir os sintomas e

a mortalidade do paciente. Existem 24 ensaios clínicos avançados nas fases II-III, III e IV relatados em vários países usando PC

para tratar esses pacientes e responder a essa pergunta.(10-33) Embora a imunização passiva seja utilizada há mais de um século

no tratamento de doenças infecciosas, os resultados recentes apresentam desafios na definição do melhor momento de extração

do plasma e na escolha do doador, além do custo de todo esse procedimento. Essa falta de informação potencializa os

movimentos de grupos antivacina e antiplasma.(34)

OBJETIVO

Destacar o esforço científico global na luta contra o coronavírus 2 da síndrome respiratória aguda grave, abordando a imunização

passiva por plasma convalescente e seus resultados preliminares.

MÉTODOS

Foi realizada uma pesquisa até 14 de setembro de 2020 em ClinicalTrials.gov (https://clinicaltrials.gov/), Chinese Clinical Trial

Registry e EU Clinical Trials Register para ensaios clínicos de intervenção sobre transfusão de PC, em pacientes com COVID-19,

usando a seguinte estratégia de pesquisa: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND (Convalescent Plasma OR Plasma

Exchange) AND (Treatment OR Therapy)]. Em seguida, a mesma estratégia foi usada para pesquisar estudos nas bases de dados

PubMed e Scopus sobre a eficácia da terapia com PC para tratar pacientes com COVID-19.

Critérios de inclusão e exclusão

Esta revisão incluiu protocolos de ensaios clínicos (PECs) (fases III e IV) que abordassem o desenvolvimento de terapias

baseadas em PC para tratamento de pacientes com COVID-19 por imunização passiva, e estudos que mostrassem a eficácia da

terapia com PC aplicada em mais de 25 pacientes com COVID -19. Os motivos para exclusão de estudos foram os seguintes: -

PECs de estudos observacionais, - PECs envolvendo vacinas, e - PECs cancelados ou não aprovados, até a data da pesquisa nas

bases de dados.

Elegibilidade dos estudos, extração de dados, coleta de dados e avaliação de risco de viés

A elegibilidade dos estudos seguiu os itens de relatório preferidos para as diretrizes de revisões sistemáticas e meta-análises

(PRISMA).(35) A extração e coleta de dados e a avaliação do risco de viés foram realizadas por seis autores (F.A.O.; M.P.N.;

G.N.A.R.; A.H.A.; L.P.N.; e J.B.M.) organizados em pares, que revisaram e avaliaram de forma independente e aleatória as

informações registradas nos PECs e estudos identificados pela estratégia de busca nas bases de dados mencionadas acima. As

discrepâncias entre os autores na seleção de estudos e na extração de dados foram discutidas com dois autores (L.C.M. e L.F.G.)

e resolvidas. A inclusão final dos estudos desta revisão foi acordada entre todos os autores.

Análise dos dados

Todos os resultados foram descritos e apresentados por meio de distribuição percentual para todas as variáveis analisadas nas

tabelas.

RESULTADOS

Seleção de estudos

Após a aplicação das estratégias de busca nas bases de dados, 170 PECs foram identificados (153 protocolos no

ClinicalTrials.gov, 14 no Chinese Clinical Trial Registry e 3 no EU Clinical Trials Register). A estratégia de busca utilizou o

PRISMA.(35)

Com base nos critérios de inclusão e exclusão estabelecidos, dentre os 170 protocolos identificados, 146 ensaios clínicos

foram excluídos após a triagem (130 protocolos eram fases I e II, e 16 eram observacionais), restando 24 protocolos selecionados

dessas bases de dados. No total, 24 PECs foram incluídos neste trabalho sobre imunização passiva para COVID-19 por meio de

terapia com PC.(10-13, 15-33)

Dentre os estudos selecionados publicados nas bases de dados citadas acima, apenas três estudos apresentaram dados

suficientes que permitem uma análise estatística dos desfechos, para avaliar a eficácia da terapia com PC devido ao número de

pacientes com COVID-19 (n≥25).(36-38)

Visão geral dos protocolos de ensaios clínicos sobre imunização passiva para COVID-19

Dos 24 ensaios clínicos mais avançados sobre terapia com PC para pacientes hospitalizados com COVID-19, apenas um (4,2%)

estava na fase IV, com taxa de progresso do estudo (TPE) de 58%, recrutando indivíduos em diferentes países pelo patrocinador

holandês (barra verde da Figura 1).(10) Nos estudos de fase III (54,2%),(11-13, 15-19) quase metade dos PECs tinha TPE de mais de

40%, principalmente no México(15, 19) e nos EUA (barras azuis da Figura 1),(18, 21) e nos estudos de fase II-III (41,7%),(24-33) um PEC

tinha TPE de 100% na Holanda,(24) e quase metade dos PECs tinham TPE de mais de 40% (barras vermelhas da Figura 1),

conforme mostrado na Figura 1 e na Tabela 1.

NCT: número de ensaio clínico.

Figura 1. Análise do percentual da taxa de progresso do estudo de protocolos de ensaios clínicos sobre terapia de plasma

convalescente para pacientes com COVID-19 hospitalizados, distribuídos por suas fases (barra verde: fase IV; barras azuis: fase

III; e barras vermelhas: fase II-III), com o correspondente país patrocinador

Tradução da figura:

Netherlands HolandaColombia ColômbiaFrance FrançaUSA EUAMexico México

Canada CanadáIndia Índia Australia AustráliaDenmark DinamarcaItaly ItáliaIndonesia IndonésiaPhase Fase

Tabela 1. Desenho do estudo, braços, intervenções e progresso do tempo de estudo

Número de identidade Fase Características do paciente Intervenção por braço Dose PC (dia)

Faixa etária(anos)

Data de início

Data de conclusão

NCT02735707(10) IVDoença respiratória aguda grave e pneumonia adquirida na comunidade grave

Corticosteroides x Antibióticos x Macrolídeo x antiviral para gripe x LPV/Rit x HCQ x IFN-β1a x Anak x Tmab x Smab x VitC x Heparina x Sinvastatina x PC x TP

1 ou 2 unidades em 48 horas > 18 11/04/2016 01/12/2023

NCT04391101(11) III Pacientes graves tratados na UTI PC + TP x TP 400-500 mL > 18 01/06/2020 01/12/2021

NCT04372979(12) III Atendimento precoce de pacientes hospitalizados PC + TP x PP + TP 200-230 mL 18-80 01/05/2020 01/05/2021

NCT04418518 (13) III Atendimento precoce a pacientes hospitalizados PC + TP x TP

500 mL de doador único ou 2 unidades de 250 mL de 1-2 doações

18-70 24/06/2020 01/12/2021

NCT04355767(14) III Pacientes graves/críticos hospitalizados PC (títulos de anticorpos ≥1:160) x placebo PC: 1 unidade x placebo: solução

fisiológica com multivitamínico > 18 11/08/2020 01/12/2022

NCT04432103(15) III Pacientes graves/críticos hospitalizados PC de IgG (pacientes graves x pacientes críticos) + TP NR > 19 19/06/2020 30/09/2020

NCT04348656(16) III Atendimento precoce a pacientes hospitalizados PC x TP

500 mL de doador único ou 2 unidades de 250 mL de 1-2 doações

> 20 14/05/2020 31/12/2020

NCT04425915(17) III Pacientes graves/críticos hospitalizados PC + TP x TP

2 doses de 250 mL em dias consecutivos iniciadas no dia 3 do início dos sintomas

> 21 14/06/2020 30/05/2021

NCT04362176(18) III Pacientes hospitalizados ou em UTI Patógeno reduzido PC x placebo

PC: 500 mL em 12 horas (dia 0) x placebo: 250 mL de Ringer lactato + multivitaminas (dia 1)

> 22 24/04/2020 01/04/2021

NCT04381858(19) IIIInsuficiência respiratória grave com ventilação mecânica invasiva

PC (títulos de anticorpos > 1:164) x HIg PC: 400 mL (2 unidades) x HIg: 0,3 g/kg/dia (5 doses) 16-18 06/05/2020 30/09/2020

NCT04361253(20) III Pacientes hospitalizados PC (título alto) x PP (PFC ou PC24) PC-AT 2 doses de 250 mL de > 1 30/04/2020 01/12/2021

doador único em 24 horas; PFC: 2 unidades de 200-275 mL

NCT04376034(21) III Gravidade leve, moderada e grave/crítica PC +TP x TP

Adultos: 200 a 250 mL; crianças: 10 mL/kg; 2 unidades de pacientes graves ou em condição crítica

>30 d 16/04/2020 30/03/2021

NCT04483960(22) III Sem pacientes graves LPV/Rit x HCQ x PC 1 unidade no dia 1 e no dia 2 > 18 21/07/2020 12/06/2022

NCT0434528 9(23) IIIPacientes hospitalizados com doença leve, moderada e grave/crítica

PC + TP (Smab x Baricitinibe x HCQ) x TP + placebo injetável

PC: (2 x 300 mL) e dose única de 600 mL; placebo: (2 x 300 mL) e dose única de 600 mL de solução fisiológica IV por placebo: 3x/dia (7 dias)

> 18 01/05/2020 15/06/2021

NCT04342182(24) II-III Pacientes hospitalizados PC + TP x TP 300 mL (de acordo com o protocolo Erasmus MC KIS) > 18 08/04/2020 01/07/2020

NCT04388410(25) II-IIIPacientes hospitalizados com doença grave ou risco de doença grave.

PC x placeboPC: 2 unidades de 200 mL dentro de 24-72 horas); placebo: 200 mL de soro fisiológico

> 18 25/08/2020 31/12/2020

NCT04374526(26) II-III Pacientes hospitalizados PC + TP x TP 200 mL/dia por 3 dias > 65 27/05/2020 30/06/2021

NCT04384588(27) II-III Pacientes oncológicos e não oncológicos com doença grave PC + TP x TP 1 ou mais unidades > 15 07/04/2020 06/04/2021

NCT04425837(28) II-IIIPacientes hospitalizados com alto risco de doença grave ou em UTI

PC (títulos de anticorpos ≥1:160) + TP x TP 2 doses de 200 mL por dia > 18 01/07/2020 01/02/2021

NCT04395170(29) II-III Atendimento precoce a pacientes hospitalizados PC + TP x Anti-COVID-19 HIg x TP

PC: 200-250 mL (dia 1 e 3); Solução IgG a 10%: 50 mL (paciente ≥ 50 Kg); 1 mL/Kg (paciente < 50Kg), nos dias 1 e 3

> 18 01/09/2020 01/06/2021

NCT04380935(30) II-IIIPacientes hospitalizados na UTI (usando ventilação mecânica)

PC + TP x TP NR > 18 18/05/2020 31/10/2020

NCT04332835(31) II-III Gravidade moderada e grave/crítica PC + TP x HCQ + TP 250 mL nos dias 1 e 2 18-60 08/08/2020 31/10/2020

NCT04385043(32) II-III Pacientes graves/críticos hospitalizados PC + TP x TP NR 18-60 01/05/2020 15/05/2021

NCT04381936(33) II-III Pacientes hospitalizados com alto risco de doença grave

(LPV/Rit x corticosteroide. X HyChl x Azi x x Tmab) + TP x PC + TP 275 mL ± 75 mL nos dias 1 e 2 Todos 19/03/2020 01/12/2031

Observação: A imunoterapia passiva através da infusão de plasma de indivíduos convalescentes - plasma convalescente, também conhecido como plasma hiperimune ou

plasma convalescente compatível com ABO. UTI: unidade de terapia intensiva; Cort.: corticosteróide; LPV/Rit: lopinavir/ritonavir; HCQ: hidroxicloroquina; IFN-β1a: interferon-

β1a; Anak: anakinra; Tmab: tocilizumabe; Smab: sarilumabe; Vit C: Vitamina C; PC: plasma convalescente; TP: tratamento padrão; PP: plasma padrão; IgG: imunoglobulina G;

HIg: imunoglobulina humana; PFC: plasma fresco congelado; PC24: plasma congelado em 24 horas após a flebotomia; Azi: azitromicina; NR: não reportar; PC-AT plasma

convalescente de alto título.

Intervenção com plasma convalescente

A intervenção com PC aplicada em todos os PECs foi para pacientes hospitalizados

com diferentes graus de comprometimento da doença, principalmente para os casos

graves internados em UTI (58,3%) com ou sem ventilação mecânica invasiva, e

todos os pacientes receberam o TP para COVID-19. Os braços de intervenção

aplicados nesses pacientes hospitalizados normalmente comparavam o PEC da

terapia com plasma mais TP em relação a somente TP associado ou não a alguns

medicamentos selecionados, como corticosteroides, antibióticos, antimaláricos

(HCQ:), anticoagulantes, HIg, medicamentos antivirais, entre outros.(10, 22, 23, 29, 31, 33) A

terapia com PC foi aplicada principalmente por meio de dose única com diferentes

volumes de transfusão (45,8%), o volume mais utilizado foi de 500 mL, em 20,8%,(13,

16, 18, 39) seguido de doses de 200-250 mL em 8,3%,(12, 21) 400 mL em 8.3%,(19, 39)

300 mL em 4.2%,(24) e 600 mL em 4,2%.(23) Nos casos com mais de uma dose, o

volume foi de duas doses de 250 mL,(13, 16, 17, 20, 29, 31, 33) utilizadas na maioria dos

PECs, seguidas de 2 x 200 mL (19, 25, 28, 29, 33) e 2 x 300 mL. (23, 33) As doses de plasma

foram derivadas de um único doador,(13, 16, 20, 23) ou de até 2 doadores diferentes em

alguns PECs.(13, 16) Quase todos os PECs testaram a intervenção em indivíduos com

mais de 18 anos, com exceção de dois PECs (Tabela 1).

Em relação às características do desenho do estudo desses PECs, a Figura 2

mostra que a intervenção foi em sua maioria (87,5%) randomizada e poucos PECs

utilizaram algum tipo de mascaramento (33,3%), tais como: 4,2% cegamento

simples (participante), 12,5% cegamento duplo (participante, avaliador dos

desfechos), 8,3% cegamento triplo (participante, prestador de cuidados, avaliador

dos desfechos) e 8,3% cegamento quádruplo (participante, prestador de cuidados,

investigador, avaliador dos desfechos). No entanto, 12,5% dos PECs não adotaram

nenhuma técnica utilizada para minimizar o viés nas alocações e cegamento,

mantendo-se “open-label”. A inscrição estimada em ensaios clínicos em fase IV é de

7.100 indivíduos,(10) em fase III é de 36 a 2.400 indivíduos(11-23) e em fase II-III é de 60

a 15.000 indivíduos.(24-33) O número estimado de voluntários em cada protocolo está

representado pela barra de escala colorida na Figura 2.

Figura 2. Desenhos de estudo de ensaios clínicos de imunização passiva contra a

COVID-19 (terapia com plasma), distribuídos sistematicamente pelos diferentes tipos

de alocação (randomizada ou não), mascaramento (nenhum, cegamento único,

duplo, triplo e quádruplo), inscrição estimada (variada de 36 a 15.000 indivíduos) e

países de estudo. A barra de escala colorida representa o número estimado de

voluntários em cada protocolo

Tradução da figura:

Randomized 87.5% Randomizado 87,5%Non-randomized 12.5% Não randomizado 12,5%None 54.2% Nenhum 54,2%Single 4.2% Único 4,2%Double 12.5% Duplo 12,5%Triple 8.3% Triplo 8,3%Quadruple 8.3% Quádruplo 8,3%None 12.5% Nenhum 12,5%UK Reino Unido

Netherlands HolandaAustralia AustráliaUSA EUACanada CanadáNetherlands HolandaIndia Índia Italy ItáliaColombia ColômbiaIndonesia IndonésiaMexico MéxicoFrance FrançaDenmark Dinamarca

Rede global de pesquisa em protocolos de ensaios clínicos

Entre os PECs multicêntricos sobre PC,(10, 12, 13, 16, 17, 22-24, 26, 30, 32) o PEC de fase IV(10) é

o único com colaborações intercontinentais representadas pelas linhas pretas

tracejadas no mapa-múndi (Figura 3), com 87 centros de recrutamento (cilindros

verdes) distribuídos na América do Norte, Europa e Oceania. Os PECs de fase III

também têm colaboração entre países e envolvem 48 centros de recrutamento

(cilindros amarelos) nos EUA e Canadá.(16) Os outros PECs multicêntricos envolvem

um número variado de centros de recrutamento dentro do mesmo país, tais como:

Austrália com 79 centros (cilindros roxos),(22) Holanda com 18 centros (cilindros

azuis),(24) Dinamarca com 12 centros (cilindros cinza escuro),(23) Itália com 6 centros

(cilindros laranja),(32) destacados na Figura 3, com a imagem ampliada para melhor

visualização do centros de colaboração e outros com cerca de 3 centros.(12, 17, 26, 30)

Os PECs de centro único concentram-se principalmente na América do Norte(15, 18-21)

e América do Sul.(11, 27-29, 31)

Figura 3. Distribuição global dos ensaios clínicos por fase (círculos) e os centros

que desenvolvem pesquisas em terapia com plasma para COVID-19 (barra

vermelha) e seus centros de recrutamento (cilindros). Os principais centros de cada

continente estão destacados na imagem ampliada em torno do mapa central. Fase

IV (círculo verde), fase III (círculo azul), fases II-III (círculo vermelho). As

colaborações intercontinentais dos protocolos de ensaios clínicos de fase IV estão

representadas pelas linhas pretas tracejadas no mapa mundial.

TRADUÇÃO DA FIGURA

Parcerias da Itália com PECs

Parcerias da Dinamarca com PECs

Parcerias da Holanda com PECs

Centros de recrutamento EUA e Canadá

Patrocinador: Plasma

Centros de recrutamento

Fase IV – Fase III – Fase II-III

Parcerias do Canadá com PECs

Parcerias da Austrália com PECs

Centros de recrutamento da Austrália

Desfecho da terapia com plasma em pacientes COVID-19

Os três estudos que avaliam a eficácia da terapia com plasma também priorizam a

avaliação da COVID-19 em pacientes gravemente doentes ou com risco de vida,

como os ensaios clínicos avançados mencionados acima. A intervenção da terapia

com PC variou muito entre os estudos, sem um consenso sobre o melhor padrão de

aplicação de PC. Em relação aos resultados, os estudos mostraram redução de 53%

na gravidade da doença (dispensando terapia intensiva),(38) de 26% no tempo de

internação,(36) e de 35 a 50% na mortalidade,(36-38) relatando efeitos adversos em

menos de 4% dos pacientes após tratamento com PC em diferentes doses e

volumes associados à terapia padrão para COVID-19,(36-38) conforme mostrado na

Tabela 2.

Tabela 2. Estudos que avaliam a eficácia da terapia com plasma em pacientes COVID-19

Referências Amostra N/PC Título de anticorpos Dose PC (mL) Carga viral (x10 ^/dL)Tratamentos

anterioresHospitalização (variação) Eventos adversos (N)

Xia et al.,(38) 1568/138

Não significativamente maior nos

que responderam de forma

rápida ao tratamento do que nos

que responderam de forma

moderada

200-1200 mL20/25 (80%) ficaram livres de

vírus após 14 diasNI

2,4% PC x 5,1% TP

PC reduziu o número de

internados na UTI em aprox.

53%

aprox. 2% PC

Prurido ou eritema durante

a transfusão (n = 3)

Li et al.,(37) 103/52 PC (23

graves + 29 com

risco de vida) x 51

TP (22 graves + 29

com risco de vida)

1:350 (6 doadores) 4 a 13 mL/kg Redução em pacientes graves:

44,7% (24 h), 68,1% (48 h) e

87,2% (72 h) livre de vírus;

Pacientes com risco de vida:

53,8% (24 h); 73,1 (48 h) e

84,6%

(72 h) 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

Graves: 32,00 (26,00-

40,00); Com risco de vida:

Indeterminado (46,00-

Indeterminado)

aprox. 4% PC

Calafrios e erupções

cutâneas em 2 h (n = 1);

Falta de ar, cianose e

dispneia intensa em 6 horas

(n=1).

[15/46 (32,6%)]; HIg

[13/46 (28,3%);

Interferon [12/46

(26,1%)

Abolghasemi

et al.,(36)

189/115 PC x 74

TP).

Índice de corte de título de

anticorpos plasmáticos > 1,12x 500 mL NI

TP + antiviral

(LPV/Rit), HCQ e

agente

antiinflamatório

9,54 dias PC x 12,88 dias

TP

PC reduziu o tempo de

hospitalização em aprox.

26%

aprox. 1% PC

Febre leve transitória e

calafrios após infusão do

plasma (n=1);

n: número; PC: plasma convalescente; TP: tratamento padrão; NI: não informado; HIg: imunoglobulina humana; LPV/Rit: lopinavir/ritonavir; HCQ: hidroxicloroquina; UTI: Unidade de

terapia intensiva; h: hora.

DISCUSSÃO

Na ausência de um tratamento efetivo para pacientes com COVID-19, muitos

estudos têm buscado alternativas para tratar os pacientes e melhorar sua defesa

imune, como é o caso do uso da terapia com PC. O ensaio de recuperação(40)

fornece evidências para apoiar algumas formas de tratamento (por exemplo,

dexametasona) e de melhora da imunidade em pacientes em condições críticas, e

esse ensaio utiliza a terapia com PC como braço terapêutico. No entanto, muitos

aspectos dessa terapia ainda estão sendo explorados, como o intervalo de tempo

limite e o momento ideal de coleta para a COVID-19, ou os títulos de IgG/IgM dos

doadores, a melhora clínica proporcionada pela terapia, sua eficácia em pacientes

críticos ou não críticos e seus efeitos adversos. Dentre os 170 PECs identificados,

apenas 24 PECs estavam em fase avançada (III/IV) com 33.000 indivíduos,

concentrados nas regiões da América, mostrando as principais questões referentes

à eficácia do uso do PC ainda incertas ou frágeis para justificar a ampliação de seu

uso no atendimento hospitalar de pacientes críticos ou não críticos. Além disso,

nenhum país, incluindo os EUA, licenciou o PC como tratamento para a COVID-19.

A Food and Drug Administration (FDA) o considerou elegível para uso mais amplo

sob uma autorização de uso de emergência,(41) embora outros países tenham

concedido aprovação para seu uso em alguns pacientes.

Um dos primeiros ensaios clínicos com PC que analisou 103 pacientes com

COVID-19 grave e com risco de vida (idade mediana de 70 anos)(37) não mostrou

significância estatística na melhora clínica após 28 dias ou redução da mortalidade.

No entanto, houve evidências de efeitos terapêuticos notáveis e possível atividade

antiviral em grupos de pacientes de 60 a 80 anos, no estágio final da evolução da

doença, após 14 dias de sintomas, utilizando apenas unidades com títulos de

anticorpos muito altos (IgG superior a 1:50) específicos para S-RBD. Outro estudo

sobre o tratamento com PC em pacientes com COVID-19 grave(42) mostrou melhora

significativa dos sintomas clínicos, com aumento da saturação da oxihemoglobina

após o terceiro dia de transfusão, redução das lesões pulmonares, melhora dos

critérios laboratoriais de rotina e da função pulmonar acompanhada por rápida

neutralização da viremia, utilizando 200 mL de PC proveniente de doadores

recentemente recuperados com títulos de anticorpos neutralizantes entre 1:160-640,

cerca de 16,5 dias após o início dos sintomas, associados ao tratamento padrão e

agentes antivirais. Apenas três PECs(14, 19, 28) mencionaram os títulos de anticorpos

usados na terapia com PC (acima de 1:160), e os estudos de Abolghasemi et al.(36) e

Li et al.(37) também relataram o uso de títulos de anticorpos acima de 1.1 na terapia

com PC associados a melhora clínica e redução da mortalidade.

Para reduzir a variabilidade na resposta terapêutica dos pacientes, a OMS

recomenda alguns cuidados e padronização na seleção de doadores de PC.(43) O

critério de elegibilidade em relação à idade do doador não varia muito: 18-67 anos. (36,

44) Os doadores eram pacientes que se recuperaram de COVID-19 e não mostraram

detecção de SARS-CoV-2 por qRT-PCR ou quaisquer sintomas relacionados após

um período que variou entre os estudos. Em um estudo, os doadores podem ter se

recuperado após uma semana, e o curto período de recuperação talvez possa ter

contribuído para a morte de 5 em 6 pacientes.(45) Recuperação mais longa permitiu

relatos de eficácia terapêutica. Esse período pode ser de 10 dias, com a coleta

realizada em duas vezes, com diferença de 24 horas,(46) de pelo menos 14 dias(36, 47)

e de mais de duas semanas.(36, 42, 44) Em alguns casos, o qPCR dos swabs

nasofaríngeos deve ser testado como negativo duas vezes, com intervalo de 24

horas entre os exames.(36, 42)

Em relação à quantificação de anticorpos, os títulos de IgG específicos para

spike (S) e domínio de ligação ao receptor (RBD) variam de doador para doador. Um

estudo demonstrou que 10 em 25 amostras de plasma coletado exibiram o título de

1:450, 6/25 1:350, ao passo que nos demais variaram de 1:1 a 1:150.(44) A maioria

dos estudos utilizou um volume de PC em torno de 500 mL, em dose única ou

dividido em duas doses, proveniente de um único doador,(12, 16, 20, 23) ou de 2 doadores

diferentes.(12, 16) Portanto, essa falta de padronização na seleção dos doadores, no

controle de qualidade do PC e nos pacientes receptores poderia explicar os diversos

efeitos terapêuticos.

Alguns possíveis efeitos adversos com o uso do PC podem ser evitados,

como o uso de PC sem antígenos, que poderia causar lesão pulmonar aguda

relacionada à transfusão (TRALI), como os antígenos leucocitários humanos (HLA)

que protegem o embrião.(36) Em ensaio clínico multicêntrico, não foi permitido o uso

de PC em mulheres grávidas, com o objetivo de prevenir a ocorrência de TRALI.(36)

A gravidade da doença do paciente transfundido com PC variou de leve,

moderada, grave a crítica. Um PEC com pacientes graves dividiu os grupos de

estudo em pacientes com doença respiratória aguda grave e com pneumonia grave

adquirida na comunidade.(10) Outro PEC comparou os efeitos do tratamento em

pacientes com COVID-19 oncológicos e não oncológicos.(27) A admissão na unidade

de terapia intensiva está relatada em alguns PECs(11, 18, 28, 30), embora se presuma que

isso se aplique a todos os pacientes graves. Em alguns PECs, o tratamento com PC

foi comparado a outros tratamentos, como corticoides, antibióticos, anticorpos

monoclonais e medicamentos antivirais.(10, 22, 23, 33)

Alguns resultados publicados permitiram a avaliação de diferentes parâmetros

quanto à eficácia do tratamento. Em um estudo em que foi aplicado o PC, 6 de 17

pacientes necessitaram de ventilação mecânica, na maioria pacientes idosos.(47) Em

um estudo multicêntrico, a taxa de mortalidade foi de 14,8% dos pacientes (n=115).

(36) Resultados semelhantes foram encontrados em outro estudo multicêntrico

(15,7%).(36) Em outro, a mortalidade foi de apenas 2,2%.(38) Um estudo utilizou essa

terapia em pacientes com hipertensão, diabetes ou doença cardiovascular, mas não

ficou claro o efeito dessas comorbidades no resultado do tratamento com PC.(36)

A transfusão da terapia com PC para COVID-19 deve seguir algumas

condições pré-estabelecidas, como: disponibilidade de uma população de doadores

que já se recuperou da doença e que pode doar soro convalescente; bancos de

sangue para processar as doações de soro; disponibilidade de testes, incluindo

testes sorológicos, para detectar SARS-CoV-2 em exames séricos e virológicos para

medir a neutralização viral; apoio laboratorial de virologia para a realização desses

exames; e padronização da fase e condição do paciente com COVID-19.(48)

As principais limitações dos estudos multicêntricos foram o número reduzido

de pacientes nos grupos de controle em comparação ao grupo de tratamento,

geralmente devido à falta de compatibilidade do grupo sanguíneo do PC e ao uso

concomitante ou prévio de outro tratamento.(36) Outra limitação é a falta de protocolos

padronizados e treinamento para a equipe do estudo, além de diversidade no

monitoramento dos pacientes.(49) Por sua vez, a principal limitação do nosso estudo

foi a impossibilidade de realizar uma meta-análise, devido à falta de um número

robusto de estudos que relatassem efeitos terapêuticos conclusivos dessa

modalidade, como diminuição dos títulos de SARS-CoV-2. No entanto, alguns

artigos publicados sobre estudos multicêntricos demonstraram que o PC pode ser

uma modalidade terapêutica promissora.

CONCLUSÃO

Atualmente, não há opções terapêuticas confiáveis para pacientes com COVID‐19

em estado crítico. Com base nos poucos resultados de dados clínicos multicêntricos

consolidados disponíveis, concluímos que os estudos de terapia com plasma

convalescente forneceram resultados relevantes em casos graves/críticos de

pacientes com COVID-19, reduzindo o tempo de internação, a gravidade da doença

e a mortalidade, com baixa frequência de eventos adversos em um número

considerável de pacientes. Porém, não é possível afirmar, de forma conclusiva,

sobre a real relevância desse tratamento, devido à falta de dados que permitam uma

análise estatística robusta, tal como uma meta-análise.

INFORMAÇÕES DOS AUTORES

Oliveira FA: http://orcid.org/0000-0002-7226-1694

Nucci MP: http://orcid.org/0000-0002-1502-9215

Rego GN: http://orcid.org/0000-0003-2011-0373

Alves AH: http://orcid.org/0000-0003-3570-0827

Marti LC: http://orcid.org/0000-0002-3890-0827

Nucci LP: http://orcid.org/0000-0002-1234-5845

Mamani JB: http://orcid.org/0000-0001-5038-0070

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

REFERÊNCIAS

1. Ge H, Wang X, Yuan X, Xiao G, Wang C, Deng T, et al. The epidemiology and

clinical information about COVID-19. Eur J Clin Microbiol Infect Dis. 2020;39(6):1011-

9.

2. Worldometer. COVID-19 Pandemic Data Update 2020 [Internet]. Worlfometer; 2020 [cited 2020 Oct 26]. [Last update posted Oct 26, 2020].Available from: https://www.worldometers.info/coronavirus/.

3. Worldometer. COVID-19 Pandemic Data Update. 2020.

4. Rego GN, Nucci MP, Alves AH, Oliveira FA, Marti LC, Nucci LP, et al. Current clinical trials protocols and the global effort for immunization against SARS-CoV-2. Vaccines. 2020;8(3). pii: E474. Review.

5. Wong HK, Lee CK. Pivotal role of convalescent plasma in managing emerging infectious diseases. Vox Sang. 2020;115(7):545-7.

6. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.

7. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357(14):1450-1.

8. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.

9. Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, Wood EM, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a rapid review. Cochrane Database Syst Rev. 2020;5:CD013600. Update

in: Cochrane Database Syst Rev. 2020;7:CD013600.

10. ClinicalTrials.gov. Randomized, embedded, multifactorial adaptive platform trial for community- acquired pneumonia (REMAP-CAP) [Internet]. Bethesda (MD): U.S. 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

11. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a pilot study [Internet]. Bethesda (MD): U.S. 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

12. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in the early care of COVID-19 patients (PLASCOSSA) [Internet]. Bethesda (MD): U. S.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://www.worldometers.info/coronavirus/


13 ClinicalTrials.gov. A trial of CONvalescent plasma for hospitalized adults with acute COVID-19 respiratory illness (CONCOR-1) [Internet]. Bethesda (MD):U.S. 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

14. ClinicalTrials.gov. Convalescent plasma in outpatients with COVID-19 (C3PO) [Internet]. Bethesda (MD): U.S. 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

15. ClinicalTrials.gov. Treatment of severe and critical COVID-19 pneumonia with convalescent plasma [Internet]. Bethesda (MD): U.S. 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

16. ClinicalTrials.gov. CONvalescent plasma for hospitalized adults with COVID-19 respiratory illness (CONCOR-1) [Internet]. Bethesda (MD): U.S. 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

17. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in patients with COVID-19 [Internet]. Bethesda (MD): U.S. 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

18. ClinicalTrials.gov. Passive immunity trial of the nation for COVID-19 (PassItOnII) [Internet]. Bethesda (MD): U.S. 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

19. ClinicalTrials.gov. Convalescent plasma vs human immunoglobulin to treat COVID-19 pneumonia [Internet]. Bethesda (MD): U.S.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

20. ClinicalTrials.gov. Evaluation of SARS-CoV-2 (COVID-19) antibody-containing plasma therapy ((ESCAPE)) [Internet]. Bethesda (MD): U.S.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

21. ClinicalTrials.gov. Convalescent plasma collection and treatment in pediatrics and adults [Internet]. Bethesda (MD): U.S. 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

22. ClinicalTrials.gov. Australasian COVID-19 trial (ASCOT) [Internet]. Bethesda (MD): U.S. 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

23. ClinicalTrials.gov. Efficacy and safety of novel treatment options for adults with COVID-19 pneumonia [Internet]. Bethesda (MD): U.S. 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

24. ClinicalTrials.gov. Convalescent plasma as therapy for Covid-19 severe SARS-CoV-2 disease (CONCOVID Study) [Internet]. Bethesda (MD): U.S. 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

25. ClinicalTrials.gov. Safety and efficacy of convalescent plasma transfusion for patients with COVID-19 (EPCOvid-1) [Internet]. Bethesda (MD): U.S. 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

26. ClinicalTrials.gov. Early transfusIon of convalescent plasma in elderly COVID-19 patients. to prevent disease progression [Internet]. Bethesda (MD): U.S. 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

27. ClinicalTrials.gov. COVID19-convalescent plasma for treating patients with active symptomatic COVID 19 infection (FALP-COVID) [Internet]. Bethesda (MD): U.S. 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

28. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma in patients with high-risk COVID-19 [Internet]. Bethesda (MD): U.S. 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

29. ClinicalTrials.gov. Convalescent plasma (PC) and human intravenous anti-COVID-19 immunoglobulin (IV anti COVID-19 IgG) in patients hospitalized for COVID-19 [Internet]. Bethesda (MD): U.S. 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

30. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma therapy on COVID-19 patients with acute respiratory distress syndrome [Internet]. Bethesda (MD): U.S. 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

31. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a randomized, open label, parallel, controlled clinical study [Internet]. Bethesda (MD): U.S.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

32. ClinicalTrials.gov. Hyperimmune plasma in patients with COVID-19 severe infection [Internet]. Bethesda (MD): U.S. 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



33. ClinicalTrials.gov. Randomised evaluation of COVID-19 therapy [Internet]. Bethesda (MD): U.S. 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

34. Wadman M. Antivaccine forces gaining online. Science. 2020;368(6492):699.

35. Moher D, Liberati A, Tetzlaff J, Altman DG ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

36. 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 Apher Sci. 2020:102875. doi: 10.1016/j.transci.2020.102875. [Epub ahead of

print].

37. 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.

38. 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.

39. ClinicalTrials.gov. .Convalescent plasma for the treatment of severe SARS-CoV-2 (COVID-19) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 18, 2020; Last update posted May 20, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04391101

40. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ.

Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl

J Med. 2020 Jul 17. doi: 10.1056/NEJMoa2021436. [Epub ahead of print].

41. Estcourt LJ, Roberts DJ. Convalescent plasma for covid-19. BMJ. 2020;370:m3516.

42. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-6.

43. World Health Organization (WHO). Blood products and related biologicals. Blood Regulators Network (BRN). Position paper on use of convalescent plasma, serum or immune globulin concentrates as an element in response to an emerging virus[Internet]. Geneva: WHO; 2017[cited 2020 Oct 26]. Available from: https://www.who.int/bloodproducts/brn/2017_BRN_PositionPaper_ConvalescentPlasma.pdf.




44. Salazar E, Perez KK, Ashraf M, Chen J, Castillo B, Christensen PA, et al. Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma. Am J Pathol. 2020;190(8):1680-90.

45. Zeng QL, Yu ZJ, Gou JJ, Li GM, Ma SH, Zhang GF, et al. Effect of convalescent plasma therapy on viral shedding and survival in patients with coronavirus disease 2019. J Infect Dis. 2020;222(1):38-43.

46. Olivares-Gazca JC, Priesca-Marín JM, Ojeda-Laguna M, Garces-Eisele J, Soto-Olvera S, Palacios-Alonso A, et al. Infusion of convalescent plasma is associated with clinical improvement in critically ill patients with covid-19: a pilot study. Rev Invest Clin. 2020;72(3):159-64.

47. Erkurt MA, Sarici A, Berber İ, Kuku İ, Kaya E, Özgül M. Life-saving effect of convalescent plasma treatment in covid-19 disease: clinical trial from eastern Anatolia. Transfus Apher Sci. 2020:102867. doi:10.1016/j.transci.2020.102867. [Epub ahead of print].

48. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545-8.

49. Joyner M, Wright RS, Fairweather D, Senefeld J, Bruno K, Klassen S, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. medRxiv. 2020. pii: 2020.05.12.20099879. Update in: J Clin Invest. 2020 Aug 10;:.

Documents

Einsteinapps.einstein.br/.../6186-6186-870-artigo-76120201125.docx · Web view(1) Até setembro de 2020, essa pandemia havia afetado cerca de 28 milhões pessoas, com cerca de 920