REVIEW PROTOCOL
Use of convalescent plasma in the treatment of COVID-19: a systematic review protocol
Marcia Rodrigues dos Santos1, Carlos Roberto da Lyra da Silva2
1 Nurse. Master’s student at the Federal University of the State of Rio de Janeiro, UNIRIO, RJ, Brazil
2 Post-Doctor in Nursing. Professor at the Alfredo Pinto School of Nursing at the Federal University of the State of Rio de Janeiro – UNIRIO, RJ, Brazil
ABSTRACT
Objective: to analyze the therapeutic effectiveness of convalescent plasma used in patients with confirmed COVID-19 diagnosis. Method: systematic review for health technology assessment to answer the PICO question: Is convalescent plasma effective in reducing the viral load of patients diagnosed with SARS-CoV-2 (COVID-19) when compared to not using plasma? A systematic search was performed in Pubmed/Medline, BVS, Embase, CINAHL, LILACS, Cochrane and Google Scholar databases. The initial screening of titles and abstracts will be independently assessed by two reviewers. To assess the risk of bias in systematic reviews, AMSTAR-2 will be used, and to assess the quality of evidence, GRADE will be used.
Descriptors: Plasma; COVID-19; SARS-CoV-2.
INTRODUCTION
The SARS-CoV-2 outbreak originated in Wuhan, China, in December 2019. This virus is the cause of coronavirus disease 2019 (COVID-19), a serious illness characterized by pneumonia with increased infiltration of inflammatory cells and higher levels of pro-inflammatory cytokines(1).
This viral infection can trigger clinical cases of mild to moderate respiratory symptoms, however, about 11.7% of those infected end up developing the severe form of the disease, often leading to death(2).
The scientific community has already found that convalescent plasma for COVID-19 can be a safe treatment for patients, based on studies carried out in the United States of America (USA), China and Europe. Thus, it is plausible that it contains antibodies capable of neutralizing the action of SARS-COV-2. Such antibodies are extracted from the blood of patients recovered from COVID-19 who have not had symptoms in the last 14 or 28 days and serological result of COVID-19, by the plasmapheresis procedure(3,4).
Through this emerging therapy in the fight against the disease, studies indicate that the use of this technique reduces the replication of the virus in the patient and his immune system is able to respond better to the aggression of the virus(5).
The Food and Drug Administration has issued an opinion on the use of experimental convalescent plasma in the US, which implicates patients with antibodies for treatment hospitalized with COVID-19 early in the course of the disease or with compromised immunity(6).
In the past, convalescent plasma was also used to fight infection during the SARS epidemic in 2003 and the Middle East Respiratory Syndrome in 2012, and no significant side effects were identified(7).
Considering the knowledge gap on this topic and the limited number of studies published so far on the use of convalescent plasma as an experimental procedure, it is important to verify the potential of this treatment in patients infected with SARS-CoV-2.
According to the Ministry of Health, Health Technology Assessment (HTA) consists of investigating the clinical, economic and social consequences of the development, dissemination and use of technologies in the context of the health system and services. Through the information generated, the manager can make the best decision to contribute to health care (efficacy, effectiveness, safety and cost) to encourage the adoption of effective technologies(8).
The relevance of the study in assessing the use of convalescent plasma in the treatment of these patients in order to reduce viral replication and, consequently, the cure of infected patients, also becomes fundamental to support the adoption of strategies and actions that promote the development and improvement of the service provided.
Therefore, health professionals and managers should be concerned with identifying the health needs of the population and assessing existing technologies as a path to equitable and universal care in the SUS, contributing to its sustainability promotion.
Thus, recommendations on the use of convalescent plasma in COVID-19 require systematic summaries of the available evidence. Therefore, the objective of this review is to analyze the therapeutic effectiveness of convalescent plasma used in patients with confirmed diagnosis of COVID-19.
METHOD
A systematic review for HTA will be carried out based on the recommendations of the PRISMA checklist(9). Therefore, the methodology proposed in the Cochrane Collaboration Manual was adopted(10) in order to answer the research question: “Is convalescent plasma effective in reducing the viral load of patients diagnosed with SARS-CoV-2 when compared to not using plasma?”. The protocol was registered in the PROSPERO database CRD42021249359.
Source of information
Electronic searches were performed in the following databases: Medline/Pubmed, BVS, Embase, CINAHL, LILACS and John Wiley & Son Cochrane Library databases, Google Scholar and the TRIP DATABASE meta-search.
Eligibility criteria
In the present review, two researchers independently applied the following eligibility criteria: languages in Portuguese, English and Spanish; articles published between 2020 and 2021; randomized clinical trial and systematic reviews that include viral load reduction and measurement time (in the first days of symptom until negative conversion of viral RNA to SARS-CoV-2 in all clinical samples); both sexes; ages between 18 and 65 years; patients admitted to a hospital unit; and available in full text.
Estudos realizados com animais, bem como teses, dissertações e editoriais foram excluídos da presente revisão. No caso de discordância entre os pesquisadores, um terceiro avaliador resolveu as divergências.
Search strategy
To identify the descriptors and free terms that composed the strategies developed, the Medical Subject Headings (MeSH) controlled vocabularies were consulted, Health Sciences Descriptors (DeCS) and Embase Subject Headings (Emtree) combined using Boolean operators (OR/AND). The representations of the search strategies are described in Figure 1.
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DATABASES
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STRATEGY
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PUBMED |
((“COVID-19”[mh] OR “COVID-19” OR “COVID 19” OR “COVID-19 Virus Disease” OR “COVID 19 Virus Disease” OR “COVID-19 Virus Infection” OR “COVID 19 Virus Infection” OR “COVID-19 Virus Infections” OR “2019-nCoV Infection” OR “2019 nCoV Infection” OR “2019-nCoV Infections” OR “Coronavirus Disease-19” OR “Coronavirus Disease 19” OR “2019 Novel Coronavirus Disease” OR “2019 Novel Coronavirus Infection” OR “2019-nCoV Disease” OR “2019 nCoV Disease” OR “2019-nCoV Diseases” OR “Coronavirus Disease 2019” OR “SARS Coronavirus 2 Infection” OR “SARS-CoV-2 Infection” OR “SARS CoV 2 Infection” OR “SARS-CoV-2 Infections” OR “COVID-19 Pandemic” OR “COVID 19 Pandemic” OR “COVID-19 Pandemics” OR “SARS-CoV-2”[mh] OR “SARS-CoV-2” OR “Coronavirus Disease 2019 Virus” OR “2019 Novel Coronavirus” OR “2019 Novel Coronaviruses” OR “Wuhan Seafood Market Pneumonia Virus” OR “SARS-CoV-2 Virus” OR “SARS CoV 2 Virus” OR “SARS-CoV-2 Viruses” OR “2019-nCoV” OR “COVID-19 Virus” OR “COVID 19 Virus” OR “COVID-19 Viruses” OR “Wuhan Coronavirus” OR “Coronavirus, Wuhan” OR “SARS Coronavirus 2” OR “Severe Acute Respiratory Syndrome Coronavirus 2”) AND (“COVID-19 serotherapy” OR “convalescent plasma therapy”)) |
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REGIONAL BVS/ LILACS |
("coronavirus infections" OR "2019 novel coronavirus" OR "2019-novel coronavirus" OR "2019-nCoV" OR "2019‐new coronavirus" OR "COVID-19" OR "coronavirus infection" OR "coronavirus infections" OR "MERS" OR "middle east respiratory syndrome" OR "novel coronavirus pneumonia" OR "wuhan coronavirus" OR "infecciones por coronavirus" OR "infeccoes por coronavirus" OR "betacoronavirus" OR “2019 new coronavirus" OR "betacoronaviruses" OR "HCoV-HKU1" OR "human coronavirus HKU1" OR "pipistrellus bat coronavirus HKU5" OR "rousettus bat coronavirus HKU9" OR "SARS-CoV-2" OR "severe acute respiratory syndrome coronavirus 2" OR "tylonycteris bat coronavirus HKU4" OR "wuhan coronavirus" OR "wuhan seafood market pneumonia virus" ) AND ("convalescent plasma" OR "convalescent plasma therapy" OR "plasma convalescente" OR "terapia de plasma convalescente" OR "plasma de convalecencia" OR "terapia de plasma convaleciente") |
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EMBASE |
('coronavirus disease 2019'/exp OR '2019 novel coronavirus disease' OR '2019 novel coronavirus epidemic' OR '2019 novel coronavirus infection' OR '2019-ncov disease' OR '2019-ncov infection' OR 'covid' OR 'covid 19' OR 'covid 19 induced pneumonia' OR 'covid 2019' OR 'covid-10' OR 'covid-19' OR 'covid-19 induced pneumonia' OR 'covid-19 pneumonia' OR 'covid19' OR 'sars coronavirus 2 infection' OR 'sars coronavirus 2 pneumonia' OR 'sars-cov-2 disease' OR 'sars-cov-2 infection' OR 'sars-cov-2 pneumonia' OR 'sars-cov2 disease' OR 'sars-cov2 infection' OR 'sarscov2 disease' OR 'sarscov2 infection' OR 'wuhan coronavirus disease' OR 'wuhan coronavirus infection' OR 'coronavirus disease 2' OR 'coronavirus disease 2010' OR 'coronavirus disease 2019' OR 'coronavirus disease 2019 pneumonia' OR 'coronavirus disease-19' OR 'coronavirus infection 2019' OR 'ncov 2019 disease' OR 'ncov 2019 infection' OR 'new coronavirus pneumonia' OR 'novel coronavirus 2019 disease' OR 'novel coronavirus 2019 infection' OR 'novel coronavirus disease 2019' OR 'novel coronavirus infected pneumonia' OR 'novel coronavirus infection 2019' OR 'novel coronavirus pneumonia' OR 'paucisymptomatic coronavirus disease 2019' OR 'severe acute respiratory syndrome 2' OR 'severe acute respiratory syndrome 2 pneumonia' OR 'severe acute respiratory syndrome cov-2 infection' OR 'severe acute respiratory syndrome coronavirus 2 infection' OR 'severe acute respiratory syndrome coronavirus 2019 infection' OR 'severe acute respiratory syndrome coronavirus 2'/exp OR '2019 ncov' OR '2019 new coronavirus' OR '2019 novel coronavirus' OR '2019 severe acute respiratory syndrome coronavirus 2' OR '2019-ncov' OR 'covid 19 virus' OR 'hcov-19' OR 'human coronavirus 2019' OR 'sars coronavirus 2' OR 'sars-cov-2' OR 'sars-related coronavirus 2' OR 'sars2 (virus)' OR 'sever acute respiratory syndrome coronavirus 2' OR 'severe acute respiratory coronavirus 2' OR 'severe acute respiratory syndorme coronavirus 2' OR 'severe acute respiratory syndrome coronavirus 2' OR 'severe acute respiratory syndrome coronoavirus 2' OR 'severe acute respiratory syndrome coronvirus 2' OR 'severe acute respiratory syndrome related coronavirus 2' OR 'severe acute respiratory syndrome virus 2' OR 'severe acute respiratoy syndrome coronavirus 2' OR 'wuhan coronavirus' OR 'wuhan seafood market pneumonia virus' OR 'ncov-2019' OR 'novel 2019 coronavirus' OR 'novel coronavirus 2019' OR 'novel coronavirus-19' OR 'severe acute respiratory syndrome 2 virus' OR 'severe acute respiratory syndrome cov-2 virus' OR 'severe acute respiratory syndrome corona virus 2' OR 'severe acute respiratory syndrome coronavirus 2019') AND ('covid-19 serotherapy' OR 'covid-19 convalescent plasma treatment' OR 'convalescent plasma treatment for covid-19' OR 'convalescent plasma therapy'/exp OR 'convalescent plasma (cp) therapy' OR 'convalescence plasma therapy' OR 'convalescent plasma (cp) immunotherapy' OR 'convalescent plasma immunotherapy' OR 'convalescent plasma therapy') AND [embase]/lim |
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COCHRANE |
ID Search #1 MeSH descriptor: [COVID-19] explode all trees #2 "COVID-19" OR "COVID 19" OR "COVID-19 Virus Disease" OR "COVID 19 Virus Disease" OR "COVID-19 Virus Infection" OR "COVID 19 Virus Infection" OR "COVID-19 Virus Infections" OR "2019-nCoV Infection" OR "2019 nCoV Infection" OR "2019-nCoV Infections" OR "Coronavirus Disease-19" OR "Coronavirus Disease 19" OR "2019 Novel Coronavirus Disease" OR "2019 Novel Coronavirus Infection" OR "2019-nCoV Disease" OR "2019 nCoV Disease" OR "2019-nCoV Diseases" OR "Coronavirus Disease 2019" OR "SARS Coronavirus 2 Infection" OR "SARS-CoV-2 Infection" OR "SARS CoV 2 Infection" OR "SARS-CoV-2 Infections" OR "COVID-19 Pandemic" OR "COVID 19 Pandemic" OR "COVID-19 Pandemics" #3 #1 OR #2 #4 MeSH descriptor: [SARS-CoV-2] explode all trees #5 "SARS-CoV-2" OR "Coronavirus Disease 2019 Virus" OR "2019 Novel Coronavirus" OR "2019 Novel Coronaviruses" OR "Wuhan Seafood Market Pneumonia Virus" OR "SARS-CoV-2 Virus" OR "SARS CoV 2 Virus" OR "SARS-CoV-2 Viruses" OR "2019-nCoV" OR "COVID-19 Virus" OR "COVID 19 Virus" OR "COVID-19 Viruses" OR "Wuhan Coronavirus" OR "SARS Coronavirus 2" OR "Severe Acute Respiratory Syndrome Coronavirus 2" #6 #4 OR #5 #7 #3 OR #6 |
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CINAHL |
((“COVID-19” OR “COVID 19” OR “COVID-19 Virus Disease” OR “COVID 19 Virus Disease” OR “COVID-19 Virus Infection” OR “COVID 19 Virus Infection” OR “COVID-19 Virus Infections” OR “2019-nCoV Infection” OR “2019 nCoV Infection” OR “2019-nCoV Infections” OR “Coronavirus Disease-19” OR “Coronavirus Disease 19” OR “2019 Novel Coronavirus Disease” OR “2019 Novel Coronavirus Infection” OR “2019-nCoV Disease” OR “2019 nCoV Disease” OR “2019-nCoV Diseases” OR “Coronavirus Disease 2019” OR “SARS Coronavirus 2 Infection” OR “SARS-CoV-2 Infection” OR “SARS CoV 2 Infection” OR “SARS-CoV-2 Infections” OR “COVID-19 Pandemic” OR “COVID 19 Pandemic” OR “COVID-19 Pandemics” OR “SARS-CoV-2” OR “Coronavirus Disease 2019 Virus” OR “2019 Novel Coronavirus” OR “2019 Novel Coronaviruses” OR “Wuhan Seafood Market Pneumonia Virus” OR “SARS-CoV-2 Virus” OR “SARS CoV 2 Virus” OR “SARS-CoV-2 Viruses” OR “2019-nCoV” OR “COVID-19 Virus” OR “COVID 19 Virus” OR “COVID-19 Viruses” OR “Wuhan Coronavirus” OR “SARS Coronavirus 2” OR “Severe Acute Respiratory Syndrome Coronavirus 2”) AND (“COVID-19 serotherapy” OR “convalescent plasma” OR “convalescent plasma therapy”)) |
Figure 1 – Database search strategy. Rio de Janeiro, RJ, Brazil, 2021
Source: Prepared by the authors, 2021.
Data extraction
After identifying the included studies, data will be extracted by the same researchers, using the Handbook Cochrane Collaboration(10) form, prepared in Microsoft Excel. The extracted data will include information on: study design; trial participants and characteristics; diagnostic criteria; number of participants selected for eligibility; allocation randomization and concealment method; use of intent-to-treat analysis; detailed interventions; duration of studies; and outcome measures (reduction in viral load presented as continuous data: final anti-SARS-CoV-2 IgG protein titers and dichotomous: reduced versus not reduced).
References found in the selected search strategies will be exported to the reference manager, Mendeley®, to remove duplicates. Disagreements regarding data extraction will be resolved by a third reviewer. When there is insufficient data, there will be attempts in contacting the corresponding authors for possible clarifications.
Treatment effect measures.
Relative risk (RR) and 95% confidence interval (CI) will be used to analyze dichotomous data. For continuous data, the mean difference method will be used, with their respective 95% CIs (dispersion data and standard deviation will also be extracted).
Heterogeneity assessment
Statistical heterogeneity between studies will be investigated using Cochran's Q test with a significance level of p value lower than 0.01 and quantified by the I² test. Although inconsistency is estimated using Cochran's Q test, the I² test is a statistic that provides complementary information because it is not influenced by statistical power. The I² statistic ranges from 0 to 100% and is interpreted as low (25%), moderate (26-74%) and high (75%) heterogeneity.
Data synthesis
The Review Manager software (v.5.3) will be used for data analysis and synthesis of quantitative data. The mean differences and/or the RR with their respective 95% CIs will be calculated using the random effect model for data synthesis, exceptionally the fixed effect will be used if there is a single study with an order of magnitude 50% greater than the other included studies.
Subgroup analysis
In the presence of heterogeneity (moderate to high) subgroup and/or sensitivity analyzes will be performed. Some factors that may be considered in the subgroup analysis are: type of intervention, concentration of inflammatory cytokines and increase in C-reactive protein. For the sensitivity analysis, if necessary, an analysis will be performed considering the studies that demonstrate low risk of bias in order to increase the confidence of the result.
Risk of bias assessment
Two authors will independently assess the risk of bias of systematic reviews through the tool Assessing the Methodological Quality of Systemathic Reviews (AMSTAR-2)(11), while for RCTs the Cochrane criteria will be used, which include: random sequence generation, allocation concealment, participant and outcome assessor masking, incomplete outcome data, selective outcome reporting, and other bias(11). The risk of bias will be classified as “low”, “high” or “some concern”. Incomplete outcome data will be judged as low risk of bias when the numbers and causes of dropouts are balanced across arms and appear to be unrelated to the outcome itself. Selective bias will be assessed by comparing outcomes reported in study protocols with published outcome results. Any discrepancy between the authors will be resolved by a third reviewer.
Evidence quality assessment
Since the weighting of other aspects can increase or decrease the quality of evidence about the effect of an intervention on an outcome, the present review will assess the outcome of viral load reduction through The Grading of Recommendations, Assessment, Development and Evaluation System (GRADE)(12).
ACKNOWLEDGEMENTS
We thank Dr. Glycia de Almeida Nogueira for her collaboration in technical support in the production of the protocol.
CONFLICT OF INTEREST
The authors have declared that there is no conflict of interest.
RESEARCH FUNDING
CAPES Funding Code 001, Process No: 88887.509512/2020-00.
REFERENCES
1. Organização Pan-Americana de Saúde (OPAS). Vigilância global das infecções humanas pelo coronavírus (2019-nCoV) [Internet]. Brasília: OPAS; 2020. (Orientação Temporária; 3) [cited 2021 Aug 12]. Available from: https://iris.paho.org/bitstream/handle/10665.2/51864/OPASBRANCOV20005_por.pdf?sequence=5&isAllowed=y
2. Ministério da Saúde (BR). Secretaria de Atenção Primária à Saúde (SAPS). Protocolo de manejo clínico do coronavírus (COVID-19) na atenção primária à saúde (Versão 7) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2021 Aug 12]. Available from: https://saude.rs.gov.br/upload/arquivos/202004/14140606-4-ms-protocolomanejo-aps-ver07abril.pdf
3. Oliveira FAD, Nucci MP, Rego GNDA, Alves ADH, Marti LC, Nucci LP, et al. Einstein. 2021;19:eRW6186. http://dx.doi.org/10.31744/einstein_journal/2021RW6186. PMid:33886937.
4. Lima A, Silva H, Vieira L. Plasma convalescente [Internet]. Goiânia: Subsecretaria de Saúde, Gerência de Informações Estratégicas em Saúde CONECTA-SUS; 2020 [cited 2021 Aug 12]. Available from: https://www.saude.go.gov.br/files//banner_coronavirus/protocolos-notas/S%C3%ADnteses%20de%20Evid%C3%AAncias/2020/Plasma%20Convalescente%20COVID-19.pdf
5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Lancet. 2020;395(10223):507-13. http://dx.doi.org/10.1016/S0140-6736(20)30211-7. PMid:32007143.
6. Food and Drug Administration (US). Hinton DM the authorized COVID-19 convalescent plasma [Internet]. Washington (DC): FDA; 2021 [cited 2021 Aug 12]. Available from: https://www.fda.gov/media/141477/download
7. COVID19 Divulgação Científica. Terapia com plasma sanguíneo no combate à COVID-19 [Internet]. Rio de Janeiro: INCT-CPCT/CNPq; 2021. Video: 5:06 min. [cited 2021 Aug 12]. Available from: https://www.youtube.com/watch?v=6JLcrL982fI
8. Ministério da Saúde (BR). Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde. Departamento de Gestão e Incorporação de Tecnologias e Inovação em Saúde. Diretrizes metodológicas: elaboração de pareceres técnico-científicos [Internet]. Brasília: Ministério da Saúde; 2021 [cited 2021 Aug 12]. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/diretrizes_metodologicas_elaboracao_parecer_tecnico.pdf
9. Siddaway AP, Wood AM, Hedges LV. Annu Rev Psychol. 2019;70(1):747-70. http://dx.doi.org/10.1146/annurev-psych-010418-102803. PMid:30089228.
10. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. BMJ. 2021;372:n160. http://dx.doi.org/10.1136/bmj.n160. PMid:33781993.
11. Higgins JPT, Savović J, Page MJ, Elbers RG, Sterne JAC. Assessing risk of bias in a randomized trial. In: Higgins J, Thomas J, editors. Cochrane handbook for systematic reviews of interventions version 6.2 [Internet]. London: Cochrane; 2019. chap. 8 [cited 2021 Aug 12]. Available from: https://training.cochrane.org/handbook/current/chapter-08
12. Lemos A. Fisioterapia Brasil. 2018;18(5):657-66. http://dx.doi.org/10.33233/fb.v18i5.1564.
Approved: 01/21/2022
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AUTHORSHIP CONTRIBUTIONS |
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Project design: Santos MR, Silva CRL |
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Data collection: Santos MR |
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Data analysis and interpretation: Santos MR |
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Writing and/or critical review of the intellectual content: Santos MR |
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Final approval of the version to be published: Santos MR, Silva CRL |
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Responsibility for the text in ensuring the accuracy and completeness of any part of the paper: Santos MR, Silva CRL |