key: cord-0756050-f5hrgykc
authors: ZHANG, Xuanguo; XI, Li; PANG, Fang; DU, Yan; YUAN, Qiuzhen; SHI, Minjuan; LIU, Jiping; MA, Hui; LI, Bo
title: Convalescent Plasma in the Treatment of Severe COVID-19: A Systematic Review and Meta-Analysis
date: 2020-11-03
journal: Iran J Public Health
DOI: 10.18502/ijph.v49i11.4716
sha: c8b752a0d1078e57bc3ebb077d61aea49c206325
doc_id: 756050
cord_uid: f5hrgykc

BACKGROUND: COVID-19 is a public health emergency of international concern. Its incidence rates and mortality are very high; however, so far, an effective drug treatment remains unknown. Based on the role of convalescent plasma therapy in previously identified viral pneumonias, patients with severe COVID-19 have been given this therapy. This systematic review and meta-analysis aimed to summarize the clinical evidence regarding the efficacy and safety of convalescent plasma therapy in the treatment of severe COVID-19. METHODS: PubMed, Embase, Ovid, China Knowledge Network, China Biomedical, VIP Chinese Sci-tech Journal, Wanfang Database, and the International Clinical Trials Registry Platform were searched up to 21 June 2020, to identify clinical studies and registered trials on the use of convalescent plasma in the treatment of critically ill patients with COVID-19. Stata 13.0 was used to perform Meta-analysis. All records were screened as per the protocol eligibility criteria. RESULTS: Nineteen clinical reports regarding convalescent plasma in the treatment of severe COVID-19 were included. Through systematic analysis, convalescent plasma was found to yield some efficacy on severe COVID-19 and had almost no obvious adverse reactions. CONCLUSION: Convalescent plasma therapy seems to yield some efficacy among patients with severe COVID-19 and almost no obvious adverse reactions were found. However, at present, the clinical evidence is insufficient, and there is an urgent need for support from high-quality clinical trial data.

id increase in the number of confirmed cases worldwide, the number of deaths had increased at an even faster rate (1) . Due to the high mortality rate of severe COVID-19, it is very important to institute effective treatment for critically ill patients. However, so far, there is no clear, effective, and proven drug treatment. Convalescent plasma therapy has been used for more than 100 years and played a role during various viral infectious disease pandemics. A metaanalysis showed that the use of convalescent plasma, serum, or hyperimmune globulin may be effective in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe acute respiratory infection due to influenza viruses, it can reduce the associated mortality, and is safe (2) . Convalescent plasma with antibody titer ≥1:80 was effective in the treatment of Middle East respiratory syndrome coronavirus (MERS-CoV) infection (3) . According to previous studies on viruses similar to SARS-CoV-2, including SARS and MERS viruses, convalescent plasma may be effective in the treatment of severe COVID-19. To seek evidence regarding convalescent plasma in the treatment of severe cases, the present paper systematically evaluated the evidence from a literature review.

We assessed studies including randomized controlled trials, clinical controlled trials, cohort studies, case-control studies, case series studies, and case reports about the use of plasma therapy among convalescent COVID-19 patients. There was no restriction on language. The participants were critically ill patients diagnosed with COVID-19. The diagnostic methods could be based on the guidelines of COVID-19 published in various countries. As intervention, the treatment group included convalescent plasma, and conventional therapy was unlimited. The treatment of the control group was unlimited. The outcome indicators included clinical efficacy, survival rate, mortality, viral load, antibody titer, and adverse reactions.

We excluded other pieces of literature that did not meet the inclusion criteria, such as nonclinical reports, reviews, inconsistent research objectives, inconsistent intervention measures, and duplicate literature.

According to the pre-established data extraction table, the literature data were extracted and a unified data table was established using Excel 2013 (Microsoft Corp., Redmond, WA, USA), including author, year of publication, sample size, sex, age, underlying diseases, plasma therapy information, intervention measures, observation indicators, and clinical outcomes.

The mortality and the negative rate of PCR data were analyzed by Meta-analysis using Stata 13.0.

According to the inclusion and exclusion criteria, 19 clinical reports were retrieved.

According to the predetermined retrieval scheme, we searched the literature, and read the titles and abstracts. We initially excluded literature that did not meet the inclusion criteria, read the full text of the remaining literature, and excluded retrospective studies, duplicate studies, studies with inconsistent intervention measures, noncontrolled studies, and other pieces of literature. Finally, 19 studies were included (Fig. 1 ).

Available at: http://ijph.tums.ac.ir Thus far, 19 clinical reports have been published on the use of convalescent plasma in the treatment of COVID-19 (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) , including those emanating from China, USA, South Korea and Turkey. Among the 146 patients who reported the clinical efficacy, the oldest was 100 years old and the youngest was 19 yr old. The most common complications of these patients were essential hypertension, cardio-cerebrovascular diseases, diabetes, and so on. The majority of patients received mechanical ventilation, while almost simultaneously else antiviral treatment including remdesivir, hydroxychloroquine, abidol, ribavirin or peramivir, and so on. According to the needs of the disease, they also received different antibacterial or antifungal treatments, hormone treatments, albumin, immunoglobulin, and other immune agent treatments. The clinical effect was evaluated after transfusion by assessing clinical symptoms, chest images or CT, nucleic acid detection, viral antibody level, blood leukocyte count, lymphocyte count, interleukin-6 (IL-6) levels, C-reactive protein (CRP) levels, disease prognosis, and so on. Most patients showed improvement in symptoms after transfusion; the inflammation had resolved on chest imaging or CT, viral nucleic acid test results returned negative, antibody titer increased, white blood cell and lymphocyte counts normalized, IL-6 and CRP levels decreased. Some studies (5, 11, 15, 20) reported mortality. Baseline characteristics (age, gender, severity of the diseases, and so on) of patients between convalescent plasma treatment group and control group in these four studies showed no significant differences. The mortality rate of the treatment group was lower than control group, and the difference was significant (RR=0.59,95% CI (0.37,0.94), P<0.05) (Fig. 2 ). In a study, the average time of plasma transfusion was 21.5 d after the onset of the disease in 5 patients who died (11) , and the effect of transfusion within 14 d of disease onset of 3 patients were better than that observed more than 14 d after onset of 1 patient, suggesting that plasma transfusion should be carried out as early as possible among patients with severe disease (5) .

In some studies, the specific requirements of plasma titer in convalescence were put forward (4) (5) (6) 15, 17, 19, 22) . The titer of antibody was higher than 1:160-1:1000. In another studies, the age that requirements for blood donors were put forward was 18-67 yr old (5, 6, 8, 10, 14, 15) . Suggesting that the titer of plasma antibody should be as high as possible and the donors should be as young as possible.

Analyzed some key safety metrics after transfusion of ABO compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life-threatening COVID-19, the incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%) [1] . Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (n=7), transfusion-related acute lung injury (n=11), and severe allergic transfusion reactions (n=3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.

The use of convalescent plasma in the treatment of patients with severe COVID-19 seemed to yield some efficacy and almost no serious adverse reactions were found. However, these results were limited by the use of antiviral, hormone, and other treatments; and the low level of clinical evidence. (Table 1 and 2). 

Convalescent plasma therapy yields some efficacy among patients with severe COVID-19 and almost no obvious adverse reactions were found. However, the clinical evidence is insufficient and there is an urgent need for support from highquality clinical trial data. In addition, special attention should be paid to the indications, contraindications, selection criteria of donors, and storage and transfusion procedures for plasma therapy. At present, under the condition that there is no effective treatment for patients with severe COVID-19, some countries have put forward some guidelines based on the clinical experience regarding convalescent plasma therapy in the treatment of SARS, MERS, and severe avian influenza. Epstein Jay et al. (23) compiled a document approved by the Global Blood Safety Working Group of the International Society of Blood Transfusion and reported that as a possible treatment for COVID-19, factors such as prescreening and pre-donation testing of donors, qualification criteria of whole blood or plasma donors and collection standards should be taken into account when preparing and transfusing COVID-19 convalescent plasma. From January 27th to Apr 1st, 2020, China has successively issued guidelines for the diagnosis and treatment of COVID-19 (the trial version and the fourth to seventh editions)(24-27), "COVID-19 Convalescent Plasma Clinical Treatment Plan (trial first and second editions)"(28), "Further strengthening COVID-19 convalescent plasma treatment work plan"(29), and "Severe COVID-19: A series of guidelines for the diagnosis and treatment of crit-ical and severe cases (trial second edition)"(30). The scope of application of plasma therapy for COVID-19 in the convalescent stage has been revised continuously. Convalescent plasma therapy should be considered for severe cases and critically ill patients under certain conditions, for patients with rapid disease progression, and convalescent plasma containing novel coronavirus antibody should be used in the treatment of early COVID-19. It can be considered as a choice for specific treatment. The titer of protective antibody in convalescent plasma should be measurable. The recommended dosage of transfusion in two stages is 200-500 ml (4-5 ml/kg body weight) and clear requirements have been put forward in three aspects: target task, work measures, and work requirements. On March 24, 2020, the United States Federal Drug Administration approved a clinical study of convalescent plasma in the treatment of COVID-19 (31). The guidelines for the diagnosis and treatment of COVID-19 issued by the National Institutes of Health (32) on Apr 21, 2020 point out that there are not enough data to recommend the use of recovered plasma or hyperimmune globulin for the treatment of COVID-19 (level of evidence: IIIA). Despite a good historical record, few controlled trials had assessed the efficacy of convalescent plasma, largely due to its emergent use during epidemics (33) . Data on the use of convalescent plasma therapy be collected and mined from ongoing clinical studies. Based on the severity of the situation in Italy, convalescent plasma therapy would be regarded as "empirical". A donor diagnosed with COVID-19, based on virology, should fully recover within at least 14 d, and a titer of at least 1:320 is recommended (34) .

In the clinical trials conducted under the guidance of normative documents in various countries or regions, the existing reported clinical data show that convalescent plasma therapy seems to yield some efficacy among patients with severe COVID-19 and almost no obvious adverse reactions were found. However, the level of clinical evidence is low due to the small sample size, as well as the influence of antiviral, hormonal, and other treatments. Therefore, this clinical treatment modality should be used cautiously in patients with severe COVID-19 when there is a lack of high-quality clinical trial data. The principle of early treatment should be followed when using it. The correlation between the plasma dose and therapeutic effect of plasma therapy in the treatment of COVID-19 cannot be confirmed. Follow-up clinical trials of plasma therapy for COVID-19 should pay attention to the differences in implementation of treatment (dose, frequency, timing, etc.) and the influence of donor plasma standards, and adopt randomized controlled studies as far as possible to arrive at conclusions that are more accurate.

Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.

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This work was supported by the Emergency launch of science and technology program during epidemic prevention and control in Shaanxi Province (grant number 2020LCZX-02).

The authors declare no conflict of interest.