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. 2021 May 18;42:100901. doi: 10.1016/j.nmni.2021.100901

Convalescent plasma therapy as a conventional trick for treating COVID-19: a systematic review and meta-analysis study

M Keikha 1,2, M Karbalaei 3,∗
PMCID: PMC8129993  PMID: 34026229

Abstract

Convalescent plasma therapy (CPT) is one of the well-known therapeutic protocols for treating infectious diseases that do not have special treatment or vaccine. Several documents confirm the clinical efficacy of this therapy for treating bacterial and viral infections. A comprehensive systematic search was conducted by August 2020 using global databases including PubMed, Scopus, Embase, Cochrane library, Google scholar, medRxiv and bioRxiv. The Joanna Briggs Institute critical appraisal checklist was used to evaluate the included studies. Using the Comprehensive Meta-Analysis software version 2.2 (Biostat, Englewood, NJ, USA), the pooled data analysis process was performed. A total of 15 eligible articles were enrolled in the current quantitative synthesis. The statistical analysis showed that clinical improvement in the group of patients who had received convalescent plasma was significantly increased compared with the control group (OR: 2.23; 1.12-4.45 with 95% CIs; p value: 0.022; Q-value: 6.11; I2: 83.64; Eggers p value: 0.064; Beggs p value: 0.093). Furthermore, the rate of hospital discharge had increased in patients receiving CPT (OR: 2.92; 1.48-5.77 with 95% CIs; p value: 0.002; Q-Value: 4.32; I2: 53.80; Eggers p value: 0.32; Beggs p value: 0.50). Because there is currently no fully effective antiviral drug against the virus and it will take time to confirm the effectiveness of new drugs, CPT can be used as an alternative treatment strategy to improve the severe clinical manifestations of COVID-19.

Keywords: Convalescent plasma, MERS-CoV, meta-analysis, SARS-CoV-1, SARS-CoV-2

Background

The family Coronaviridae is known as one of the most important etiologic factors for severe acute respiratory diseases for 21st-century human beings. The members of this family are enveloped, single-stranded, positive-sense RNA viruses (26-32 kbp length), and also have many spikes proteins on their surfaces that mediate virus entry into the cells [1,2]. Coronaviruses have a broad spectrum of the host including avian species, humans and several mammals such as bats, camels, mice, cats, dogs and anteaters [3]. Among them, several coronaviruses (CoVs) such as 229E, OC43, NL63, HKU1, severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), MERS-CoV and more recently SARS-CoV-2 can infect human [4]. Before 2002, CoVs were known only as of the causes of common cold; however, in the 21st century, the large pandemic of betacoronavirus revealed that these RNA viruses can cause the life-threatening severe respiratory diseases [5]. In 2002, the first pandemic, severe acute respiratory syndrome (SARS) was caused by SARS-CoV-1, so that had the mortality rate about 10% [6]. The second pandemic, Middle East respiratory syndrome (MERS), was occurred by MERS-CoV in 2012, with mortality rate about 35% [7]. In December 2019, a new member of betacoronavirus, 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China, causing a severe pneumonia, that was called coronavirus disease 2019 (COVID-19) [8]. The clinical manifestations of COVID-19 are fever, dyspnoea, myalgia and invasive multilobular lesions (in chest radiological findings), and these are much like SARS and MERS diseases [5,9]. The nucleotide sequence of the 2019-nCoV genome is very similar (88%) with both bat-SL-CoVZC45 and bat-SL-CoVZXC21 genomes. In addition, the phylogenetic analysis revealed that the similarity of its genome with both SARS-CoV-1 and MERS-CoV is 79% and 50%, respectively [10]. SARS-CoV-2 is a highly contagious virus and rapidly spread worldwide. In March 2020, the World Health Organization announced the COVID-19 pandemic, and nowadays more than 13 million cases are infected by this virus [11]. Despite the rapid spread of the virus, so far there is no vaccine or drug approved by the Food and Drug Administration (FDA) against COVID-19 [12]. The lack of a protective vaccine and yet the need to avoid of spread of virus has been led to use of alternative strategies such as convalescent plasma therapy (CPT) for the treatment of patients [13]. Historically, passive immunisation is as one the therapeutic protocols against infectious agents, and first was used in 1880s [14]. In passive immunisation, the individuals who recover from an infectious disease are investigated, and the convalescent plasma (CP) with high titres of neutralising antibodies is used for other similar patients, so that leads to reduce the clinical sings, treatment duration and mortality rate [15]. As per review of literature, CP has been used for treating diseases such as diphtheria, Spanish influenza, Ebola, West Nile fever, SARS and MERS, and has been satisfactory results in amelioration and reduction of mortality rate [[16], [17], [18], [19], [20]]. Owing to advantages such as clinical efficacy, viral therapy, reducing death and low side effects, CPT is considered as a suitable therapeutic option in complications such infectious diseases, immune deficiencies, allergies and autoimmune diseases [14,21,22]. Furthermore, based on studies, it is demonstrated that CP has the satisfying results in improving and increasing the survival of COVID-19 patients [23]. CPT is one of the most reliable therapeutic options during the outbreaks of infectious agents, in particular in the absence of the appropriate vaccine [13]. Recently, FDA has announced that CP can be used as a trustworthy way in cases of widespread outbreak of COVID-19 [24]. In the present meta-analysis, we fulfilled a comprehensive evaluation study about the effects of CP on clinical improvement, increase of discharged cases, as well as reducing mortality of infected patients by viruses SARS-CoV-1, MERS-CoV and SARS-CoV-2.

Methods

Search strategy

Comprehensive systematic search was conducted independently by two authors (MK1 and MK2) using several databases including PubMed, Scopus, Embase, Cochrane library, Google scholar, medRxiv and bioRxiv. Our search strategy was based on MeSH and using keywords such as “convalescent plasma”, “COVID-19”, “SARS-CoV-1”, “MERS-CoV”, “SARS-CoV-2” and “Coronavirus”. Next, we retrieved all relevant articles (up to August 2020) about the evaluation of CP effect on infected patients by SARS-CoV-1, MERS-CoV and SARS-CoV-2. The inclusion criteria were as follows: 1) articles containing the characteristics such as clinical improvement, viral therapy, mortality rate, the number of discharged cases and adverse event rate, in CP therapy patients; 3) patients infected by SARS-CoV-1, MERS-CoV and SARS-CoV-2; 3) articles containing the full text; 4) English articles. Also, duplicate studies were considered as exclusion criteria (Fig. 1). We reviewed all potentially relevant articles, and finally disagreements were resolved through discussion.

Fig. 1.

Fig. 1

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The flowchart of search strategy.

Quality assessment and data extraction

The Joanna Briggs Institute critical appraisal checklist was used for the evaluation of included studies. The main findings and characteristics of included studies include first author, country, viral aetiology, number of patients, CP dosages, outcome endpoint, number of improved patients, number of death, viral therapy rate, adverse event rate, number of cases weaned from the mechanical ventilation, number of discharged cases, therapeutic received drugs and reference number. The information is summarised in Table 1 [[25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]]. The process of extracting the required data was also performed by both authors (MK1 and MK2).

Table 1.

Characteristics of included studies

First author Country Viral Etiology Patients CP dose Outcome endpoint Clinical improvement Death Viral therapy Adverse event Weaned ventilation Discharge Drugs Ref
Li China SARS-CoV-2 52 case
51 control		 S-RBD–IgG
1:640
200 ml		 28 days 27/52
22/51		 15.7%
24%		 87.2%
37.5%		 2/0 NA 51%
36%		 Antiviral, antibacterial, antifungal, interferon, steroids [25]
Shen China SARS-CoV-2 5 IgG (1:1000)
200-250 ml		 12 days 3 0 5 NA 3 3 Lopinavir/ritonavir, favipiravir, interferon alfa-1b, arbidol, darunavir [26]
Joyner USA SARS-CoV-2 5000 IgG
500 ml		 7 days NA 602 NA 36 NA NA NA [27]
Zeng China SARS-CoV-2 6/15 IgG
300 ml		 22 days 6 5/6
14/15		 6/3 0 NA 1/1 NA [28]
Ahn Korea SARS-CoV-2 2 IgG
500 ml		 26 days 2 0 2 0 2 2 Lopinavir/ritonavir, hydroxychloroquine, methylprednisolone, antibiotics [29]
Ye China SARS-CoV-2 6 IgG
400-600 ml		 33 days 5 0 2 0 NA 3 Arbidol, levofloxacin [30]
Zhang China SARS-CoV-2 4 IgG
200-400 ml		 NA 4 0 4 0 2 4 Arbidol, lopinavir-ritonavir, interferon alpha [31]
Duan China SARS-CoV-2 10 IgG
1:640
200 ml		 20 days 10 0 7 0 3 10 Arbidol, remdesivir, ribavirin, peramivir, antibacterial [32]
Ko Korea MERS-CoV 3 IgG
1:80		 3 days 3 0 2 NA 3 3 NA [33]
Chun Korea MERS-CoV 1 IgG
500 ml		 NA 1 0 NA 1 NA 1 Ribavirin, lopinavir/ritonavir, interferon alpha [34]
Wong China SARS-CoV-1 1 IgG
200 ml		 NA 1 0 NA 0 NA 0 Cefotaxime, levofloxacin, oseltamivir, ribavirin [35]
Yeh Taiwan SARS-CoV-1 3 IgG
1:640
500 ml		 NA 3 0 2 NA 1 3 Lopinavir, ritonavir, methylprednisolone [36]
Soo China SARS-CoV-1 19/21 IgG
600-900 ml		 22 days 14/4 0/5 NA 0 NA 74%
19%		 Ribavirin,
methylprednisolone		 [37]
Kong China SARS-CoV-1 1 IgG
500 ml		 7 days 1 0 NA NA 1 1 Steroids, antiviral [38]
Cheng China SARS-CoV-1 40 IgG
600-900 ml		 22 days 40 13 NA 0 NA 26 Cefotaxime, levofloxacin, ribavirin, prednisolone, methylprednisolone [39]
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Quantitative synthesis

Using the Comprehensive Meta-Analysis software version 2.2 (Biostat, Englewood, NJ, USA), the pooled data analysis was performed. In the present study, the cases who had received CP therapy were evaluated from aspects such as clinical improvement, discharged from hospital, weaned from mechanical ventilation, viral therapy, adverse events and mortality rate. For assessing the mentioned information, we used from event rate with 95% confidence intervals (CIs). Also, for evaluating, the clinical efficacy of CP therapy was used from the odds ratio (OR) with 95% CIs as well. Using the random-effects model, the pooled OR was estimated. It is noteworthy that, based on the Dersimonian and Laird method and random-effects model, the high heterogeneity cases included I2 index >25% and Cochrane Q test p value ≤ 0.05.

Results

In the present meta-analysis, from all fifteen studies (5240 participants), eight studies were on SARS-CoV, while the other two and five were about MERS-CoV and SARS-CoV-1, respectively. The studies had been conducted in four countries China, Korea, Taiwan and the United States (USA). From all of the infected patients, 5151 were infected by SARS-CoV-2, while four patients were infected by MERS-CoV, as well as eighty-five were infected by SARS-CoV-1. The patients had received 200-900 mL of CP in addition to medication with steroids, antibiotics, anti-fungi drugs and also anti-viral drugs containing lopinavir/ritonavir, favipiravir, IFN-alpha 1b, arbidol, darunavir, ribavirin, remdesivir and peramivir. However, the parameters such as IgG titre, therapeutic regimens, disease status and outcome endpoint varied in different patients.

Overall, the results indicate that the CPT has good clinical effects on the patients infected by CoVs (SARS-CoV-1, MERS-CoV and SARS-CoV-2). Except for antiviral effects, the recovery rate in patients that had received CP was satisfying; adverse events or even mortality rate was low as well. The statistical analysis showed that clinical improvement in the group of patients who received CP significantly increased compared with the control group (OR: 2.23; 1.12-4.45 with 95% CIs; p value: 0.022; Q-value: 6.11; I2: 83.64; Eggers p value: 0.064; Beggs p value: 0.093). Furthermore, discharge rate of patients from hospital in the group that were received CPT had increased (OR: 2.92; 1.48-5.77 with 95% CIs; p value: 0.002; Q-Value: 4.32; I2: 53.80; Eggers p value: 0.32; Beggs p value: 0.50).

In the subgrouping analysis, we determined the efficacy of CPT in each patient separately. The statistical analysis on the eighty-five patients infected by SARS-CoV-1 demonstrated that the parameters such as clinical improvement, weaning from mechanical ventilation and discharging from the hospital in patients under the CPT significantly had increased (Table 2). On the other hand, the rate of mortality had a significant decrease in patients who had received CP compared with the control group (OR: 0.077; 0.004-1.497 with 95% CIs; p value: 0.090; Q-value: 0.00; I2: 0.00; p value: 1.00).

Table 2.

Summarised events rate

Viral etiology Clinical improvement
 Death
 Virological cure
 Adverse event
 Weaned ventilation
 Discharge
Event rate (95% CIs) Heterogeneity Publication bias Event rate (95% CIs) Heterogeneity Publication bias Event rate (95% CIs) Heterogeneity Publication bias Event rate (95% CIs) Heterogeneity Publication bias Event rate (95% CIs) Heterogeneity Publication bias Event rate (95% CIs) Heterogeneity Publication bias
Total CoVs 66.5% (56.7-75) p value:
0.001		 Q: 18.28
I2: 39.85 p value: 0.075		 Eggers p value:
0.04
Beegs p value:
0.50		 12.2% (11.3-13.1) p value: 0.001 Q: 29.98
I2: 59.98 p value: 0.003		 Eggers p value:
0.34
Beegs p value:
0.25		 13.1% (12.2-14.1) p value:
0.001		 Q: 158.96
I2: 93.70 p value:
0.001		 Eggers p value:
0.001
Beegs p value:
0.46		 1% (0.7-1.3) p value: 0.001 Q: 28.98
I2: 68.94 p value: 0.001		 Eggers p value:
0.001
Beegs p value:
0.10		 49.7% (38.6-0.8) p value: 0.95 Q: 4.75
I2: 0.00 p value: 0.57		 Eggers p value: 0.24
Beegs p value: 0.18		 52.3% (44.4-0.2) p value: 0.56 Q: 20.31
I2: 45.85 p value: 0.041		 Eggers p value: 0.081
Beegs p value: 0.15
SARS-CoV 1 81% (64.9-91.4) p value:
0.001		 Q: 5.04
I2: 40.52 p value: 0.169		 Eggers p value:
0.14
Beegs p value:
0.50		 27.7% (17.1-41.5) p value: 0.002 Q: 4.62
I2: 35.15 p value: 0.020		 Eggers p value:
0.76
Beegs p value:
0.50		 66.7% (15.4-56.6) p value:
0.57		 Q: 8.96
I2: 5.00 p value:
0.1		 Eggers p value:
NA
Beegs p value:
NA		 1.7% (0.2-1.13) p value: 0.001 Q: 0.14
I2: 0.00 p value:
0.70		 Eggers p value:
NA
Beegs p value:
NA		 40.0% (10-80) p value: 0.65 Q: 1.15
I2: 0.00 p value: 0.97		 Eggers p value:
NA
Beegs p value: NA		 67.9% (55.5-8.2) p value: 0.006 Q: 1.35
I2: 0.00 p value:
0.71		 Egger p value: 0.33
Beegs p value: 0.15
MERS-CoV 85.6% (41.6-98) p value:
0.10		 Q: 0.02
I2: 0.00 p value: 0.87		 Eggers p value:
NA
Beegs p value:
NA		 14.4% (2-58.4) p value: 0.100 Q: 5.04
I2: 40.52 p value: 0.169		 Eggers p value:
NA
Beegs p value:
NA		 66.7% (15.4-95.7) p value:
0.57		 Q: 0.00
I2: 0.00 p value:
1.0		 Eggers p value:
NA
Beegs p value:
NA		 26% (5-69) p value: 0.276 Q: 0.215
I2: 0.00 p value: 0.643		 Eggers p value:
NA
Beegs p value:
NA		 55.3% (12-91) p value: 0.845 Q: 2.698
I2: 62.931 p value: 0.100		 Eggers p value:
NA
Beegs p value: NA		 85.6% (41-98) p value: 0.100 Q: 0.24
I2: 0.02 p value: 0.876		 Eggers p value:
NA
Beegs p value: NA
SARS-CoV 2 60.4% (48-71) p value:
0.082		 Q: 10.141
I2: 40.83 p value: 0.119		 Eggers p value:
0.002
Beegs p value:
0.183		 12.1% (11–13) p value: 0.001 Q: 12.147
I2: 42.371 p value: 0.096		 Eggers p value:
0.24
Beegs p value:
0.19		 80.6% (69-88) p value:
0.001		 Q: 9.153
I2: 34.44 p value:
0.165		 Eggers p value:
0.46
Beegs p value:
0.27		 0.9% (0.7-1.2) p value: 0.001 Q: 18.391
I2: 67.37 p value:
0.05		 Eggers p value:
0.001
Beegs p value:
0.08		 46.7% (26-68) p value: 0.77 Q: 2.70
I2: 0.00 p value: 0.44		 Eggers p value:
0.003
Beegs p value: 0.15		 54.5% (43-65) p value: 0.44 Q: 9.514
I2: 36.93
P value: 0.147		 Eggers p value:
0.154
Beegs p value: 0.11
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In the group infected by MERS-CoV, we analysed the information of four patients. Although owing to the low sample size, we did not achieve significant results; however, using CPT had satisfying results in improving the clinical manifestations (Table 2). Interestingly, statistical analysis of information of 5151 COVID-19 patients confirmed the efficacy of CPT during the treatment. Improvement of clinical symptoms in patients who had received CP was more compared with the control group, although we observe the significant changes (OR: 1.66; 0.78-3.53 with 95% CIs; p value: 0.183; Q-value: 2.613; I2: 61.72; p value: 0.106). Negative virus test for this disease in recipients of CP had the meaningful change (OR: 2.59; 1.65-3.52 with 95% CIs; p value: 0.001; Q-value: 0.67; I2: 0.00; p value: 0.41). To discharge the patients in this group significantly increased as well (OR: 2.02; 0.94-4.35 with 95% CIs; p value: 0.07; Q-value: 0.049; I2: 0.00; p value: 0.824). As well as, based on statistical analysis results, CP could be significantly decreased the mortality rate in COVID-19 patients (OR: 0.311; 0.12-0.76 with 95% CIs; p-value: 0.011; Q-value: 0.009; I2: 0.00; p-value: 0.923). The mentioned data are listed in Table 2.

Discussion

So far, several genera of family Coronaviridae such as 229E, OC43, NL63, HKU1, SARS-CoV-1 and MERS-CoV have been known; however, in 2019, a new genus of this family, SARS-CoV-2, was considered as the etiologic agent of COVID-19 [40,41]. The first outbreak of COVID-19 occurred in more than 800 health care workers in Wuhan, China; however, the disease rapidly was spread in other countries, in particular Thailand, Japan, South Korea and the USA [5,42,43]. Today, various studies have shown that some underlying factors such as old age, pregnancy, cancer, diabetes, hypertension, as well as AIDS are specifically considered for the fatal outcomes and severity of this disease [44]. At the moment, several drugs such as teicoplanin, hydroxychloroquine, remdesivir, lopinavir, oseltamivir, ribavirin, favipiravir and tocilizumab are used for the treatment of COVID-19 [10,45]. Currently, regarding the importance of COVID-19 on one hand, and lack of the protective vaccine or effective drug, on the other hand, COVID-19 convalescent plasma (CCP) therapy can be considered as one of the fundamental ways for the treatment of this disease [46]. Studies show that the transfusion of plasma from patients who have recovered from COVID-19 infection to other SARS-CoV-2-infected patients can be led to their treatment without the occurrence of severe adverse events [47]. As per a study that Shen et al. conducted on five critically ill patients, following plasma transfusion, body temperature normalised during 3 days in four patients, the viral load became negative within two weeks after CCP therapy in all patients, and also, and 3 patients were weaned from mechanical ventilation [26]. Ye et al. conducted a study on six COVID-19 patients who had been admitted to Wuhan Huoshenshan Hospital from 11th February to 12th March 2020, and among them, there was a patient with Sjögren syndrome as well. They observed that the treatment of patients with CP had satisfying outcomes in all of them. Although the exact mechanism of action of CPT is not understood, they proposed that the antibodies IgM and IgG can directly neutralise the SARS-CoV-2, and probably, the anti-inflammatory contents of CP prevent cytokine storms [48]. In another study, Ahn et al. estimated the viral load of two cases that were affected by COVID-19 and acute respiratory distress syndrome by rRT-PCR technique, before and after CPT. In both cases, the value of the cycle threshold (Ct) had changed, which indicated a reduction in viral load after CP transfusion. In case 1 Ct changed from 24.98 on day 10 to 33.96 on day 20 after plasma transfusion, and in case 2 Ct changed from 20.51 on day 5 to 36.33 on day 9 after plasma transfusion [29]. Li et al. (2020) realised that CPT could be led to the negative conversion of SARS-CoV-2 in PCR (OR: 11.39; 3.91-33.18 with 95% CIs; p-value: 0.01) [49]. Based on studies, the exception with itching or skin rash and sometimes the little increase in body temperature, so far no serious adverse events have been reported with CPT [50]. Our present study had several limitations including 1) low population sample size, 2) evaluating limit published articles till August 2020, 3) significant heterogeneity in some cases, 4) presence of publication bias, 5) inaccessibility to raw data to evaluate several variables such as non-uniform details on interactions of medications, comorbidities, risk factors, morbidity, complications and randomised data. However, further investigations are necessary to examine the clinical benefit of CPT in CoVs with more sample size as well as randomised controlled studies to reduce certain sources of bias.

Conclusion

Based on different studies, it seems that in the absence of full effective antiviral drug or vaccine, CPT is an appropriate alternative for the treatment of patients infected by CoVs. The results of the present meta-analysis showed a reasonable conclusion about the clinical efficacy of CPT against COVID-19. In this study, we showed that CPT can be considered as a candidate for treating the patients who were infected by CoVs. This therapeutic protocol is an effective solution for characteristics such as clinical improvement, weaning from mechanical ventilation, hospital discharge, viral treatment and also prevention of mortality.

Ethics approval and consent to participate

Not applicable (this article was provided based on research in global databases).

Consent to publish

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Transparency declaration

There is no conflict of interest among all authors.

Funding

We have not received any funding for this research.

Authors' contributions

  • 1.

    MK1 has contributed to the design of the work and analysis of data.

  • 2.

    MK2 has drafted the work and substantively revised it.

All authors read and approved the final manuscript.

Acknowledgements

The authors appreciate both Mashhad University of Medical Sciences and Jiroft University of Medical Sciences.

Editor: Michel Drancourt

Abbreviations

CoVs

Coronaviruses

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

MERS

Middle East respiratory syndrome

2019-nCoV

2019 novel coronavirus

COVID-19

Coronavirus disease 2019

WHO

World Health Organization

FDA

Food and Drug Administration

CPT

Convalescent plasma therapy

CP

Convalescent plasma

JBI

Joanna Briggs Institute

CMA

Comprehensive Meta-Analysis

CIs

Confidence intervals

OR

Odds Ratio

USA

United States

ARDS

Acute respiratory distress syndrome

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Data Availability Statement

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