Convalescent Plasma Therapy and Its Effects On COVID-19 Patient Outcomes: A Systematic Review of Current Literature

Started in late 2019, coronavirus disease 2019 (COVID-19) has rapidly turned into a global pandemic. Considering there is no proven therapy for COVID-19 infection, there is a need to propose potential treatment options. The use of convalescent plasma is one such option as convalescent plasma has previously been used for treating outbreaks of Ebola, influenza, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and severe acute respiratory (SAR) viruses. Therefore, we carried out an early systematic review to evaluate the efficacy of convalescent plasma (CP) therapy and its effects on COVID-19 patient outcomes. A structured and rigorous systematic review was carried out that included all studies conducted on this topic between December 2019 and June 2020. A total of 10 studies containing a mix of case reports, case series, observational studies, and randomized control trials were identified. Most of the studies lacked randomization and included only small groups of patients. Considering the limitations in the design of current studies, it is difficult to draw a definitive conclusion. However, our results showed that plasma therapy produces notable improvements in patients' clinical symptoms and radiological and biochemical parameters associated with COVID-19 infection. Based on the available information, it is difficult to draw a tangible conclusion about whether plasma therapy improves patient mortality. Until we have concrete evidence to prove otherwise, convalescent plasma therapy may be used as adjuvant therapy for treating COVID-19 infection in critically ill patients.


Introduction And Background
The coronavirus disease 2019 (COVID-19) has turned into a rapidly evolving pandemic. As of 13th July 2020, the World Health Organization (WHO) has confirmed that the number of COVID-19 cases has reached 12,768,307, and the recorded death toll has crossed 566,654 [1]. WHO estimates that the COVID-19 related mortality curve will level off at 5.7% [2]. Convalescent plasma has previously shown clinical efficacy in other virus-borne infections. WHO recommended the use of convalescent plasma from recovered patients for empirical treatment during the Ebola outbreak [5]. During the 2019 influenza A virus subtype H1N1 pandemic, the use of convalescent plasma therapy by Hung et al. showed a significant reduction in mortality rates in the treatment group compared to control (20.0% vs. 54.8%; p=0.01) [6]. Convalescent plasma therapy has also shown benefit in the treatment of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and severe acute respiratory infections (SAR) viruses [7,8]. Several randomized control trials are underway to determine the efficacy of convalescent plasma therapy for COVID-19 infection [9].
There is a lack of structured systematic reviews looking into the efficacy of convalescent plasma therapy for COVID-19 patients. Therefore, we have conducted this early systematic review to provide an insight into the clinical effectiveness of convalescent plasma as a potential therapy for COVID-19 patients.

Information Sources
Two independent reviewers (Bakhtawar Nabiyah [BN] and Usman Muhammad [UM]) carried out a literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for a systematic review. This was followed by an independent evaluation of the extracted data by Khan Malik Uzair (KM). We used electronic databases such as PubMed®, Embase®, Google Scholar, Cochrane Library, and MEDLINE® to look for case reports, case series, observational studies, and randomized control trials conducted between December 2019 and June 2020. Two search themes were used for literature review and were joined using the Boolean operator "AND". For the theme "COVID", we used keywords such as "coronavirus", "COVID-19", and "SARS-COV-2". For the theme "convalescent plasma", we used "convalescent plasma" and "plasma therapy" as the main keywords.

Inclusion Criteria
We included all articles published between December 2019 and June 2020. We included case series, case reports, observational studies, and randomized control trials. We only included fulltext manuscripts available in the English language.

Exclusion Criteria
We excluded review articles, commentaries, notes to editors, and all other articles in which convalescent plasma therapy was not used as a treatment option. We also excluded studies published in languages other than English for which there were no available translated manuscripts.

Data Extraction and Study Selection
BN and UM carried out a rigorous literature review independently. KM then independently evaluated the results from both the researchers. Once the literature review was complete, the researchers compiled and compared their results for any conflicts that were resolved through mutual consultation.
A total of 156 studies were identified following the initial literature review. The reviewers used 17 studies after excluding duplicate studies and after reading through the titles, abstracts, and methodologies of the studies. They used 10 studies for their final analysis.

FIGURE 1: Flowchart describing study identification and selection process
CPT -convalescent plasma therapy
Most of the studies reported patient mortalities on follow-up, and almost all patients were alive at the time of follow-up in some studies [10][11][12][13][15][16]. In the study by Zeng at al., five out of six patients died despite receiving plasma therapy [18]. Similarly, Li et al. did not report any difference in mortalities in the treatment vs. control group on the 28th day of follow-up (15.7% vs. 24.0%; p=0.30) [19]. Most of the studies reported a reduction in viral shedding with the viral load turning negative following plasma therapy [10][11][12][13][14][15][16][18][19].
The duration of discharge varied from as little as four days following CP therapy to as much as 35 days following CP therapy [13,15]. However, Li et al. did not report any difference in the time of discharge following CP in treatment vs. control groups (51.0% in treatment vs 36.0% in the control group on day 28 of follow-up; p=0.120) [19].
Ahn et al. reported a reduction in fever [10], and six studies reported an improvement in the demand for oxygen [10,11,13,[15][16][17]. However, the randomized controlled trials (RCT) by Li et al. did not report any statistically significant difference in clinical improvement in the CP vs. control group on the 28th day of follow-up (51.9% on convalescent plasma group showed clinical improvement vs. 43.1 in the control group; p=0.26) [19].
Ahn et al. reported improvement in pulmonary infiltrates as noted on chest X-ray [10]. Three more studies reported improvement in pulmonary infiltrates on repeat CT scans of the chest [11,15,16]. Table 2 describes the effects of CP therapy on patient outcomes in detail.   ICU -intensive care unit, CRP -C-reactive protein; IL-6 -interleukin 6; CP -convalescent plasma; RT-PCR -reverse transcription polymerase chain reaction; PaO2/FiO2 -partial pressure of oxygen in arterial blood/fraction of inspired oxygen.

Discussion
The randomized evaluation of COVID-19 therapy (RECOVERY) trial is the only large scale trial suggesting dexamethasone as an effective treatment for reducing COVID-19 mortality in critically ill patients [20]. Despite the acceleration of the COVID-19 spread, we are still struggling to find a concrete treatment. Therefore, our systematic review is valuable as it explores the current literature and aims at assessing the efficacy of convalescent plasma therapy for treating COVID-19.
Plasma therapy has long been used for the treatment of infectious diseases such as Ebola, MERS, and SARS [5][6][7][8]. Schoofs et al. suggested that antibodies in convalescent plasma suppresses viremia and tested 3BNC117 antibody for its ability to suppress HIV-1 viremia. 3BNC117 is a potent antibody that binds to the CD4 binding sites on the viral envelope. Even after a single passive administration in animal models, Schoof et al. noted the antibody to suppress HIV-1 viremia [20]. In-vivo studies also suggest that antibodies not only reduce the viral load and reduce the rate of infection of new cells but increase the clearance rate of existing infected cells as well [21].
Our systematic review noted that there was no standardization in terms of the time of administration of plasma therapy. Existing research suggests that SARS viral viremia peaks during the first week of infection and patients usually start to develop primary immune response by the end of the second week of their infection. Therefore, the administration of plasma early during the early stage of the disease might lead to more favorable clinical outcomes [22].
Most of the studies included in our systematic review showed that convalescent plasma therapy leads to an improvement in clinical outcomes. However, the only RCT by Li et al. showed that the patients receiving CP did not differ from control groups on the six-point clinical severity scale on the 28th day of follow-up [19]. Furthermore, almost all patients were discharged in the rest of the studies by the only RCT by Li et al. noted that the mortality did not change significantly between CP and control groups [19].

Limitations
The results of the available research should be interpreted with great caution. The available data suggesting positive effects of CP on patients' clinical symptoms and mortality mainly come from case reports and case series that lack randomization, have a limited data set, and have a high risk of bias. The only available RCT suggests otherwise and does not report any changes in mortality and improvement in clinical symptoms with the use of CP. Furthermore, it must also be noted that the use of convalescent plasma for COVID-19 has significant clinical and practical limitations. As noted in previous studies, patients recovering from SARS infection require at least 12 weeks for their IgG neutralizing antibody titer (NAT) to reach ≥1:160 and only the CP that had a NAT of ≥1:160 reduced mortality in SARS cases [23]. Moreover, limitations such as getting informed consent from the donors and recipients, state of health of donor and recipient, the amount of plasma acquired from one donor, and the mismatch of the number of donors versus the patients who need this therapy may significantly limit the clinical utility of CP for treating COVID-19 cases [24]. Also, adverse reactions such as transfusionrelated anaphylactic reactions, the transmission of infections, and other adverse events such as fever, chills, and lung injury are valid clinical concerns that should not be overlooked [25].

Conclusions
COVID-19 is a global pandemic with no proven treatment. The changing situation is posing a serious therapeutic dilemma for the clinicians and there is an urgent need for therapies that could help reduce patient mortality. Amidst the therapeutic uncertainties, convalescent plasma therapy might have some therapeutic potential. Our systematic review shows that plasma therapy might produce a notable improvement in patient symptoms and clinical and biochemical parameters associated with COVID-19 infection. Although there is some preliminary evidence that plasma therapy might improve patient mortality but this fact needs to be validated through organized RCTs. Despite the potential benefits, plasma therapy has significant limitations such as lack of availability, a dearth of standardization of this treatment method, and paucity of compelling clinical evidence advocating its use. Despite these limitations, the early use of convalescent plasma therapy may be considered as an adjuvant for critically-ill COVID-19 patients.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.