Systematic Literature Review: Could Plasma Convalescent Prevent Death on COVID-19?

systematic


INTRODUCTION
At the end of 2019, the Chinese government announced a novel coronavirus pneumonia (NCP) case caused by the 2019-novel coronavirus (2019-nCoV) (Gil et al., 2020).The name NCP was replaced by COVID-19, while SARS-CoV-2 was replaced 2019-nCoV by the International Committee on Taxonomy of Viruses and WHO (Zhang et al., 2020).Global data on the number of confirmed cases and deaths from COVID-19 have steadily climbed, prompting WHO to declare it a global health emergency (Zhang et al., 2020).New cases of COVID-19 reached 103 million in February 2021, with 2.2 million deaths; these numbers suggest a global decrease trend (Garibaldi et al., 2021).However, British authorities reported infection with a new variant of SARS-CoV-2 in early 2021, which is more virulent, more readily transferred, and reduces the effectiveness of the vaccination used by the United Kingdom government (Hacisuleyman et al., 2021).The SARS-CoV-2 delta variant development was linked to an increase in confirmed cases and deaths in India by the end of March 2021.This variant had been identified in 43 countries spanning six continents (Lopez Bernal et al., 2021).
Numerous of registered clinical studies are currently underway, the vast majority of which are testing antiviral medications, anti-inflammatory or immunosuppressive therapies, and antibody therapy (Mehta et al., 2020;Nasrallah et al., 2020).In a randomized controlled investigation, remdesivir, an RNA polymerase inhibitor, was shown to be effective against SARS-associated coronavirus, and certain COVID-19 recoveries require less time (Beigel et al., 2020;Gil et al., 2020).Remdesivir, an RNA polymerase inhibitor, is an antiretroviral, was proven to be effective against SARS-associated coronavirus in a randomized controlled study, certain COVID-19 recoveries take less time (Beigel et al., 2020).Furthermore, dexamethasone has recently been demonstrated to decrease mortality in oxygen-treated patients, particularly intubated patients (Horby et al., 2021).Efforts to prevent COVID-19 through the development of numerous vaccinations have been made; however, these efforts have not been successful in reducing COVID-19 morbidity and mortality since the emergence of the Delta variant.As a result, although several preventive and therapeutic techniques are being researched, supportive therapy is the main treatment for COVID-19.
Convalescent plasma (CP) therapy has been used to treat patients during previous outbreaks of COVID-19.The administration of CP is still controversial due to the lack of research data that can prove the effectiveness and efficiency of CP in COVID-19 cases.Several studies have shown that CP can improve the outcome of COVID-19 patients, but several studies have stated that there is no significant improvement and differences.Meanwhile, despite the limitations imposed by the Emergency Use Authorization (EUA) law and the ability to be used in clinical trials, various COVID-19 treatment centers use CP in clinical practice (Rejeki et al., 2021).Based on the principle of passive immunization, the administration of convalescent plasma (CP) from donors of COVID-19 patients who have been proclaimed cured is a viable alternative for COVID-19 prevention and therapy because it is widely available.Giving CP containing neutralizing antibodies / NAb will bind to the epitope on the outer surface of the virus particle, preventing virus invasion and replication (Salazar et al., 2020).Another pathway of administering CP is by antibodydependent cellular cytotoxicity and/or phagocytosis (Dai, Gu and Hao, 2020).CP treatment may potentially have immunomodulatory effects by increasing macrophage activation and avoiding systemic hyperinflammation, often known as a "cytokine storm."The results of a serial case study on the administration of CP in COVID-19 demonstrate its prospective role in improving disease manifestations, suppressing viral replication, and elevating levels of antibodies (Mair-Jenkins et al., 2015;Ingraham et al., 2020).
However, the previous studies have various weaknesses and limitations to be generalized in the population and become a reference for establishing CP as standard therapy for COVID-19.Related to the lack of data, WHO opens opportunities for researchers to explore CP associated with the method of administration, dosage, donor requirements, conditions of patients who meet the requirements for administration, and side effects.These results will be the basis for researchers to conduct clinical trials and ultimately produce a standard guideline used by medical personnel in dealing with COVID-19 cases.Based on these phenomena and conditions, The authors would like to undertake a systematic literature study on the administration of CP to COVID-19 patients.

METHODS
This systematic review implemented the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocols (Peng, Rhind and Beckett, 2021).PRISMA diagrams help authors develop structured and transparent articles in systematic review articles and meta-analyses (Permana et al., 2020).

Searching Strategy
The authors selected articles published between January 2020 until March 2021 using several keywords: COVID-19 OR SARS-CoV-2 AND convalescent plasma from relevant databases such as PubMed, Google Scholar, and Science Direct.All papers that covered the administration of convalescent plasma or CP in the treatment of COVID-19 were eligible, including experimental (true experimental, quasi-experimental, preexperimental study), observational (cohort, casecontrol/retrospective study, and cross-sectional study), and full-text articles.This study's inclusion criteria: 1.

Article Screening
The screening procedure begins with a thorough assessment of article titles to eliminate article duplication.Then we evaluated the title and abstract to see if they were related to the study's goals; if they were, the complete article was examined by two reviewers separately.The reviewers reached a consensus with the other reviewers to resolve rating disputes.The data extraction procedure, covered in another subchapter, employs the same method and strategy (Peng, Rhind and Beckett, 2021).

Data Extraction and Study's Critical Appraisal
The authors compiled the data extraction for the selected articles by creating a table that included the author's name, country of origin, research period, population or research respondents, CP dose and time of administration, use of other drugs, respondent's condition before CP administration, results, and side effects of CP administration.
The Effective Public Health Practice Project (EPHPP) equipment tools are used by researchers to critically evaluate each quantitative research publication (experimental study, quasi-experimental study, and observational study) that meets the inclusion requirements.Study design, sample selection, confounder identification and treatment, outcomes blinding between participants and assessors, data collecting procedures and analysis, withdrawals, and dropouts, are all areas where EPHPP is used to evaluate the quality of a study in three categories: strong, moderate, and weak.The authors used the six-component ratings to get the overall rating of each study.A good rating was awarded to those with no weak evaluations and at least four strong reviews.Moderate was defined as having four or fewer strong reviews and one or fewer weak reviews.Those who obtained two or more poor reviews were categorized as weak (Peng, Rhind and Beckett, 2021).
The assessor team will review the results of the EPHPP assessment on all papers to determine the significant elements that will serve as a reference for evaluating the usage of articles in this literature study (Long, French and Brooks, 2020;Peng, Rhind and Beckett, 2021).

RESULT Searching Result
Researchers used three primary search platforms in this study: PubMed, Google Scholar, and Science Direct., to find 1934 publications using the search methods stated before.The first phase in the selection process filtered duplicate articles and full-text documents that are not accessed and purchased for then the authors acquired 1423 documents.We made the second step selection by evaluating the relevancy of the article's title and abstract, selecting 350 documents.The third step evaluation used inclusion criteria, and there were 16 document articles.The final step in the selection process was the assessment of articles using EPHPP equipment tools and discussion among the assessor members, resulting in the acquisition of 10 article papers.This study's PRISMA flow diagram is shown below:

Critical Appraisal Result
The initial critical appraisal is performed independently by two reviewers.A discussion procedure is followed if there are discrepancies in the assessment to create a final critical appraisal result.The reviewers examined the manuscript on six components: probability sampling, design of the study, confounding variables, blinded, data gathering, and dropout or withdrawal.The following table shows the outcomes of the EPHPP appraisal criticism:

Articles Included in the Systematic Review
This systematic review includes original research consisting of clinical trial studies (preexperimental, non-randomized control trials, and randomized control trials) and analytical observational studies (cohort/prospective studies and case-control/retrospective studies).One article features a clinical trial with a pre-experimental/ pilot research design.One study with a nonrandomized control trial design; 2 research with a randomized controlled trial design; There are three cohort/prospective studies and two retrospective/ case-control studies.Based on the critical appraisal evaluation of articles that meet the inclusion criteria, there are ten articles presented in the table below:

DISCUSSION
According to the findings of a systematic literature review, eight study articles stated that CP transfusion provided benefits for mild, moderate, severe, and persistent cases of COVID-19 (Maor et al., 2020;Alsharidah et al., 2021).However, according to two studies, CP administration did not result in significant clinical improvement (Li et al., 2020;Omrani et al., 2021).delivering CP to COVID-19 patients, the global results in eight articles reported that significantly reduce mortality, length of hospital stay, clinical manifestations, and viral load.The success in these studies could be associated with characteristics of study participants (age and comorbidity disease), the initial condition of study subjects (using supplemental oxygen or not, and the type of oxygen support), disease severity (mild, moderate, severe, or critical illness), the content of transfused antibody levels, and time of CP administration after first onset or hospitalization.
Neutralizing antibodies play a critical function in eliminating viruses and preventing viral illness.The success of this medication was linked to the concentration of neutralizing antibodies in CP.Other antibodies, including IgG and IgM, are found in plasma, but they do not affect the virus's replication.Plasma-transferred IgG neutralizes cytokines like IL-6 and TNF, suppressing the inflammatory response.After receiving CP, participants' IgG and IgM titers grew timedependent.By interacting with viruses, antibodies could decrease virus entrance into cells and boost viral clearance via antibody-dependent phagocytosis or antibody-dependent cellular toxicity.In excessively inflammatory conditions, passive immunity provided by COVID-19 CP may minimize the inflammatory cascade triggered by pathogenic antibodies, as well as the cellular damage generated by complement cascade activation (Rojas et al., 2020;Bloch, 2021;Franchini, Glingani and Liumbruno, 2021).Even though CP has several action methods, it is most effective because it contains anti-SARS-CoV-2 antibodies, which block the virus from entering cells and multiplying.CP's antiviral action is thus proportional to the quantity of antibodies present.The more neutralizing antibodies in the plasma, the better it stops viral reproduction (Franchini and Liumbruno, 2021).
COVID-19 has a poor prognosis due to several factors, including being over the age of 65 years; complaining of shortness of breath; having comorbidities (heart disease, respiratory problems, and diabetes); a decreased lymphocyte count and an increased neutrophil/lymphocyte ratio; elevated LDH, AST, bilirubin procalcitonin; and elevated inflammatory markers (CRP, IL-6, serum IL-6); and the presence of endothelial abnormality and angiogenesis (Zhou et al., 2021).The first consideration is the characteristics of the study's respondents, such as their age, comorbidities, degree of illness, and oxygen supplementation.The respondents' ages ranged from 18 to 80 years, with median values ranging from 52.5 to 77 years.Two articles used respondents' median age of 70 without mentioned about comorbidity (Li et al., 2020) and 77.2 years with comorbidities in all respondents (Libster et al., 2021).Four articles mentioned that almost all participants have at least one comorbidity.Three articles didn't mention comorbidity.Two articles mentioned that respondents' conditions varied; some had comorbidities, while others did not (using the propensity score-matched method).
Antibody titer level is also thought to influence COVID-19 clinical progress.The dose of CP administration varied across the ten articles in this study, with three articles mentioning the administration of 400 ml (administered a single dose of 400 ml or double dose of 200 ml for a total of 400 ml); one article giving one dose of 300 ml, one article using a double dose of 250 ml; two studies using a single dose of 250 ml; and one study using a triple dose of 3 mL/BW.Based on these dosages, the CP dose varies from at least 200 ml to the maximum of 400 -500 ml CP.Median IgG titers administered to patients or respondents vary between 1:160 until 1: 1350 (three articles used 1:160; two articles apply 1: 640; two articles apply 1:1350; only one article applies 1: 1000; one article didn't mention the titter of IgG on CP donors).The prior study of Maor et al. with multivariate analysis stated that administration of CP with antibody titer factors had a dominant influence among other variables.Antibody titers above four can significantly improve all conditions of COVID-19 patients (marked by staying alive, not using mechanical ventilation, symptoms being mild or moderate during the 14-day observation period) (Maor et al., 2020).Administration of CP with a high titer of anti-spike protein receptor-binding domain more than or equal to 1: 1350 significantly suppressed mortality throughout 28 days of observation (Salazar, Paul A. Christensen, Graviss, et al., 2020).The FDA has also determined that the standard neutralizing antibody titer for CP donors for COVID-19 was ≥ 1:160 (Barone and DeSimone, 2020).Maor et al.'s research demonstrated that the improvement in the result is related to the Ab titer administered to the patient (dose-dependent) (Maor et al., 2020).These research's results suggested that the neutralizing antibodies were a consequence of a short-term humoral immune response, and hence plasma of recently recovered individuals should be more beneficial (Duan, Liu, C. Li, et al., 2020).
Another element influencing the efficacy of CP therapy is the time of administration.The timeline for delivering CP between ten articles differs from one another, based on the median value of the period between the first onset of illness and the administration of CP, the shortest median value was 72 hours, and the longest was 45 days.If the administration is based on the hospital admission range to CP administration, the fastest range was 24 hours, and the longest range was 72 hours following hospital admission.CP administration is carried out within 72 hours (using Youden index analysis revealed that the cut point of transfusion is 44 hours) after being hospitalized, demonstrating a significant improvement in outcomes (Salazar, Paul A Christensen, Graviss, et al., 2020).The severity of illness impacted the effectiveness of CP therapy (Tirnea et al., 2021); mild and moderate COVID-19 patients improved faster than severe COVID-19 patients, and severe COVID-19 patients had a better outcome than lifethreatening COVID-19 patients.Another study stated that giving CP to critically ill patients of COVID-19 did not significantly reduce the mortality rate (Luchsinger et al., 2020).
Two articles studies produced contradictory results that the administration of CP did not significantly improve clinical outcomes, mortality, or length of hospital stay, but it has a potent antiviral effect (Li et al., 2020;Omrani et al., 2021).Several factors could alter these outcomes, including a limited sample size, and the researchers ended the study observation prematurely.The limited-time of the trial follow-up may have prevented observing clinical outcomes in patients with severe disorders, particularly life-threatening COVID-19, as they may take longer to show significant improvement.The trial was probably underpowered to find a clinically significant advantage of convalescent plasma treatment.Another issue that influenced the results was the length of time between the onset of the first symptoms and the randomization process and delivery of CP in the research, which made it difficult to determine whether the improvement was due to CP or the administration of other medications.Patient clinical improvement can also be influenced by clinician decisions and other nonstandardized therapies, impacting patient outcomes (Li et al., 2020;Omrani et al., 2021).In the research of Omrani et al. using respondents who use mechanical ventilation (86.2%) and have a chronic disease, the median age of respondents is 53.5 years and has a BMI above the normal standard of 27.4, with a neutralizing antibody titer with a median value of 1:160.The characteristics of respondents with severe-life threatening COVID-19 and the administration of CP with a low antibody titer could be factors that caused no significant difference after CP administration.In the study of Li et al., factors such as a short observation time, a small sample size, and a long delay between CP administration and the beginning of symptoms all contributed to no significant differences in the respondents' results.On the other hand, CP therapy decreased viral load significantly (negative RT PCR results) at 24, 48, and 72 hours following CP administration (Li et al., 2020).
In the study conducted by Maor et al. and Wu et al. using a CP dose with the same median neutralizing antibody titer (median 1: 160) (Maor et al., 2020;Wu et al., 2020) (Maor et al., 2020).
These systematic reviews reveal that the author detected no serious side effects in CP administration.Four studies reported side effects with CP administration, while the other six studies did not identify any negative effects.In one study, at least only one respondent and a maximum of seven respondents suffered side effects from CP treatment.Although CP is beneficial, its administration carries several concerns, including spreading a pathogenic microorganism and extensive lung injury in critically ill patients.Another uncommon concern is antibodydependent infection enhancement, occurring at sub-neutralizing concentrations and inhibiting innate antiviral mechanisms, allowing logarithmic intracellular virus development (Duan, Liu, C. Li, et al., 2020).CP transfusion-related adverse reactions also induce febrile, allergic, dyspnea, hypotensive, hemolytic event, septic reactions, and circulatory overload (Li et al., 2020).The clinical manifestations among the ten respondents who suffered side effects such as rash or red patches on the skin in seven respondents; mild fever in one respondent; and shortness of breath in two respondents due to an allergic reaction and fluid overload.All negative reaction after CP administration treatable and does not lead death.Overall, this review article found no reports on pulmonary harm or infection enhancement The current systematic literature study had certain limitations.First, other than the CP transfusion, the patients got conventional care in nine articles.Despite the uncertainty about the medications' efficacy, all patients got antiviral treatment.As a result, the idea that these antiviral medications could help patients' recovery or synergize with CP's therapeutic impact cannot be ruled out.Furthermore, some patients were given corticosteroid medication, which may interfere with immune response and cause virus clearance to be delayed.Only one article mentioned that the control group only received a placebo, and the treatment group received CP administration only, the procedure can be applied because all selected respondents have mild COVID-19 symptoms (Libster et al., 2021).The research by Libster et al. was the only study that apply double blinds in its research design, whereas other studies utilized open labels since the baseline conditions of respondents used ranged from moderate to critical disease, making double blinds challenging to apply.The diversity of doses (the volume, the administration procedure, and antibody titer) of CP between studies is additionally a drawback during this study, so an efficient and efficient standardized CP dose is required in every case of COVID-19 (a mild, moderate, severe, persistent, and critical illness).

CONCLUSION
Based on the systematic review results in this study, we can conclude that CP administration has benefits in mild, moderate, severe, and persistent COVID-19 patient outcomes, including decreased viral load, length of hospitalization, and use of oxygen supplements, markers of inflammation, and mortality.However, its use in terminal/critical phase cases does not show significant results, so further studies are needed.The positive response to CP administration is directly proportional to the patient's baseline condition before CP administration, the antibody titer contained in the plasma, the distance between the administration and the onset of symptoms, or the beginning of hospitalization (the shorter, better the outcome).CP administration should be done carefully and with the proper procedure, and monitoring should be done to ensure that there are no negative side effects for the patient.The existence of differences in CP doses, antibody titers, and the applied transfusion procedures requires a consensus on the standard of administering CP in various COVID-19 cases.

Figure
Figure 1.PRISMA Diagram Flow

Table 2 .
Description of Articles(Continue)

Table 2 .
Description of Articles(Continue)

Table 2 .
Description of Articles(Continue) as Omrani et al. but the results of Maor et al. and Wu et al. showed significant improvement.These different outcomes may be due to the patients' different general conditions (severe and life-threatening symptoms did not dominate the respondent's condition).Maor et al. used two different titer antibodies and found that administering IgG titers above 4 resulted in considerably better outcomes than administering IgG titers below 4, and CP should be transfused ten days after the onset of first symptoms