Safety of convalescent plasma to treat COVID-19: Systematic review

The Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is a novel strain of coronavirus that was fi rst detected in the city of Wuhan, China [1,2]. It was named as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [3,4]. The outbreak SARS-CoV-2 was named as a pandemic disease by WHO on March 11, 2020. Currently, the disease was reported in more than 204 countries. As of April 10, 2020, a total of 1,605,729 confi rmed cases and 95,766 deaths had been reported worldwide [5]. Currently, due to an alarmingly spreading of the virus worldwide, the incidence and deaths are increasing. However several efforts made to treat COVID-19, there are no approved specifi c antiviral agents targeting the novel virus, and no vaccines have Abstract

been fully tested for safety and effi cacy while some drugs are still under investigation.
Convalescent Plasma (CP) therapy is an immunotherapy that has been applied to the prevention and treatment of many infectious diseases for more than one century. So, the use of convalescent plasma is not a new method rather it was used for poliomyelitis [6], measles [7], mumps [8], and infl uenza [9], Severe Acute Respiratory Syndrome (SARS), several hemorrhagic fevers such as Ebola, and other viral infections treatments [10]. Even more recently during H1N1 infl uenza virus pandemics in 2009-2010, convalescent serum antibody preparations obtained by apheresis were used to treat individuals with severe H1N1 infection requiring intensive care [11]. This was the baseline lesson for convalescent plasma to treat COVID-19.
Plasma from people who have recovered from COVID-19 may contain antibodies to the virus that causes the disease and might be effective against the infection [12]. Food and Drug Administration (FDA) has also approved the emergency use of investigational COVID-19 convalescent plasma to treat severely ill COVID-19 patients [12]. The general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease [13]. When used for therapy, the antibody is most effective when administered shortly after the onset of symptoms [14]. So it is required to evaluate the effectiveness of convalescent plasma therapy. So this study planned to conduct systematic analysis of literatures on Convalescent plasma treatment in severely ill COVID-19 patients.

Objective
The main aim of this study is to systematically review the safety of convalescent plasma to treat COVID-19.

Types of participants
The study population of interest was human subjects of any age or sexes who were hospitalized or were in ICU with COVID-19 infection. The intervention of interest was convalescent plasma transfusion. Outcomes of disease progress after Convalescent therapy that was extracted from included studies was used predict the clinical effectiveness of therapy.

Search strategy
We searched literatures published in English from December 20 /2019 to April 10/2020 on electronic data bases PubMed, Cochrane library, EMBASE, Escopus, Hinari, CINAHL, Open Access Journals (OAJ) and Google scholar, for studies conducted trial of convalescent plasma treatment of COVID-19. We simultaneously searched reference lists of all recovered articles for potentially eligible studies. All identified keywords, and mesh terms were combined using the "OR" operator and "AND" operator for searching literatures. Keywords used in the search included were those that explain infection of severe acute respiratory syndrome 2 (SARS CoV 2) (i.e., COVID-19, severe acute respiratory syndrome 2, SARS CoV 2, novel corona virus). Full-text articles were retrieved after review of the title and abstract.

Inclusion and exclusion criteria
Inclusion criteria: All studies published in English from December 20 /2019 to April 10/2020 were included in the review. There was no restriction to study design made.

Data extraction
Data were extracted from included study by two investigator (EA, and KD) using a standardized data extraction form. Then the extracted data were merged together for systematic analysis. Primary outcomes extracted from each study were, the citation details, sample size, number of cases, year of publication, location of study, method of identifi cation of COVID-19.
Secondary outcomes for this study included clinical data including the stage of disease, treatment received, co-morbidities, co-infection, and dates of recovery after convalescent plasma transfusion, progress opacities in the lung.

Statistical analysis
The R software was used to conduct systematic analysis, frequency, mean, standard deviation, and chi-square test.

Identifi ed studies
Following the initial search of data bases four eligible studies have been accessed and were reviewed by the authors. Following methodological quality assessment, all 4 articles were eligible [15][16][17][18] and included in this systematic review and meta-analysis. In the included studies the total of 21 patients infected with COVID-19 were obtained convalescent plasma therapy. All 4 papers were published in English.

Characteristics of included study
Of the 4 studies included in the Systematic review and Meta-analysis, all studies reported the detail case report of COVID-19 patients. All patients were severely ill and were put to Intensive Care Unit (ICU) ( Table 1). All 4 studies included in the systematic review and Meta-analysis, infections of COVID-19 were examined using PCR which is of high quality diagnostic method. Most of the studies conducted are of higher quality because of method of diagnosis using highly sensitive and specifi c PCR techniques.

Systematic analysis outcome
The average age of the participants in the included was 55.7 with standard deviation of 13.9. From a total of 21 patients 12 of them were male. The average days between admissions to start of convalescent plasma therapy was 10 ± 4.5 days and the average days of recovery or test negative for CIVID-19 PCR test after convalescent plasma therapy was 9.6 days (95% CI 2-30 days). About 43% (9/21) had history of comorbidity and about 24% (5/21) have co-infections, while 19% (4/21) patients are have both history of co-existing disease and co-infections ( Figure 1).

Common sign and symptoms and complications of in patients of COVID-19
In this systematic review the most common symptoms at disease onset were fever, cough with clear sputum, and shortness of breath, while less commonly observed sign and symptoms were; chest pain, sore throat, myalgia and arthralgia ( Figure 2). Majority of complications observed in the study participants were severe acute respiratory distress (85.7%), pneumorrhagia, cystorrhagia and gastrointestinal bleeding, myocardial damage, and cardiac dysfunction.

Reduction of pulmonary lesions on chest X ray examinations
According to chest CTs, all patients showed different degrees of absorption of pulmonary lesions after convalescent plasma transfusion. With average range of 1-10 days after convalescent plasma therapy, a chest X-ray revealed further resolution of lung infi ltrates which is from partial to persistent absorption of consolidation or absorption of interstitial pneumonia was observed.

Convalescent plasma adverse effects
None of the studies analyzed in this systematic review reported serious adverse events. During convalescent plasma transfusion to severely ill COVID-19 patients, no serious adverse effects were reported. Only one patient (1/21) showed minor facial red spot. As a limitation there is no well-designed study conducted to see effectiveness of convalescent plasma transfusion therapy we included systematic analysis of detail case reports of patients who have received convalescent plasma transfusion therapy for COVID-19 and the clinical outcome after transfusion. The other limitation is that this study is a systematic review of case series which does not have control.

Conclusions and recommendation
This study indicated that convalescent plasma transfusion might be a potential treatment for critically ill patients infected with COVID-19 and it can be helpful to reduce the risk of mortality of critically ill patients. We demonstrated no serious adverse reactions associated with the transfusion of convalescent plasma. This review suggests that convalescent plasma from patients who have recovered from COVID-19 infection might be an option to treat patients without causing severe adverse effects. Adequately assessing safety and effi cacy of convalescent plasma therapy is essential. So, this study recommends that safety and effi cacy of convalescent plasma transfusion in SARS-CoV-2-infected patients should be studied using well-designed clinical trial. The good outcome observed in critically ill patients; push us to recommend well organized trial of convalescent plasma transfusion in early infection before get in to critical illness stage.

Availability of data and materials
All the datasets generated and analyzed during the review are included in this article.