COVID-19 convalescent plasma: Mechanisms of action and rationale for use: A narrative review

The use of convalescent plasma (CP) transfusions for patients with coronavirus disease 2019 (COVID-19) has gained great interest during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. This review aims at summarizing the literature on the potential mechanisms of action of COVID-19 CP (CCP) and the rationale for use. A narrative review of the literature was conducted using PubMed, Google Scholar, and the Cochrane Database through October 2020. The rationale of CCP deployment was based on historical use in other outbreaks and pandemics and the emergent need at the time of lack of proven therapies and vaccines. There are many proposed mechanisms of action including direct neutralization and suppression of viremia, antibody-dependent cellular cytotoxicity, modification of the inflammatory response, restoration of the coagulation factors, immunomodulation of the hypercoagulable state and the potential role of ABO naturally occurring iso-agglutinins. Many donor, product, and patient factors can impact the response to CCP, such as antibody titer in the CCP product, CCP dose, frequency of administration, the severity of underlying illness, and the timing of administration from time of disease onset. Based on current evidence, CCP appears to be safe. However, it remains unknown whether it impacts the improvement of clinical symptoms, time to death, and all-cause mortality. In conclusion, the use of CCP offers quick access as an empirical therapy when specific therapies are not available or under development. Ongoing clinical trials are expected to add to the breadth of knowledge on the safety and efficacy of CCP use in patients with COVID-19.Copyright © 2021 AME Publishing Company.

Factors influencing plasma donation behavior of COVID-19 recovered patients in Bangladesh: A pilot study.

Background and Aim: The COVID-19 pandemic has plagued our lives for more than 2 years, and the preference for convalescent plasma (CP) as a life-saving treatment since CP has proven as a potential therapeutic option for acute COVID-19 patients who were suffering from severe disease. It is important to identify which factors are associated with plasma donation. Therefore, this study aimed to assess the associated factors for CP donation to COVID-19 patients. Methods: A cross-sectional study was conducted online from December 21, 2021 to February 15, 2022 to identify different socio-demographic factors and knowledge related to CP donation. People who recovered from the COVID-19 infections and those who are willing to participate were included in the study. A total of 60 participants were included in the study. The data were analyzed using descriptive statistics, correlation matrix, and factor analysis. Results: The analysis results confirm that 41.67% (n = 25) of the participants aged 26-30 years; among the recovered patients, only about 23% (n = 14) of the participants donated plasma. Though 97% (n = 58) of the participants agreed to donate plasma when it will be needed, however, when someone asked to donate plasma then 76.67% (n = 46) of the patients declined it. Findings depict that gender had a weak positive relationship with ever decline in plasma donation at 5% level of significance and the age of the participants inversely related to plasma donation. Conclusion: Almost all the recovered participants were willing to donate plasma, however, due to a lack of knowledge and misconception, relatively few people actually did. This study reemphasizes the importance of health education to overcome the misconception about plasma donation, which is crucial for the treatment of COVID-19 infection.

Application of convalescent plasma from patients with COVID-19 treatment of Coronavirus Disease 2019

The pandemic of Coronavirus Disease 2019 (COVID-19) in 2020 has posed a great challenge to global public health resources. Since there are no specific antiviral drugs at present, convalescent plasma (CP) from patients who have recovered from COVID-19 is one of the specific biologic therapies being considered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Preliminary studies have shown that the CP containing high titer neutralizing antibody against SARS-CoV-2 is safe and promising in blocking viral replication and improving patients'clinical symptoms. In this article, we briefly summarize the application of CP in treatment of COVID-19, and explores possible action mechanism, relevant clinical research and possible influencing factors of clinical effect, which may be helpful to the rational application of CP in treatment of COVID-19. Copyright © 2021 Changchun Institute of Biological Products. All rights reserved.

The application of COVID-19 convalescent plasma in clinical treatment

The severe acute respiratory syndrome (SARS) coronavirus disease known as coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 has caused a global pandemic since late 2019. As of 7 February 2020, more than 106 million people have been infected, and approximately 2,317 thousand people have died due to SARS-CoV-2 across 200 countries. Unfortunately, to date, many aspects of pathogenesis, infection, clinical manifestations and treatment methods remain unclear, no specific antiviral drugs or vaccines have been reported for patients with COVID-19 infection. Most patients with severe infections require supportive organ function therapies in the intensive care unit (ICU). Passive antibody therapies such as convalescent plasma (CP) therapy have been proved to be effective in the treatment of many infectious diseases such as SARS and Middle East respiratory syndrome (MERS), which are also assumed as a promising strategy in the treatment of critically ill COVID-19 patients. With the increasing investigation, the objective understanding of COVID-19 prevention, treatment and comorbid disease is beneficial for the application of the strategy applied in the clinical trials. Herein, we briefly discuss the current therapeutic approaches for patients with COVID-19, especially focuses on the application of therapeutic plasma exchange (TPE) for selected critically ill patients, aiming to provide some guidance for the treatment of severe COVID-19. © Annals of Blood. All rights reserved.

Usefulness of convalescent plasma transfusion for the treatment of severely ill COVID-19 patients in Pakistan.

BACKGROUND: Convalescent plasma(CP) was utilized as potential therapy during COVID-19 pandemic in Pakistan. The study aimed at appraisal of CP transfusion safety and usefulness in COVID pneumonia. METHODS: Single arm, MEURI study design of non-randomized open label trial was conducted in five centers. Patients werecategorized as moderately severe, severe, and critical. The primary endpoint was a) improvement in clinical status and change in category of disease severity; secondary endpoint was b) CP ability to halt disease progression to invasive ventilation. CP transfused to hospitalized patients. Statistical tests including median (interquartile ranges), Mann-Whitney U test, Fisher's exact test using SPSS ver. 23, ANOVA and Chi-square test were applied for the analysis of results parameters before and after CP treatment. SOFA score was applied for multiorgan failure in severe and critical cases. RESULTS: A total of 50 adult patients; median age 58.5 years (range: 29-92 years) received CP with infusion titers; median 1:320 U/mL (Interquartile range 1:80-1:320) between April 4 to May 5, 2020. The median time from onset of symptoms to enrollment in trial was 3 to 7 days with shortness of breath and lung infiltration as severity criterion. In 35 (70%) recipients, oxygen saturation improved from 80 to 95% within 72h, with resolution of lung infiltrates. Primary endpoint was achieved in 44 (88%) recipients whereas secondary endpoint was achieved in 42 (84%). No patient experienced severe adverse events. A high SOFA score (> 7) correlated with deaths in severe and critical patients. Eight (16%) patients expired due to comorbidities; cardiac arrest in 2 (4%), multiorgan failure secondary to cytokine storm in 5 (10%) and ventilator associated complications in 1 (2%). CONCLUSION: CP transfusion can be used as a safe and useful treatment in moderately severe and severe patients. TRIAL REGISTRATION: The trial registration number is NCT04352751  ( https://www.irct.ir/search/result?query=IRCT20200414047072N1 ). Trial Registration date is 28th April 2020.

Convalescent Plasma Treatment in Patients with Covid-19: A Systematic Review and Meta-Analysis.

Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17th, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021284861).

Recent advances in passive immunotherapies for COVID-19: The Evidence-Based approaches and clinical trials.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing a global pandemic called COVID-19. Currently, there is no definitive treatment for this emerging disease. Global efforts resulted in developing multiple platforms of COVID-19 vaccines, but their efficacy in humans should be wholly investigated in the long-term clinical and epidemiological follow-ups. Despite the international efforts, COVID-19 vaccination accompanies challenges, including financial and political obstacles, serious adverse effects (AEs), the impossibility of using vaccines in certain groups of people in the community, and viral evasion due to emerging novel variants of SARS-CoV-2 in many countries. For these reasons, passive immunotherapy has been considered a complementary remedy and a promising way to manage COVID-19. These approaches arebased on reduced inflammation due to inhibiting cytokine storm phenomena, immunomodulation,preventing acute respiratory distress syndrome (ARDS), viral neutralization, anddecreased viral load. This article highlights passive immunotherapy and immunomodulation approaches in managing and treating COVID-19 patients and discusses relevant clinical trials (CTs).

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity.

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.

COVID-19 Pandemic and the Convalescent Plasma Therapy: Possible Benefits and Risks.

PURPOSE OF REVIEW: COVID-19 pandemic has been the major threat to the global public health for a year (last of 2019-till date); and unfortunately, there is still as no specific antiviral agent which can be effectively used against this disease curation. Present review focused on the application of the convalescent plasma (CP) therapy as a quick remediation of the disease severity. RECENT FINDINGS: While several drugs have been repurposed based on a number of completed clinical trials together with a huge ongoing effort to develop appropriate vaccine against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the therapeutic approach of the CP therapy appears to be one of the effective methods to rescue the severely affected COVID-19 patients. Such a therapy based on passive immunity evolved from the SARS-CoV-2-infected patients who have fully recovered from COVID-19; and hence these individuals are quite likely to possess high titers of the SARS-CoV-2-neutralizing immunoglobulins (antibodies). However, there are some risks such therapy, and its effectivity also appeared doubtful in some cases. Thus, the current review discussed the issues raised by the administration of such plasma into the SARS-CoV-2-infected individuals. SUMMARY: Application of CP therapy has been conducted since long time; and for the mitigation of COVID-19 severity, such pharmaceutical strategy is also being employed in spite of several risks which actually can be monitored as well as optimized in order to combat the SARS-CoV-2 infection.

Case Report: Convalescent Plasma Therapy Induced Anti-SARS-CoV-2 T Cell Expansion, NK Cell Maturation and Virus Clearance in a B Cell Deficient Patient After CD19 CAR T Cell Therapy.

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convalescent plasma therapy natural killer cells matured and virus-specific T cells expanded, presumably allowing virus clearance and recovery from the disease. Our findings, thus, suggest that convalescent plasma therapy can activate cellular immune responses to clear SARS-CoV-2 infections. If confirmed in larger clinical studies, these data could be of general importance for the treatment of COVID-19 patients.

Combination of Angiotensin (1-7) Agonists and Convalescent Plasma as a New Strategy to Overcome Angiotensin Converting Enzyme 2 (ACE2) Inhibition for the Treatment of COVID-19.

Coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most concerning health problem worldwide. SARS-CoV-2 infects cells by binding to angiotensin-converting enzyme 2 (ACE2). It is believed that the differential response to SARS-CoV-2 is correlated with the differential expression of ACE2. Several reports proposed the use of ACE2 pharmacological inhibitors and ACE2 antibodies to block viral entry. However, ACE2 inhibition is associated with lung and cardiovascular pathology and would probably increase the pathogenesis of COVID-19. Therefore, utilizing ACE2 soluble analogs to block viral entry while rescuing ACE2 activity has been proposed. Despite their protective effects, such analogs can form a circulating reservoir of the virus, thus accelerating its spread in the body. Levels of ACE2 are reduced following viral infection, possibly due to increased viral entry and lysis of ACE2 positive cells. Downregulation of ACE2/Ang (1-7) axis is associated with Ang II upregulation. Of note, while Ang (1-7) exerts protective effects on the lung and cardiovasculature, Ang II elicits pro-inflammatory and pro-fibrotic detrimental effects by binding to the angiotensin type 1 receptor (AT1R). Indeed, AT1R blockers (ARBs) can alleviate the harmful effects associated with Ang II upregulation while increasing ACE2 expression and thus the risk of viral infection. Therefore, Ang (1-7) agonists seem to be a better treatment option. Another approach is the transfusion of convalescent plasma from recovered patients with deteriorated symptoms. Indeed, this appears to be promising due to the neutralizing capacity of anti-COVID-19 antibodies. In light of these considerations, we encourage the adoption of Ang (1-7) agonists and convalescent plasma conjugated therapy for the treatment of COVID-19 patients. This therapeutic regimen is expected to be a safer choice since it possesses the proven ability to neutralize the virus while ensuring lung and cardiovascular protection through modulation of the inflammatory response.

Evaluation of convalescent plasma versus standard of care for the treatment of COVID-19 in hospitalized patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial.

BACKGROUND: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. METHODS/DESIGN: The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to category 5, 6, or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. DISCUSSION: This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04345523 . Registered on 30 March, 2020. First posted date: April 14, 2020.

A review of COVID-19 convalescent plasma use in COVID-19 with focus on proof of efficacy.

Convalescent plasma (CP) therapy is rapidly becoming an established consideration in the treatment of COVID-19 patients though there is a need to critically review this area for proof of efficacy. Neutralizing antibodies (NAb) present in CP generated in response to SARS-CoV-2 infection directed against the receptor-binding domain (RBD) of the spike protein are considered to play main role in viral clearance. CP infusion may also help in the modulation of immune response by its immunomodulatory effect. The FDA allows for administration of CP to COVID-19 patients. The present published literature in COVID-19 is limited to case series and randomised controlled trial where plasma therapy was used in moderate, severe and critically ill patients. Though multiple uncertainties exist regarding to its efficacy, appropriate donor selection and NAb titres, the efficacy data of CP use inCOVID-19 is limited having shown hope with early and severe to critically ill COVID-19 patients.

Emergence of ancient convalescent plasma (CP) therapy: To manage COVID-19 pandemic.

Since December 2019, the human populations of the 195 global countries continue experiencing grave health and life threats due to the current COVID-19 pandemic. As a result of the novelty of the pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at present there is lack of preventive as well as therapeutic options for treating and managing the infection. The use of ancient immunotherapeutic technique - the convalescent plasma (CP) therapy, may act as an immediate and available option to control the COVID-19 pandemic. This review provides a concept and understanding on the CP therapy, its potential to control SARS-CoV-2 pandemic. The CP therapy might act as an immediate saviour for society from the virus. Although the CP therapy has exert affirmative result against COVID-19 it has not been recommended for long time use in COVID-19 and this review gives support for its possible application.

Convalescent plasma may be a possible treatment for COVID-19: A systematic review.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has spread globally. Therapeutic options including antivirals, anti-inflammatory compounds, and vaccines are still under study. Convalescent plasma(CP) immunotherapy was an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. In the epidemic of COVID-19, a large number of literatures reported the application of CP. However, there is controversy over the efficacy of CP therapy for COVID-19. This systematic review was designed to evaluate the existing evidence and experience related to CP immunotherapy for COVID-19. METHODS: A literature search was conducted on Pubmed, Cochrane Library, Clinical Key, Wanfang Database; China National Knowledge Infrastructure(CNKI) were used to search for the proper keywords such as SARS-CoV-2, COVID-19, plasma, serum, immunoglobulins, blood transfusion, convalescent, novel coronavirus, immune and the related words for publications published until 15.10.2020. Other available resources were also used to identify relevant articles. The present systematic review was performed based on PRISMA protocol. Data extraction and risk of bias assessments were performed by two reviewers. RESULTS: Based on the inclusions and exclusions criteria, 45 articles were included in the final review. First, meta-analysis results of RCTs showed that, there were no statistically significant differences between CP transfusion and the control group in terms of reducing mortality(OR 0.79, 95% CI 0.52-1.19, I2 = 28%) and improving clinical symptoms(OR 1.21, 95%CI 0.68-2.16; I2 = 0%). The results of controlled NRSIs showed that CP therapy may reduce mortality in COVID-19 patients(RR 0.59, 95% CI 0.53-0.66, I2 = 0%). Second, limited safety data suggested that CP is a well-tolerated therapy with a low incidence of adverse events. But, due to lack of safety data for the control group, it is really not easy to determine whether CP transfusion has an impact on moderate to serious AEs. Thirdly, for children, pregnant, elderly, tumor and immunocompromised patients, CP may be a well-tolerated therapy, if the disease cannot be controlled and continues to progress. Studies were commonly of low or very low quality. CONCLUSIONS: Although the results of limited RCTs showed that CP cannot significantly reduce mortality, some non-RCTs and case report(series) have found that CP may help patients improve clinical symptoms, clear the virus, and reduce mortality, especially for patients with COVID-19 within ten days of illness. We speculate that CP may be a possible treatment option. High-quality studies are needed for establishing stronger quality of evidence and pharmacists should also be actively involved in the CP treatment process and provide close pharmaceutical care.

Progress in Studies on Structural and Remedial Aspects of Newly Born Coronavirus, SARS-CoV-2.

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.

A potentially effective treatment for COVID-19: A systematic review and meta-analysis of convalescent plasma therapy in treating severe infectious disease.

BACKGROUND: Convalescent plasma (CP) has been used successfully to treat many types of infectious disease, and has shown initial effects in the treatment of the emerging 2019 coronavirus disease (COVID-19). However, its curative effects and feasibility have yet to be confirmed by formal evaluation and well-designed clinical trials. To explore the effectiveness of treatment and predict the potential effects of CP with COVID-19, studies of different types of infectious disease treated with CP were included in this systematic review and meta-analysis. METHODS: Related studies were obtained from databases and screened according to the inclusion criteria. The data quality was assessed, and the data were extracted and pooled for analysis. RESULTS: 40 studies on CP treatment for infectious diseases were included. Our study found that CP treatment could reduce the risk of mortality, with a low incidence of adverse events, promote the production of antibodies, lead to a decline in viral load, and shorten the disease course. A meta-analysis of 15 controlled studies showed that there was a significantly lower mortality rate in the group treated with CP (pooled OR=0.32; 95% CI=0.19-0.52; p<0.001, I2=54%) compared with the control groups. Studies were mostly of low or very low quality, with a moderate or high risk of bias. The sources of clinical and methodological heterogeneity were identified. The exclusion of heterogeneity indicated that the results were stable. CONCLUSIONS: CP therapy has some curative effect and is well tolerated in treating infectious diseases. It is a potentially effective treatment for COVID-19.