key: cord-0766511-oljbvl0y
authors: Verma, Henu Kumar; Farran, Batoul; Bhaskar, Lakkakula V K S
title: Convalescent plasma transfusion a promising therapy for coronavirus diseases 2019 (COVID-19): current updates
date: 2020-05-27
journal: Antib Ther
DOI: 10.1093/abt/tbaa010
sha: be4fcb6f008fc240b136a952e87dee6aa8d82cbe
doc_id: 766511
cord_uid: oljbvl0y

While there is no proven treatment available for coronavirus disease 2019 (COVID-19), convalescent plasma (CP) may provide therapeutic relief as the number of cases escalate steeply world-wide. At the time of writing this review, vaccines, monoclonal antibodies or drugs are still lacking for the recent large COVID-19 outbreak, which restores the interest in CP as an empirical life-saving treatment. However, formal proof of efficacy is needed. The purpose of this review is to summarize all historical clinical trials on COVID-19 infected patients treated with CP to provide precise evidence for the efficacy and effectiveness of CP therapy in severe COVID-19 patients. Although there are many clinical trials in progress, high-quality clinical evidence is still lacking to analyze the existing problems. Meanwhile, based on the previous successful outcomes, we recommend healthcare systems to use CP therapy cautiously in critically ill COVID-19 patients.

World populations are currently facing an unprecedented health crisis caused by the spread of an infectious virus, the coronavirus-induced pneumonia, known as the Novel Coronaviruses disease (COVID- 19) , which has seriously affected human health worldwide [1] . Patients infected with this virus suffer from potential damage to vital organs especially the lungs, heart, liver and kidney [2, 3] . Furthermore, this infection poses a considerable risk to patients due to the high frequency of pneumonia, fever and dry cough [4] .

The Author(s) 2020. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals. permissions@oup.com This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com many vaccines are often not affordable in developing countries, and their production is hard to scale up in short times, which further contributes to the severity of the pandemic.

A few treatment trials have been conducted since the emergence of COVID-19, in an effort to contain and restrain its effects, with limited success so far. For instance, a recent trial (ChiCTR2000029308) investigating lopinavir/ritonavir showed no significant benefit for SARS-CoV-2 infection [11] . Earlier, it was proven that transfusion of convalescent blood products (CBP), especially convalescent plasma transfusion (CPT), might be useful against a variety of pandemic outbreaks, including influenza, Ebola virus, SARS, MERS by reducing the hospital stays and improving patient survival [12] .

The latest pilot study on CP therapy shows a potential emergent therapeutic effect and low risk in COVID-19 patients [13] . As we know, since COVID-19 is a novel infectious disease, scientists and doctors still lack the indepth understanding of its mechanisms of transmission, infection and action that would permit the development of effective vaccines or therapies. To date, not a single clinical intervention trial of CP in COVID-19 has been completed, highlighting the necessity for conducting thorough research and meta-analyses to uncover novel treatments that will allow disease control and prevention. In order to palliate the lack of updated clinical trial reviews assessing the existing challenge and its potential clinical solutions, we have endeavored to summarize all clinical trials of COVID-19 patients treated with CP in an effort to provide updated evidence for the effectiveness and efficacy of this strategy in treating COVID-19.

All registered clinical trials studies that were published from 1 January 2020 to 14 April 2020 were identified from Chinese Clinical Trial Registry (chiCTR), European union clinical trials database (EUCTD), Clinicatrial.gov, Pubmed, National Library of Medicine (NLM), using the keywords CP and novel coronavirus 2019, CP and COVID-19, comorbidities, clinical manifestation, immunotherapy, vaccine and SARS CoV-2. Eligible studies were extracted by electronic searching of databases and an additional search was performed using the International Clinical Trials Registry Platform (WHO ICTRP) to identify ongoing trials. The last analysis was executed on 14 April 2020.

Two investigators selected the eligible studies independently. Inclusion criteria were: (1) case-control with COVID-19 patients, (2) clinical trials with a CP protocol, (3) published full-text with maximum detail on COVID-19 therapy, (4) any type of study design (interventional and observational), (5) studies involving the treatment of COVID-19 with CP and (6) studies written in English were preferred. Exclusion criteria were: (1) studies with duplicate data; (2) studies with no specific control group and (3) unclear theoretical research, and unregistered clinical trials.

The quality evaluation of all registered clinical studies and data extraction of each literature was critically appraised and discrepancy between investigators was resolved by dialogue. All studies were tabulated and summarized narratively and grouped by the treatment strategy. We categorized the table depending on trial numbers. Furthermore, we classified results as: type of study, title of study, sponsor, recruitment status, intervention, age, phase, date enrollment, study type, country and the number of patients included in that study.

Searches were performed until 14 April 2020, using EUCTD, ChiCTR and NIH (Clinical Trails.gov), and 25 registered clinical trials of COVID-19 were retrieved with active and recruiting status. Subsequent screening of headings and abstracts allowed us to exclude withdrawn clinical trials. Overall, 22 studies used CP alone, one study used PC with combinations (Hydroxychloroquine, Azithromycin), one trial used umbilical cord blood plasma and one investigation used IgG Antibody Testing Kit for clinical trials. Summaries of detailed studies were presented in Table 1 . Most of the registered trials have cleared ethical statements. Some of the studies are still in the recruiting stage, 10 trials have started to the recruitment of patients. Finally, remaining trials showed an active status and it will start recruiting patients upcoming days.

During the pre-antibiotic era, infectious diseases had high morbidity and mortality. Plasma antibody was developed against a variety of infectious diseases because there were no alternative therapeutic options. Plasma antibody uses a potential therapeutic strategy initially obtained from immune survivors of an infectious disease that was formally introduced in 1910 for poliomyelitis in animal model [14] . Subsequently, plasma therapy was tested in human patients with acute poliomyelitis treated with CP from polio survivors and showed promising results [15] . CP was later introduced as a primary drug against several infectious diseases including influenza pneumonia, chicken pox, measles and mums [16, 17] Transfusion of CP has been shown to reduce viral load, serum cytokine response and mortality in severe H1N1 influenza patients [18] . Recently, Mair-Jenkins et al. have conducted a systematic review and meta-analysis to assess the effectiveness of CP, serum or hyperimmune immunoglobulin for the treatment of SARS coronavirus infection, severe influenza (H1N1, H5N1) and Ebola virus disease (EVD). Their results revealed that CP therapy significantly reduced mortality without causing any severe adverse effects [19, 20] .

The US Food and Drug Administration (FDA) have recently approved the use of plasma therapy from recovered COVID-19 patients to treat critically ill patients. As per FDA recommendations, the plasma must be collected from a donor who showed no symptoms for the last 14 days and had negative recent COVID-19 results [21, 22] . The first pilot CP treatment study was conducted in three participating hospitals for 10 severe COVID-19 [13] . After COVID-19 was declared a global pandemic, many scientists suggested that CP could be used as a potential therapeutic strategy to alleviate the infection's symptoms [23] [24] [25] . A China-based study demonstrated that the inflammatory cytokine IL-6 levels were significantly elevated in critically ill COVID-19 patients, indicating that the viral load was strongly associated with a cytokine storm and can be used to predict poor COVID-19 prognosis [26] . Another case report study in five patients reported that maximal supportive care and administration of antiviral agents with CP transfusion (neutralizing antibody titers 1:640) could potentially improve clinical outcomes without severe adverse effects [27] Furthermore, Zhang et al. showed that after 11 days of CP infusion, patients did not require mechanical ventilation and were moved to the general ward with better outcomes [28] . Additionally, six more confirmed COVID-19 patients showed better improvement after treatment with CP in Wuhan, China [29] . Based on these preliminary results, USA-based John Hopkins University is currently leading a randomized trial (Phase 2) on 150 older participants undergoing CP treatment with a titer of neutralizing antibody > 1:64 for post-exposure prevention [30] . A Mayo Clinic-sponsored phase 2 trial investigating CP treatment with a titer > 1:64 is also currently recruiting [31]. Another study analyzing results from 173 patients traced the dynamics of antibody responses during disease progression. Periodic antibody detection revealed that the appearance of antibodies was <40% among patients in the first week of COVID-19 infection, then rapidly increased to 100% Ab, 79.8% IgG and 94.3% IgM, respectively, since 2nd week after infection onset, highlighting the importance of routine testing in the context of COVID-19 infections [32] . Furthermore, it was noticed that the average IgG antibody level was higher in female patients than in male patients, particularly in severe cases, which could account for the differences in COVID-19 outcomes between genders [33] . Previous studies on the duration of the serological response profile in patients infected with earlier strains of the SARS coronavirus revealed that IgM was still detectable after 7 months of postinfection. Hence, a suitable donor could donate 200 × 3 times single dose of plasma during a period of 6 months [34] . Based on these findings, many pharma companies such as Israeli company Kamada are collecting plasma in different facilities from people who have recovered from this viral disease [35] . As the various results summarized in this section indicate, CP administration seems to reduce viral load and is a safe treatment strategy with minimal side effects. A CP collections workflow and protocol are presented in Fig. 1 .

In this paper, we have summarized the current registered clinical trials on CP initiated following the onset of the COVID-19 pandemic outbreak. Despite the potential utility of CP treatments, there have been few concerted efforts to use them as initial therapies against pandemic. The main contraindications to CP therapy are an allergic reaction to plasma protein. As in many other trials examining clinicalpathological symptoms observed during viral or bacterial infections, thrombosis, multiple organ failure, as well as pregnant or lactation schedules are also contraindications.

The advantages and disadvantages of human plasma therapies are often related to conventional antiviral drugs. However, Abs are specific in their modes of action in diverse therapeutic classes. Anti-COVID-19 plasma differs from regular human plasma only by the presence of antibodies against the coronavirus. Donor selection criteria are the same as outlined by FDA guidelines. Therefore, the risks to transfusion receivers are likely to be same as those of standard plasma therapy.

One of the major challenges and concerns with plasma therapies is ensuring the prevention of transfusiontransmitted infections (TTI). Recent pathogen inactivation (PI) technologies, combined with nucleic acid testing (NAT) of an individual donor may represent a good option to reduce the risk of additional TTIs. At present, due to globalization, regulatory systems may require further tests to ensure additional transfusion safety. For instance, one UK based study suggests that blood donors are not screened for HEV infections although this infection is widespread in English populations. In fact, it was reported that after CP transfusion, 10 recipients developed prolonged or persistent hepatitis E virus infection [36] . Although this does not preclude COVID-19 with CP from being therapeutically utilized in the UK, these risks should be considered in clinical trials at the individual patient level.

There are also some non-infectious risks linked with CPT, such as allergic transfusion reactions and transfusion associated circulatory overload (TACO). Another major concern is transfusion-related acute lung injury (TRALI), an immune-mediated transfusion reaction that can cause severe complications or even death. Previous reports have shown that female donors with a history of pregnancy have higher risk of TRALI [37, 38] . TRALI is particularly challenging in patients presenting with severe COVID-19 symptoms given the potential priming of the pulmonary endothelium. Male donors are the first choice to further decrease the risk of transfusing human leukocyte antigen (HLA) antibody from parous women. Recent COVID-19 data show that female patients display higher IgG levels [39] . In certain cases, the presence of specific antibodies may account for antibody-dependent enhancement (ADE) before this phenomenon is noticed for dengue virus [40] . This virus-specific antibody enhancement could theoretically increase COVID-19 virus entry in monocytes or macrophages cells and increase its severity. In this context, ADE infection could pose major concerns during vaccination. However, the identification and characterization of viral epitopes are important before CPT for COVID-19 [41] .

A recent study of six COVID-19 patients with respiratory failure that received CPT after 21.5 days of first viral detection indicated that they all tested negative for COVID-19 by 3 days after infusion, and five died in due course. These findings suggest that CP treatment may reduce COVID-19 RNA shedding but cannot decrease mortality rates in critical patients [42] . Deploying CP therapies against the COVID-19 patients provides an unprecedented opportunity to perform clinical research and gather evidence of the effectiveness of this treatment against viral infection. At present, both academic researchers and industry groups have started to investigate the effectiveness and clinical usefulness of CP therapies for COVID-19. If clinical trials results clearly establish the effectiveness and potential benefit of CP, the USA and other countries that have exponential growth of coronavirus deaths, may consider a national campaign to provide plasma treatment. Although a logistical challenge may be one an evidence-based approach to protect particularly high-risk populations.

Based on the current study and available clinical trial results, we unable to make a definitive conclusion on CPT as a treatment option for COVID-19. Due to some limitations, first, insufficient clinical trial evidence. Most of these trials are still ongoing and their result has not been published yet. Second, it is unclear if patients would have improved with CP or other medication because at present, it is not clear that the administration timing of CP after admission. Third, whether CP treatment strategy would reduce mortality rates of COVID-19 patients is still unknown.

Plasma therapy from recovered COVID-19 patients is anticipated to be safe and potentially useful for treatment, based on the available data. In the current situation, COVID-19 requires urgent development of effective treatment modalities. The use of CP may be the first potential option to consider during this pandemic while antiviral drugs are being tested. Developing successful therapies will require the engagement and coordination of several different entities, such as blood banking specialists, virologists, hematologists and other health care workers, to ensure the proper interpretation of disease severity. It also requires ethical statements and controlled hygiene to ensure optimal safety to both donors and recipients. In the context of the public health emergency posed by COVID-19, the FDA has issued a special guidance (24 March 2020) on exploring the use of CP treatment against COVID-19. The released guidelines introduce measures for assessing the safety and efficacy of CP in clinical trials to monitor the success rates of the therapy and evaluate its safety and suitability in the clinical setting. As most countries are beginning to recover from the outbreak and ease lockdown measures, we recommend that, while the medical community still awaits the results of current randomized controlled trials of CP, hospitals can nonetheless consider the emergency use of CP to treat critically ill COVID-19 patients under the current challenging circumstances posed by the pandemic.

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