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Abstract

The outbreak of coronavirus disease (COVID-19) requires multidisciplinary teamwork to explore new methodological designs with the aim of approaching treatment strategies on different fronts. In principle, the rationale for the use of convalescent plasma is consistent from both an efficacy and safety point of view. Although there are still few completed randomized trials, the latest published results regarding efficacy are inconclusive. Immediate studies should target convalescent plasma preparations with a high titer of anti–SARS-CoV-2 antibodies and given early in the disease course. Regarding safety, its use with minimum risk factors or side effects is well documented. However, comparative research studies that involve the determination of antibody titers to support efficacy are required. Moreover, regulatory agencies and national blood systems should take a positive position via evaluation, supervisory, and control systems to maintain a blood-tissue store that meets the needs of the community and its hospitals.

Keywords

Convalescent plasma COVID-19 SARS-CoV-2 immune response antibodies

Introduction

The current crisis caused by the outbreak of coronavirus disease (COVID-19) requires the undertaking of intensive scientific research that responds to the needs of the community faced with a significant number of deaths and patients in critical condition. This must be a time of reflection and of multidisciplinary teamwork, to explore diverse hypotheses, raise questions and consider methodological designs that will provide information and knowledge to comprehensively face and resolve the problem of the current pandemic.

COVID-19 Background

The current COVID-19 pandemic is a viral infection caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a new positive-sense, single-stranded RNA (ribonucleic acid) virus variant that belongs to the coronavirus family, so named because of the appearance of its outer surface under electron microscopy.^1,2 This variant seems to be similar to the SARS-CoV-1 virus that circulated from 2002 to 2003, but a homology close to 96% was identified between SARS-CoV-2 and a bat coronavirus and, probably, other intermediate hosts.³ The virus primarily causes an acute respiratory infection, although a significant number of symptoms or clinical manifestations have been described that affect other systems, including cardiovascular, gastrointestinal, neurological, hematological, renal, and skin. In the majority of cases (80%-85%), patients are asymptomatic or exhibit mild symptoms.⁴ However, some people do not show clinical improvement and the disease progresses to moderate or severe forms. Hospital admission may be required, mainly to intensive care units, in which a 50% mortality rate has been reported among ventilated patients.^5-7

To enter cells, the virus uses the protein known as coronavirus spike (S) protein, which binds to ACE2 receptors (angiotensin-converting enzyme 2) widely distributed throughout the body, as well as the receptor known as CD147.⁸ From a pathophysiological perspective, the disease has been divided into 3 well-defined stages or phases: the initial or early stage lasting approximately 7 to 10 days, which is characterized by a high level of replication and viral load and start of the innate immune response; subsequently, from 7 to 14 days, the acquired immune response begins, which is mainly mediated by T lymphocytes and humoral response. This stage is critical as it consists of a low viral load and an intense inflammatory response characterized by the release of inflammatory cytokines, principally IL-6, IL-1 and IL-21, and Th17 lymphocyte activity. The balance between the humoral and cellular response and the production of cytokines in response to this balance influences progress towards the most serious stage, a low regulatory cell response triggers what has been characterized as a cytokine storm, inflammatory immune response with intense macrophagic activity and coagulation cascade with the formation of systemic microthrombi and autoimmune phenomena.^9-13

There are a significant number of diverse clinical trials investigating treatments for the SARS-CoV-2 virus, its genome and cell cycle, including anti-viral drugs such as hydroxychloroquine, as well as immunomodulators and passive immunization against the possible hyperinflammatory response. However, although there are multiple therapeutic options against this new emergency, there is currently no standardized optimum treatment plan.^9,14

Immune Response to Viral Disease, a Review

The initial response to all viral infection is characterized by a primary stage, with the release of type 1 interferon molecules and NK and NKT lymphocyte activity, activation of the inflammatory process in situ, activation of macrophages, migration of dendritic cells and release of interferon gamma, all of which together promote effective control of the viral infection. Both dendritic cells and phagocytes will present viral antigens taken up via Toll-like receptors 7 or 8 (TLR 7-8) at the intracytoplasmic level to generate an innate defense response and interact with the response acquired in a second stage. Given the presentation of these viral antigens in MHC molecules, lymphocytes CD8 and CD4 are involved to generate sensitization of effector and memory CD8 lymphocytes.¹⁵ Similarly, via the cytokine network and the activation of different cell types, CD4 Th1, Th2, and Th17 lymphocytes will tend to eliminate the antigen, thereby limiting the damage.¹⁵ The antibodies support this elimination by forming neutralizing antibodies and phenomena such as antibody-dependent cellular cytotoxicity, phagocytosis and cell lysis.¹⁵

Review of Neutralizing Antibodies

The capacity of the humoral response to generate potentially neutralizing antibodies has been widely demonstrated and used in the field of medicine. They have been used in a wide range of viral diseases such as Zika, Ebola, hantavirus, Junin virus, measles, HIV (with an interesting design to create vaccines at test stage), as well as in previous diseases due to coronavirus such as SARS-CoV-1 and MERS-CoV.^16-19 In medical practice, the use of monoclonal or polyclonal antibodies obtained via immunization in animals or via the use of human hepatitis B immunoglobulin for specific treatment of diseases such as hepatitis B, Clostridium, aplastic anemia (with the use of antithymocyte globulin) and others, is completely validated and is applicable according to the guidelines.^20,21

Neutralizing antibodies play a critical role in several diseases, including viral diseases. In the process of viral clearance and neutralization, neutralizing antibodies can block the entry process into cells by interfering with their antigens and binding to their receptors, and have been the “gold-standard” in the development of passive immunity, vaccines against poliomyelitis, measles and influenza.^19-21 With a practical and applicable design, Wu et al²² presented evidence of the role that these neutralizing antibodies play in infection by SARS-CoV-2. They used a 293T cell model, cells that express ACE2 receptor and that can be infected by pseudovirus, a vector that expresses the proteins S1 and S2 specific to SARS-CoV-2. Subsequently, using ELISA (Enzyme-Linked Immunosorbent Assay), they determined the antibody titers and their neutralizing capacity. This model was applied in 175 patients who had recovered from different clinical stages of the disease, although none had been seriously ill or had required intensive care. The results revealed that the antibody titers became evident between 10 and 14 days of infection onset and remained stable. No cross-reaction with SARS-CoV-1 was observed in the SARS-CoV-2 neutralizing antibodies. However, 30% of patients had low titers at a non-neutralizing level, 10 patients who had recovered had very low or undetectable titers, suggesting a heterogeneity of the immune response and perhaps more a cellular than humoral response in these patients. In middle-aged to elderly subjects (40-59 and 60-85 years, respectively), the neutralizing antibody titer was significantly higher than that found in young people (15-39 years), which, combined with an inverse correlation with lymphocyte count and high levels of C reactive protein, suggests a strong induction of the innate immune response in the group of patients studied by Wu et al.²² In contrast to the above study, Díez et al^23,24 demonstrated that antibodies with specific cross-neutralizing activity against SARS-CoV-2 were present in commercial polyvalent intravenous immunoglobulins prepared from plasma collected out of general population donors.

Sera with high SARS-CoV-2 antibody levels (>960 enzyme-linked immunosorbent assay titer) showed maximal activity, but not all high-titer sera contained neutralizing antibodies at FDA-recommended levels, particularly at high stringency. Thus, high neutralizing antibody titer may be desirable for plasma therapy but not be required for protection from reinfection with SARS-CoV-2. We also note that the role or importance of non-neutralizing antibodies for either protection or therapy has not yet been determined but should not be discounted.²⁵ In summary, the development of potently neutralizing humoral immunity against SARS-CoV-2 appears to increase survival and may protect against re-infection with other circulating strains of SARS-CoV-2. However, it is generally unlikely to provide protection against subsequent coronavirus pandemics.²⁶

The World Health Organization (WHO) has reviewed the existing evidence to determine if the responses of antibodies against SARS-CoV-2 confer immunity against subsequent infections and has published that the most people will develop a cellular and humoral immune response 1 or 2 weeks after infection, which will result in the presence of antibodies.²⁷ However, although the plasma of a high percentage of convalescent patients has been shown to contain specific antibodies against SARS-CoV-2, the antibody detection and titration tests must be performed in a sample obtained from a donor prior to or during plasma donation, or from donated plasma after donation or after all processing steps, when pathogen reduction is applied.²⁸ Blood collection establishments should apply adequate selection criteria, adequate testing, and surveillance procedures to discriminate convalescent plasma containing high titer neutralizing antibodies.²⁹ In addition, blood collection establishments may play a role in recruitment of donors in collaboration with partner hospitals. Regulation of every single step of convalescent plasma collection is important from assessment of donors to administration to patients. Both the criteria for eligibility of convalescent plasma donors and for patient selection may vary between countries.³⁰ However, selection and qualification only of donors who carry the highest levels of detectable neutralizing antibody to SARS-CoV-2 is recommended.³¹

Clinical Uses of Convalescent Plasma

On April 2020, the European Commission recommended that transfusion of COVID-19 convalescent plasma, as an immediately available experimental therapy with low risk, should be considered as an urgent priority and its outcome monitored.²⁸ The same month, the FDA issued guidance to provide recommendations to health care providers and investigators on the administration and study of convalescent plasma to patients currently seriously ill with COVID-19.³² On August 23 2020, FDA issued an Emergency Use Authorization (EUA) for COVID-19 convalescent plasma for the treatment of hospitalized patients with COVID-19. In successive updates and revisions, both agencies have provided recommendations on pathways available to health care providers for use of investigational COVID-19 convalescent plasma; patient eligibility; collection of COVID-19 convalescent plasma, including donor eligibility and donor qualifications; and labelling and recordkeeping.^28,32

Five clinical scenarios are important for passive immunity research and development in the context of COVID-19: (i) The prophylactic use of convalescent plasma after exposure, for example, individuals with direct, close or continuous contact or at risk of developing serious disease, such as healthcare personnel, immunosuppressed patients, individuals with heart disease, etc.; (ii) Use in moderate disease to prevent progression to severe stages that are difficult to reverse and that involve hospital admission and respiratory therapy; (iii) Hospitalized patients with moderate to severe disease to reduce the need for mechanical ventilation, admission for treatment and mortality; (iv) Use of convalescent plasma as rescue therapy in critical patients; and finally, (v) Use in the pediatric population, with pharmacokinetic validation, since pediatric COVID-19 cases might experience different symptoms and overall have shown less severe disease than adults.^33-35

The use of convalescent plasma for passive immunity or polyclonal antibody transfusion has been shown to be effective in a diverse range of viral diseases, such as Spanish flu (1915), type A flu (H1N1, 2009-2010), avian flu (H5N1), Ebola virus, Zika virus, Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome in the specific case of SARS-CoV-1. In 2015, a meta-analysis that included 32 studies and a total of 699 treated and 568 untreated subjects, demonstrated a significant reduction in mortality.³⁶

In patients with SARS-CoV-1, an improvement in prognosis due to the use of passive immunization has been reported.³⁷ The study demonstrated that patients with a positive PCR test for the virus but seronegative at the time of receiving a convalescent plasma infusion, that is without antibodies against the virus, had a higher rate of hospital admission on day 22 than PCR-positive and seropositive patients. These results support the usefulness of passive immunization using convalescent plasma to treat the disease. The study also suggests that the use of convalescent plasma should be more effective if administered at the beginning of the disease. Consequently, it is important to mention that this study emphasizes that passive immunization is more effective before day 14 following the onset of the disease.³⁷

In previous studies on both SARS-CoV-1 and MERS-CoV in Hong Kong, Taiwan and South Korea with different patient groups, clinical improvement and a reduction in disease progression and severity after the administration of convalescent plasma was observed.^14,38-40

In the current pandemic, convalescent plasma has been included in the treatment of patients with COVID-19 with positive outcomes reported. The characteristics of these studies differ in terms of number of patients, severity of the condition, viral load of the patient, volume of convalescent plasma used, titer of neutralizing antibodies and others.

The study by Shen et al included 5 patients aged between 36 and 65 years with confirmed COVID-19, in critical condition and with severe respiratory disorder. 400 mL of convalescent plasma with high titers of SARS-CoV-2-specific antibodies (1:1000) were administered between days 10 and 22 after admission. The results revealed an improvement in 4 patients, according to criteria such as the sequential organ failure assessment (SOFA) score, clinical recovery and even early discharge in 3 of the patients.⁴¹

The report by Duan et al regarding the treatment of 10 patients in a serious condition, with a 200-mL dose of serum with a neutralizing antibody titer of 1:640, showed satisfactory results in all 10, with clinical improvement on day 1 to 3 post-transfusion, a reduced viral load and radiological improvement In 5 cases, the antibody titers were prematurely elevated and high neutralizing antibody titers (greater than 1:60) were maintained. The rest of the patients improved gradually. At the end of the protocol, all the patients (7 of 10) who had previously tested positive for SARS-CoV-2 RNA, went on to give a negative PCR result, and all patients exhibited clinical and radiological improvement and increased lymphocyte count, with no evident adverse events.⁴²

Zhang et al reported a study of 4 cases of patients in critical condition. In this report, the investigators used variable volumes of convalescent plasma and the PCR test was negative in all cases between 3 and 22 days. There was an immune response, measured as the titer of anti-SARS-CoV-2 IgG neutralizing antibodies, in 2 of the cases (around day 14), whilst in all patients there was clinical improvement with optimal safety margin.⁴³

In a report on a series of cases, a total of 20 patients in hospital due to COVID-19 (mean age of 60 years) were treated with convalescent plasma and showed an improvement in symptoms associated with a reduction in mortality.⁴⁴

Another report on a series of 25 cases with severe or life-threatening disease, 19 (76%) of COVID-19 patients had at least a 1-point improvement in clinical status by day 14 after convalescent plasma transfusion, and 11 were discharged. No adverse events as a result of plasma transfusion were observed.⁴⁵ These case series and others^46,47 that have evaluated treatment of patients with COVID-19 convalescent plasma are summarized in Table 1.

Table 1.

Summary of relevant case series that have evaluated treatment of patients with COVID-19 convalescent plasma (CCP).

Type of study	COVID-19 patients	N	Summarized findings/key facts	References
Case series	Hospitalized patients in ICU	26	Patients had no severe adverse reactions after CCP transfusion	Erkurt et al⁴⁶
Case series	Hospitalized patients with severe or life-threatening COVID-19	25	By day 14 after CCP transfusion, most patients improved in clinical status and early discharge. No adverse events as a result of CCP transfusion were observed.	Salazar et al⁴⁵
Case series	Hospitalized patients	20	Improvement in symptoms associated with a reduction in mortality	Hegerova et al⁴⁴
Case series	Hospitalized patients	10	Clinical improvement in all patients on day 1 to 3 post-transfusion. No evident adverse events.	Duan et al⁴²
Case series	Hospitalized patients in ICU	5	4 patients improved in SOFA score, clinical recovery and early discharge	Shen et al⁴¹
Case series	Hospitalized patients in ICU	4	Clinical improvement in all patients with optimal safety margin	Zhang et al⁴³
Case report	Centenarian patient with cough and dyspnea	1	After CCP transfusion, significant improvement was observed on laboratory indicators and clinical symptoms of the patient	Kong et al⁴⁷

There are currently estimated to be more than 100 research projects or studies into the use of convalescent plasma in COVID-19. Some reports primarily demonstrate its safety, while the majority document evidence of therapeutic efficacy, with inconclusive results.

Among the clinical trials with recently published results, the largest one enrolled 526 hospitalized COVID-19 patients. It was a retrospective, multicenter study that compared convalescent plasma transfusion with standard treatment in matched controls. An early mortality benefit was found at 7 and 14 days of transfusion (9.1% vs 19.8%, P < .001) but not at 28 days compared to standard treatment. Moreover, a trend toward a quicker improvement for patients requiring nasal cannula in transfused patients (3 days vs 6 days, respectively, P = .02).⁴⁸ However, in a phase 2, multicenter, randomized, controlled trial performed on 464 hospitalized patients, convalescent plasma transfusion was not associated with a reduction in progression to severe COVID-19 or all-cause mortality at 28 days compared with standard of care.⁴⁹ In another large (228 patients) randomized, double-blind trial, no significant differences were observed in clinical status or overall mortality between patients transfused with convalescent plasma and those who received placebo, although SARS-CoV-2 antibody titers tended to be higher in the treated patients at day 2 after the intervention.⁵⁰

Positive results were reported by 2 randomized trials that enrolled 189 patients (open-label) and 160 (double-blind). In the first one, convalescent plasma treatment significantly reduced patients’ hospitalization period (9.54 vs 12.88 days in patients with standard treatment; P = .002), and substantially reduced all-cause mortality (14.8% vs 24.3%,), without adverse effects being observed.⁵¹ In the second trial, early administration of convalescent plasma reduced the progression of COVID-19 to severe respiratory disease in mildly ill older patients compared to placebo (16% vs 31% of patients, respectively, P = .03), with no solicited adverse events being observed.⁵² These trials and others^53-56 are summarized in Table 2.

Table 2.

Summary of relevant clinical trials that have evaluated treatment of patients with COVID-19 convalescent plasma (CCP).

Type of study and dates	COVID-19 patients	N	Summarized findings/key facts	References
Retrospective, multicenter, health system-based, matched cohort study. March 15 to July 7, 2020.	Hospitalized patients	526	An early mortality benefit was found at 7 and 14 days of CCP transfusion but not at 28 days compared to standard treatment. A trend toward a quicker improvement in the oxygen device category was observed in CCP patients.	Shenoy et al⁴⁸
Open label, parallel arm, phase 2, multicenter, randomized controlled trial. April 22 to July 14, 2020.	Hospitalized patients	464	CCP was not associated with a reduction in progression to severe COVID-19 or all cause mortality at 28 days compared with standard of care	Agarwal et al⁴⁹
Randomized, double-blind, placebo-controlled trial. May 28 to August 27, 2020.	Hospitalized patients	228	No significant differences were observed in clinical status or overall mortality between CCP patients and those who received placebo	Simonovich et al⁵⁰
Open-label, single center, randomized clinical trial. March to April, 2020.	Hospitalized patients	189	CCP significantly reduced patients’ hospitalization period, and substantially reduced all-cause mortality compared with standard treatment. No adverse effect was observed resulting from CCP.	Abolghasemi et al⁵¹
Randomized, double-blind, placebo-controlled trial. June 4 to October 25, 2020.	Mildly ill older patients	160	Early administration of CCP reduced the progression of COVID-19 to severe respiratory disease compared to placebo	Libster et al⁵²
Open-label, multicenter, randomized clinical trial. February 14 to April 28, 2020.	Patients with severe or life-threatening COVID-19	103	CCP added to standard treatment did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard treatment alone	Li et al⁵⁵
Open-label, single-center randomized phase 2 trial. May 10 to August 17, 2020.	Hospitalized patients with risk factors	58	The study failed to show that early CCP administration improved the outcome (mechanical ventilation, hospitalization for >14 days, or death) compared to CCP use only in case of clinical deterioration	Balcells et al⁵⁴
Single arm, phase 2a trial. April 15 to June 16, 2020.	Outpatients and hospitalized patients	51	The non-mechanically ventilated patients had a lower intubation rate and higher 30-day survival rate compared with a group based on network data. There was only 1 mild adverse event	Donato et al⁵³
Retrospective, single-center, controlled. March 1 to November 30, 2020.	Patients with haematological malignancies and COVID-19	45	Early administration of CCP effectively lead to clinical improvement, increased viral clearance and longer overall survival, compared with patients who received other therapy	Biernat et al⁵⁶

A meta-analysis of 10 722 patients that included the studies by Agarwal et al,⁴⁹ Simonovich et al,⁵⁰ Libster et al,⁵² and Li et al⁵⁵ and added 6 unpublished studies (5 preprints, 1 news release), concluded that treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes.⁵⁷ Additional data form studies not included in the meta-analysis (eg, see Table 2) would suggest that convalescent plasma preparations with high titer of anti–SARS-CoV-2 antibodies and given early in the disease course (ie, before the patient needs mechanical ventilation) may be effective. The FDA revised its Emergency Use Authorization accordingly.⁵⁸

Challenges and Problems to be Resolved in the Use of Convalescent Plasma

Despite demonstrating a high level of safety with no serious adverse effects, the clinical trials assessing the efficacy of using convalescent plasma from convalescent patients to treat COVID-19 present certain limitations. Firstly, with regard to quantity, in the United States ClinicalTrials.gov database (April 2021), there are currently 1648 registered international studies into COVID-19 treatment,⁵⁹ of which only 56 are on the use of convalescent plasma from patients and 10 of these have finished.⁶⁰ Studies mentioned above (Table 2) were conducted with a limited number of patients of different ages, comorbidities, severity and at different clinical stages of the disease. Apart from receiving convalescent plasma, the patients also received various drugs, making it highly complex to determine the net effect of convalescent plasma use. In addition, the convalescent plasma dose used and the titration of neutralizing antibodies in the different studies varies, where these determinations are reported.^42,43 The optimum time for harvesting antibodies is not known. Consequently, although currently published studies are of great value in assessing the safety of using convalescent plasma and its efficacy as part of a treatment, it is difficult to standardize a clinical protocol and it is evident that the efforts to achieve this are completely justified. Immediate studies should target convalescent plasma preparations with high titer of anti–SARS-CoV-2 antibodies and given early in the disease course.⁵⁸

Undesirable Effects or Risks Associated with the Use of Convalescent Plasma

The use of plasma as a source of proteins, plasma volume expander or component replacement, mainly in patients with a high risk of bleeding, has frequently been considered a therapy with little justification, in spite of the fact that in the literature it is associated with a low frequency of adverse effects.^36,61 In a systematic review that included 32 studies on the use of convalescent plasma for the treatment of viral infections, no serious adverse effects were reported.³⁶ For the treatment of patients with Ebola, there are several reports available. A study with 99 patients reported mild adverse effects such as fever (8%), pruritus (5%) and skin rash (4%), but no serious adverse effects,⁶² while there is a report of 1 case of a patient who presented with TRALI (transfusion-related acute lung injury).⁶³ A case of possible TRALI has also been reported in a patient with MERS-CoV.⁶⁴ It has been suggested that the risk of TRALI may be greater in infections by SARS-CoV-1 and MERS-CoV with acute lung damage due to inflammatory mechanisms related to the antibody-mediated immune response, especially in patients with comorbidities such as prior lung or myocardial damage. These comorbidities could promote the development of transfusion-associated circulatory overload (TACO), another uncommon but serious adverse effect of the use of plasma.^36,65

Complications such as hemostasis due to some loss of coagulation factors caused by pathogen inactivation/reduction methods, and complement activation due to small amounts of IgA proteins, are other adverse effects associated with plasma transfusion.⁶⁶ Opsonization by non-neutralizing antibodies may increase lymphopenia in patients with COVID-19. The increase of antibody-mediated cellular cytotoxicity, described as a phenomenon of antibody-dependent cellular cytotoxicity (ADCC), principally by IgG1 which activates NK cells, should also be evaluated. This adverse effect has mostly been reported in diseases such as dengue, Ebola, SARS-CoV-1 and MERS-CoV in animal models. However, there is also a potential risk in the clinical setting. It is currently known that this increase in cytotoxicity is related to the specificity of the antibodies, their neutralizing role and when they appear. The presence of antibodies in 108 sera of 23 patients very early on, before day 14, is associated with a greater toxicity than if they appear later, around day 20, with a better response and similar outcomes.^67,68 Recent studies associate a greater risk of complications derived from COVID-19 with people primarily from group A or B related to this cytotoxicity phenomenon.^9,14,65,69

In a retrospective analysis performed on 215 adult patients with COVID-19, 55 reactions from 427 transfusions (12.9% incidence) were identified, and only 13 (3.1% incidence) were attributed to transfusion.⁷⁰ In a study performed from April 3 to June 2, 2020 in a sample of 20 000 hospitalized patients with COVID-19 transfused with convalescent plasma, the US Food and Drug Administration Expanded Access Program for COVID-19 found <1% transfusion reactions, with the vast majority of the thromboembolic or thrombotic events and cardiac events were judged to be unrelated to the plasma transfusion per se.⁷¹ Both studies concluded that safety of transfusion of convalescent plasma in hospitalized patients with COVID-19 was robust.

Conclusions

The critical times the world is currently living through require the intense and open participation of the areas of research that seek to mitigate the pandemic and reduce the lethality or mortality of COVID-19. The scientific community has to provide leadership and empathy for society by supplying innovative therapies.

The arguments for the use of convalescent plasma are consistent and solid from a safety point of view. The majority of studies document its use with minimum risk factors or side effects. Regarding to efficacy, although it is true that there are still not many comparative studies, the latest efficacy results are inconclusive. However, there is interest on the part of healthcare service providers and scientists in the use of convalescent plasma. It is important to promote strategic alliances between both parties in order to support its use with solid arguments.

Some studies have demonstrated reduced length of hospitalization, reduced progression to severe COVID-19, and reduced mortality compared to standard treatment or placebo, whereas other trials found no clinical improvement. Immediate efficacy studies should target convalescent plasma preparations with a high titer of anti–SARS-CoV-2 antibodies given early in the disease course. In addition, comparative research studies that involve the determination of antibody titers to demonstrate efficacy are required.

Moreover, given the current pandemic and crisis, it is hoped that a positive and innovative position will be taken by the regulatory agencies via evaluation, supervisory and control systems. To have access to this treatment is a patient’s right and an obligation of the local and national blood systems in the context of a research project. These are times of crisis, in which teamwork should be the priority.

Footnotes

Acknowledgements

The authors thank Jordi Bozzo, PhD CMPP and Michael James, PhD (Grifols, a manufacturer of plasma derivatives), for providing editorial support in the preparation of this manuscript. This paper is dedicated to the memory of our dear co-worker Jorge Duque, who passed away while this paper was being written.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GPES, currently receives support from CONACYT [Mexican Council for Science and Technology] for scientific research projects, technological development and innovation in COVID-19 healthcare. “Immunological monitoring of patients infected by coronavirus SARS-CoV-2 (COVID-19),” No. 312147.

Author Contribution

All authors have participated in the conception or design of the work, data collection and critical revision of the article.

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The Therapeutic Use of Plasma from Covid-19 Convalescent Patients

Abstract

Keywords

Introduction

COVID-19 Background

Immune Response to Viral Disease, a Review

Review of Neutralizing Antibodies

Clinical Uses of Convalescent Plasma

Challenges and Problems to be Resolved in the Use of Convalescent Plasma

Undesirable Effects or Risks Associated with the Use of Convalescent Plasma

Conclusions

Footnotes

Acknowledgements

Funding:

Declaration of conflicting interests:

Author Contribution

References