Role of Blood Plasma Transfusion Against COVID-19

Muhammad Ibrar¹, Abdullah², Iyad Ibrahim Shaqura^{3, 4}, Ahmed Abdelmajed Alkhodary^{4, 5}, Fazlullah Khan^{6, *}

¹ Department of Allied Health Sciences, Iqra National University Peshawar, Swat Campus, KP, Pakistan

² Department of Pharmacy, University of Malakand, Chakdara Dir Lower, KP, Pakistan

³ Department of Health Management and Economics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

⁴ Ministry of Health, Gaza Governorates, Palestine

⁵ International Centre for Casemix and Clinical Coding, Faculty of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia

⁶ Department of Allied Health Sciences, Bashir Institute of Health Sciences, Bharakahu, Islamabad, Pakistan

Abstract

Historically, convalescent plasma (CP) has been successfully used in pandemics caused by the influenza A (H1N1) virus, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola. As the current pandemic by SARS-CoV-2 poses an unprecedented threat to humanity. The number of infections is increasing exponentially day by day. Identifying, qualifying, collecting, and preparing plasma from convalescents with sufficient SARS-CoV-2 neutralizing antibody titers in this pandemic may be challenging but within the approach of most blood establishments. Careful clinical evaluation may rapidly establish whether CP therapy at the early onset of disease in patients of high risk may improve symptoms, reduce hospital stay and decrease mortality due to COVID-19. Moreover, CP is an excellent therapeutic option due to the lack of specific treatment for COVID-19, as the availability of anti-viral drugs/vaccines may take more time.

Keywords: Adverse effects, Antibody titer, Convalescent plasma, Safety and efficacy, Transfusion.

^* Corresponding author Fazlullah Khan: Department of Allied Health Sciences, Bashir Institute of Health Sciences, Bharakahu, Islamabad, Pakistan; Tel: +92 3469 433 155; E-mail: fazlullahdr@gmail.com

INTRODUCTION

Many patients were suffering from chest infections of unknown cause in December 2019 in Wuhan, China. The causative agent was found to be a new coronavirus (CoV), named nCoV2019 (2019 novel coronavirus) by the World Health Organization (WHO) on January 7, 2020 [1]. Subsequently, the virus was retitled severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the resulting infection was named coronavirus disease-2019 (COVID-19). This disease spread in many countries within three months, and the WHO declared it a global pandemic on March 11, 2020 [1].

Convalescent plasma (CP) therapy, prime adoptive immunotherapy that has been used in the treatment and prevention of various diseases for more than one century [2]. In the last two decades, CP therapy has been successfully applied with satisfactory efficacy and safety in the treatment and prevention of the Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and H1N1 pandemic [3]. In passive immunization therapy, the antibodies are administered to the susceptible person to treat or prevent the infectious disease caused by the same agent

On the contrary, active immunization requires the inductance of an immune response which takes time to develop and varies depending on the recipient. Therefore, for providing prompt immunity to a susceptible person, passive immunization is considered the only way [4]. For therapeutic purposes, passive immunization is the most effective way to administer in a short time after the appearance of symptoms. Passive administration of antibodies works by neutralization of the initial inoculation in which the amount is much smaller than that of established disease [5]. A sufficient amount of antibodies must be administered for passive immunization therapy to be effective. When given to a susceptible individual, the antibodies circulate in the bloodstream for some time. After it reaches the tissues, and provides proper protection against an infectious agent.

According to WHO, the current management and treatment of COVID-19 have been mainly centered on case detection, treatment, monitoring, prevention of infection, and supportive care [6]. Currently, due to the lack of evidence, no specific treatment against nCOV-19 has been recommended [7]. So CP therapy is the only choice for the treatment of severe patients infected with nCOV-19. In the current pandemic of SARS-CoV-2, CP therapy was tested to treat COVID-19 patients in China, as claimed in several studies [8, 9], as shown in Fig. (1) . A research study on 10 COVID-19 patients with severe symptoms, CP with neutralizing antibody titers equal to or greater than a 1:640 dilution, was collected and transfused to all severe COVID-19 patients [10]. No serious side effects were reported in the recipients of CP transfusion. Moreover, the improvement in radiological pulmonary lesions and other symptoms was observed in all 10 patients within 1-3 days of CP transfusion. Studies revealed that CP obtained from COVID-19 recovered patients could be used for the treatment without producing severe adverse effects. Recently, Food and Drug Administration (FDA) has recommended the administration of investigational CP may result in clinical benefits for the management of COVID-19 patients during public health emergencies [11]. The current chapter aimed to summarize all the possible CP transfusion studies that might be beneficial for the treatment and management of individuals infected with SARS-CoV-2.

Fig. (1))

Flow diagram of blood plasma preparation from infected individuals.

Therapeutic Agents (Convalescent Plasma and Immune Globulin)

Convalescent plasma, convalescent serum, and hyperimmune immunoglobulin prepared from convalescent plasma are interventions that have been used in the past to treat conditions when no vaccine or pharmacological interventions were available. Diphtheria, pneumococcal pneumonia, mumps, measles, hepatitis A and B, rabies, and polio are conditions where convalescent plasma is effective [12].

CP contains pathogen-specific neutralizing antibodies, which can neutralize viral particles, and treatment with CP or hyperimmune immunoglobulin confers passive immunity to recipients. The duration of granted protection can differ depending on the timing of administration, ranging from weeks to months after treatment [13]. Apheresis is the approved technique to obtain plasma. Blood from the donor is continuously centrifuged to allow the selective collection of plasma for COVID-19 patients. From a single apheresis donation, the efficiency of this method is about 400–800 mL. The amount of plasma received from the blood through apheresis is frozen and stored in units ranging from 200 to 250 ml which can be used for transfusion to severe patients [14]. Natural defense (antibodies) to the disease is developed in the blood of the patients recovered from COVID-19 present in the plasma portion of the blood.

Plasma from the blood of recovered patients, which contains antibodies against SARS-CoV-2, can be utilized to make two preparations that include CP and hyperimmune immunoglobulin. Later on, it is more concentrated and therefore has more antibodies. The main objective of CP therapy is to neutralize the infectious agent to combat the disease [15]. The composition of CP obtained is variable and may consist of a wide variety of components present in the blood.

It consists of a mixture of organic and inorganic salts, water, and above one thousand proteins, including immunoglobulins, albumin, coagulation, and antithrombotic factors and complement [16]. These components are responsible for the immunomodulatory potential of CP in COVID-19 patients with severe symptoms. It is suggested that plasma obtained from healthy volunteers exerts immunomodulatory actions via the infusion of antibodies and anti-inflammatory cytokines that blocks autoantibodies, cytokines, and complement proteins [17].

After the onset of infection, the first antibody produced is IgM by day-7 and is detectable in serum till day-21. IgG antibody production starts at around day-14 and continues for a longer time [18]. Plasma rich in IgG antibodies is usually collected after 14 days from the date of recovery for convalescent plasma therapy. The first high antibody titers can be observed in recovered patients' serum on the 21^st day because the immune system starts developing antibodies from day 0 of exposure to the antigen (SARS-CoV-2). A rise in antibody production can be observed 14^th day. A significant increase in these specific antibodies (raised against COVID-19) in the serum of the recovered patients can be determined upon further antibody development in the host immune system by the 21^st day. Hence, it can be recommended to use the plasma collected during this peak of antibody increase period for therapeutic purposes effectively [19]. Hyperimmune immunoglobulin has the advantage of preventing harmful coagulation factors from transferring present in plasma products compared to convalescent plasma. The amount and antibody concentration can be more accurately dosed compared to convalescent plasma. Hyperimmune immunoglobulin can be prepared in a consistent manner [20]. The primary accepted mechanism of action for convalescent plasma therapy is the clearance of viremia, which typically happens 10–14 days after infection [21]. For the first time, Shen et al. [9] reported the experience of critically ill patients who received a single dose of 400 mL CP with neutralizing antibody titer in the range of 1:80- 1:480. This increased anti-SARS-CoV-2 IgG and IgM titers in recipients in a time-dependent manner. All the patients were recovered in a short time with improvement in fever and other biochemical parameters. CP therapy in COVID-19 patients is considered an effective and safe technique for the prophylaxis and treatment of COVID-19; however, it needs further investigation in randomized clinical studies.

Safety and Efficacy of CP for COVID-19 patients

Till the discovery of proper drugs for treating COVID-19 or the development of vaccines, the therapeutic strategy is primarily supportive. Several medications, including anti-HIV and anti-viral agents, are clinically effective, but their efficacy was not found satisfactory [22, 23]. The alternate strategy to overcome this viral infection is the use of convalescent plasma. Studies revealed that the patients treated with CP had a short stay in the hospital and lower mortality than those treated with other drugs [24].

The safety and efficacy of CP for COVID 19 were reviewed from 12 different studies [25]. Out of these, 9 studies have shown improvement in clinical symptoms due to CP therapy, while research carried out by Joyner et al [26] did not notice much improvement. About 75 patients in 9 studies required different forms of respiratory support at baseline. The efficacy and safety of CP were significant after therapy initiation in the early stages of viremia as shown by the results. In another study, the patient was clinically stable before and after CP therapy [3].

Pathways Use for Investigational COVID-19 CP

As the Federal Drug Administration (FDA) has not yet approved the CP treatment of COVID-19 patients, so it is regulated under the status of “investigational product”. FDA released the guidelines for investigational COVID-19 CP in March 2020 [27]. These guidelines plan three different pathways for access to CP. The first pathway includes the application of an investigational new drug (IND) in an emergency. It grants permission to the providers to apply for compassionate use of this treatment in a patient having life-threatening COVID-19 with severe symptoms [28]. It should be noted that this pathway does not allow the use of this treatment in individuals for prophylactic purposes. Minimum requirements for requesting permission for the first pathway include a brief history and a description of indications. The first pathway has been allowed in the current situation to cope with the given public health emergency that the COVID-19 pandemic presents [29].

The second pathway relates to the clinical trial research for the management of COVID-19 with CP. Under this pathway, providers are required to request an IND for clinical trials in a traditional pathway as it is for other clinical trials [29]. The third pathway is that of expanded access under the government-led initiative. According to this pathway, expanded access of CP to collaborative research institutes following a master protocol can be provided through a government-led initiative. This pathway would enable the institutions to collect extensive data through a non-randomized study pattern [30].

Collection of COVID-19 Plasma and Eligibility to Donate Blood Plasma (Precautionary Measures)

Convalescent plasma needs immobilization using the blood collection and transfusion infrastructure. The collection and administration of convalescent plasma require standard practices of collection and transfusion [31]. The following points should be noted while collecting CP for administration into COVID-19 patients.

Eligibility of Donors

The first important thing for treating the COVID-19 patients with CP is the determination of the right donor. The eligibility criteria for CP include a person with a history previously confirmed case of COVID-19 with approved laboratory test from nasopharyngeal swab sample, have passed not less than two weeks after the resolution of symptoms such as cough, fever, and SOB. Finally, have a negative COVID-19 history confirmed by standard molecular test in nasopharyngeal swab sample [32]. The donors should be confirmed to be virus-free; negligence in this regard can cause potential problems for the target patients or receivers and the health staff dealing with the donors for the collection of plasma. Approaches for the recruitment of donors include community outreach in places with robust epidemics, communication, and advertising directly via providers, professional organizations, or media. Patients can also be contacted directly; however, this approach poses the issue of patient confidentiality. Blood centers having well-developed and well-equipped infrastructure can be the best option for recruiting donors [33].

Pre-screening of Donors

Pre-screening of donors before donating plasma is the prerequisite for successful therapy of COVID-19 patients with CP. Clinical providers are responsible for the pre-screening of donors. They collect a nasopharyngeal swab sample from the donor and test it for the virus's nucleic acid to ensure the donors are free from the virus. If the donors are free from the virus, they further collect the blood samples from donors for testing antibodies before referring to a collection facility [33].

Antibody Screening

When reflecting on FDA guidance, the tests for antibodies have their challenges. Generally, an individual cannot qualify to be an appropriate donor while using tests that have not been carefully and appropriately examined. It is still not known that which types of antibodies are maximally effective COVID-19 contexts [14]. Antibody neutralization assay is required to be correlated better with its function. However, these assays are not widely available in clinical laboratories. Though quantitative assays such as enzyme-linked immunosorbent assay (ELISA), however, commercially available assays cannot be trusted as they are not appropriately validated [34].

There is limited data available on ELISA. Similarly, the correlation between neutralizing anti-SARS-CoV-2 antibodies and total anti-SARS-CoV-2 antibodies is still not clear. Furthermore, more spike proteins have been tested and used to see if subclasses such as IgG, IgM, or IgA and total antibodies are optimal measures [35]. Thus, an urgent need for an assay is highly validated and a refined treatment modality.

Blood Collection and Testing

Upon qualification of the donors, they are referred to the blood centers that are specialized and well-equipped. A specialized form designed for ensuring the meeting of pre-screening criteria is sent to the blood center. This also ensures that the donors have been appropriately examined. At this stage, the FDA specifies that the donors should go through a complete questionnaire about donor history and standard physical screening. This process helps in preventing the spread of other communicable diseases [36]. For optimizing the yield of CP, apheresis is recommended rather than whole blood donation. This helps in the targeted collection of the required blood volume fraction, and the other components to the donor are returned during the process [36].

Dosing and Transfusion

CP dosing has been considerably variable due to severity and different indications (i.e., treatment vs . prevention). Recently, during the COVID-19 pandemic in china, an investigative study used a single dose (200 mL) of CP [10]. The dose that has been suggested for treatment is 1-2 units, while for post-exposure prophylaxis, the suggested dose 1 unit in the planned clinical trials. The duration of the efficacy of antibodies is not known but has been suggested to last for few weeks [37]. The dosing regimen selected was based on a previous study with the use of CP therapy in SARS, wherein plasma (5 mL/kg) was used at a titer of >1:160 [21]. Previously it has been reported that the prophylactic doses successfully used were only in a short time than the proposed treatment dose. This experience was utilized even in the designing of clinical investigations. The amount of plasma 3.125 mL/kg with a titer of >1:64 would provide an equivalent immunoglobulin level to one-quarter of 5ml/kg plasma with a titer of > 1:160 following first-order linear proportionality. For a typical patient (~80 Kg), this would result in 250 mL of plasma (3.125 ml/kg x 80 kg = 250 mL > 1:64), approximately the same as the amount of a standard unit of plasma in the United States. This stratagem provides logistical ease in the preparation of the product for adult transfusions [31]. Clinical investigations are being programmed for pediatrics where transfusions will be needed to aliquot large volume units and CP dose per body weight. Based on the latest degree of situations, accurate models to determine the bioavailability of CP dose in tissues where virus and host interactions are not yet possible [38].

Patient Eligibility

Patient eligibility criteria are essential to meet FDA requirements for successful treatment of COVID-19 with CP. FDA has suggested the following criteria for patient eligibility for treating COVID-19 with CP.

1. COVID-19confirmed in laboratory.

2. Severe, life-threatening COVID-19: Patients having blood oxygen saturation less than 93%, shortness of breath, respiratory frequency less than 30 per minute, lung infiltrates greater than 50% within 24 to 48 hours, septic shock, and multiple organs failures.

3. Informed consent is provided by the patient or healthcare proxy [28].

Labeling and Recordkeeping

The CP labeled container of COVID-19 units shall have the following statement, “Caution: New Drug--Limited by Federal (or the United States) law to investigational use with reference to the circular of information”. FDA considers that label for COVID-19 CP container does not provide specific information about CP concerning dosage information, indications, cautions, or contraindications. A uniform container label for COVID-19 CP is recommended, especially using the format recommended by the International Society of Blood Transfusion (ISBT) for the Uniform labeling using ISBT 128.

COVID-19 CP should be stored below or at -18°C, frozen within 8 hours, and have an expiry date one year from the collection date. Expiry date and the manufacturing process applied on the label must be the same and for other plasma products of the same type. Health professionals participating in an IND or an expanded access IND (eIND), must keep a record of the units of COVID-19 CP given to the patient suffering from COVID-19. A unique identification number(s) must be a part of such records.

Adverse Effects of CP Therapy

The most common side effects observed with CP therapy include transfusion-related events, such as fever, chills, acute lung injury relating to transfusion, anaphylactic reactions, hemolysis, and cardiovascular problems, etc [39, 40]. Moreover, the risk of infections transmitted by transfusions, such as the hepatitis C virus, human immunodeficiency virus, syphilis, and hepatitis B virus, should not be neglected. Therefore, we need to pay attention to the proper use of CP therapy [41]. The following adverse effects have been noted in several studies. Many of the CP transfusion studies did not report the grade of adverse reactions. Reportedly the participants involved in two studies have experienced adverse reactions data, presumably grades 3 or 4 [42]. A case of severe anaphylactic shock was recorded in another study (3 participants). In contrast, 4 studies (19 participants) have recorded no moderate or severe adverse reaction [43]. A participant in one case study reported mild fever (38.9 °C). One serious adverse event (anaphylactic reaction) was reported in one study (3 participants) after receiving CP. Additionally, 6 case studies described the occurrence of no serious adverse reactions. We are unsure whether or not CP therapy increases the risk of severe adverse reactions (very low-certainty evidence) [42].

Optimal Dose and Clinical Benefits of CP Therapy

CP should be administered to high-risk patients in the early course of the disease. The high-risk patients have an oxygen saturation level below 94% or have an age of more than 70 years [44]. The most appropriate time for CP transfusion is within 5 days after the onset of the disease. The main objective of the treatment of such patients is survival, while secondary outcomes are avoiding the need for ICU and shortening the length of hospital stay [45]. Transfusion (200-250 ml CP/patient/50-80 kg) earlier in the course of the disease or even up to days of the onset of the disease is required. The volume of CP may be adjusted for patients weighing the range of 50-80 kg. The infusion should be slow and closely monitored to avoid circulatory overload and other immediate side effects related to transfusion. After confirmation of sufficient tolerance, 2 units after 24-48 h may be administered [27]. Almost all COVID-19 patients exhibited improvement of symptoms after the transfusion of CP. The acute respiratory distress syndrome was resolved; body temperature became normal, varying degrees of absorption of lung lesion, weaning from ventilator within 1 to a maximum of 5 weeks after transfusion of CP [11].

FUTURE PERSPECTIVE

The convalescent plasma of COVID-19 can be used to treat people having early symptoms and prevent disease in exposed individuals. Healthcare professionals, including physicians and nurses, are exposed to COVID-19 and are being quarantined, collapsing [46]. It is hoped that CP will prevent SARS-CoV-2 infection and if it gets established. It may prevent the health care providers from getting quarantined, and therefore, they will play their critical role. CP may be used prophylactically to prevent COVID-19 among individuals caring for patients of the disease [31].

CONCLUSION

There is a dire need to control the unprecedented global calamity of public health due to the pandemic of COVID-19. At present, no reliable therapeutic option is available for COVID-19 patients having severe symptoms. Based on the aforementioned facts and figures, it may be concluded that CP may be an effective therapeutic option in addition to anti-viral drugs, with some evidence of a reduction in mortality, safety, and improvement of clinical symptoms. However, conclusive evidence on the optimum dose and time-point of treatment for CP to COVID-19 are not available, for which large multicenter clinical trials are urgently required to combat this pandemic.

CONSENT FOR PUBLICATION

Not Applicable.

CONFLICT OF INTEREST

The authors confirm that this chapter contents have no conflict of interest.

ACKNOWLEDGEMENT

Declared none.

REFERENCES