Reviewing the Ethical Concerns of the Convalescent Plasma Therapy in COVID-19

Addressing the Ethical Concerns of Blood Donors

In all circumstances, the harvest of either WBD or CCP must be voluntary and nonremunerated as published in the ICMR guidelines; no coercion should be imposed on the donor, including indemnity, which is an obligation by the patient party to provide compensation (either in cash or kind) for either a WBD or a CCP donation. Besides that, the informed consent and confidentiality of the donor merit ethical consideration. Further, in compliance with the internationally established and local/regional guidelines, all processes, including apheresis, must be defined and performed appropriately. In principle, all CCP donors should qualify as regular healthy blood donors based on history (including recent recovery from COVID-19), physical examination, and rigorous testing for transfusion-transmitted infection (TTI) markers according to local guidelines. Collections and their justified use are worthy of critical evaluation through regular audits. Additionally, product wastage must be avoided by all possible means.^[19]

Facilitating Eligibility, Recruitment, and Transportation for Donors

The U.S. FDA, United Kingdom BTS, Saudi FDA, ICMR, and other regional health authorities define the criteria for one's eligibility to be a CCP donor as follows:

• Laboratory evidence of COVID-19 disease is confirmed by either a nasopharyngeal swab and/or a positive serological test for SARS-CoV-2 antibodies.

• Complete symptom resolution 28 days before apheresis at the earliest.

Before apheresis, it is important to bear in mind that only those female donors are eligible who are nulliparous; if multiparous, they must carry laboratory evidence of the absence of human leukocyte antigen (HLA) antibodies. This decreases the recipient's risk of acquiring transfusion-related acute lung injury (TRALI) that may happen due to the presence of anti-HLA antibodies in their CCP. Therefore, both ICMR and FDA recommend testing for SARS-CoV-2 neutralizing antibody titers, if the option is available. A neutralizing antibody titer of at least 1:160 is likely to be more beneficial. Otherwise, for the estimation of antibody levels, a sample from the donated CCP should be retained later on.^[9] Saudi Arabian national collaborative study opted for an interesting strategy of utilizing a rapid antibody screening using a handy lateral flow cartridge method to mandate evidence of anti-SARS-CoV2 IgG antibodies in prospective CCP donors and saved aliquots of donated CCP for later testing when this facility would widely be available in the country.^[20] Further, in other studies, CCP donors were selected based on a predefined minimum neutralizing antibodies titer only.^[21,22] Besides, to assess their eligibility for blood donation, CCP donors may even be encouraged to travel to the nearest blood center. Conveyances could also be provided, if needed, to facilitate travel for the same intention.

Safety Assessments and Adverse Event Reporting

• Any unfavorable event that occurs in a patient receiving regular donor plasma or CCP therapy is an adverse event (AE).^[23,24] In general, it is possible to further identify these as:

• AEs related to donors: These events are differentiated into local and systemic reactions. Based on their intensity, they can also be classified as mild, moderate, or severe. Hypotensive reactions, citrate reactions, hematomas, loss of consciousness, seizures, and allergic reactions may further be described in an etiology-based classification.

• Equipment- and/or kit-related AEs: These events are secondary to disposable sets that are defective or erroneous. They can lead to hemolysis, formation of thrombosis, air embolism, leakage, infection due to improper equipment installations, and so on.

• Recipient-based AEs: A transfusion-related AE in a recipient is a consequence that is momentarily related to the administration of blood or blood components. TRALI, transfusion-related circulatory overload, allergic/anaphylactic reactions, TTI transmission, and febrile nonhemolytic transfusion events make up the majority of semilethal and medically curable AEs generally associated with plasma transfusions.

Addressing the Ethical Concerns of Recipients

Before any blood or blood component transfusion, recipients are entitled to receive adequate and legible information on the associated risks of plasma transfusions, particularly the AEs. If any extra steps have been taken to mitigate the risk of TTI (for example, pathogen reduction treatment), it should be mentioned in the informed consent. Their informed consent forms must be kept safely, following local hospital transfusion policies.^[19] Signed documents must then be collected and kept in the medical records of the patients, and the doctors must ensure that they do so regularly. Besides that, all paper and computer data entered in the recipient's medical record must be kept confidential and accessible to authorized personnel only. These confidential records and data can be stored under the properly specified disposition policies at the local hospital facilities. Although the relevant country/regional guidelines do mention recommendations toward one's candidature for CCP therapy, they do not provide a decision-making benchmark as to who should be the first to start receiving CCP therapy. They leave it entirely up to the clinicians and hospitals to decide who would need it the most. This merits ethical consideration on the part of the treating physician and the hospitals collaboratively. The best approach may be to have a multidisciplinary team make a decision. To resolve this ethical problem, hospitals may opt to use a predetermined randomization model, such that the decision does not fall within the scope of their individual preference. Another resolution could be the use of CCP therapy in recipients on a first-come-and-first-served basis. The hospitalization costs incurred and the facility for availing medical insurance claims also need to be critically analyzed.

Financial Support and Sponsorship

None.

Informed Consent

As per the department policy, an informed consent is obtained from all donors prior to blood donation in accordance with our department protocol.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Ethics Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The article does not contain any regulated human participant or animal research.

Authors’ Contribution List

Manish Raturi and Mansi Kala designed the concept. Manish Raturi and Kunal Das did the literature search. Manish Raturi compiled the data. Manish Raturi, Mansi Kala, Kunal Das, and Anuradha Kusum prepared and edited the manuscript. Manish Raturi, Mansi Kala, Kunal Das, and Anuradha Kusum reviewed the manuscript. Manish Raturi, as a guarantor, takes the responsibility of the integrity of the work, as a whole, right from its inception to being a published article.