|Year : 2022 | Volume
| Issue : 1 | Page : 65-70
Experiences, challenges, and their mitigation during COVID convalescent plasma donation management: Data from a single center in India
Geet Aggarwal, Aseem Kumar Tiwari, Swati Pabbi, Arghyadeep Marik, Ganesh Rawat, Jyoti Sharma, Nixon P Joseph, Vikash Vashisth, Govind Sharma
Department of Transfusion Medicine, Medanta-The Medicity, Gurgaon, Haryana, India
|Date of Submission||02-Dec-2021|
|Date of Decision||21-Feb-2022|
|Date of Acceptance||21-Feb-2022|
|Date of Web Publication||29-Apr-2022|
Dr. Aseem Kumar Tiwari
Department of Transfusion Medicine, Medanta-The Medicity, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Background and Objectives: ICMR conducted a multicentric trial “PLACID” that allowed COVID convalescent plasma (CCP) as an experimental drug for the management of moderate COVID-19 disease and the authors' institute was one of the participating centers. The efficacy of CCP in COVID-19 is still debatable. However, unlike therapeutic efficacy, there is not enough literature on issues and challenges faced by health-care institutions in donor recruitment, and the entire vein-to-vein process and approach of CCP transfusion. The authors would like to share their experiences, challenges faced, and their mitigation during the course of donor recruitment, screening, testing, apheresis donation, storage, inventory management, and issue and transfusion of CCP including the regulatory provisions, as their evolution. Methods: This retrospective study was conducted over a period of 7 months at a large tertiary care hospital in north India. Based on ICMR guidelines, the study analyzed the screening process and donation from all consecutive potential CCP donors. The study also identified various issues and challenges faced by the institute and how they were resolved. Results: Prospective donors registered at the blood center were 843. Majority were males (96.6%), first-time CCP donors (93%), age interval 31–45 years (52.2%), who had a history of mild COVID-19 symptoms (86.9%), and were home-quarantined (83.8%). The most common blood group was B positive (50.6%). Only 6.3% of donors were deferred due to the absence of anti-COVID-19 antibodies. Of 843, 705 selected CCP donors donated 1488 CCP units and six donors (0.8%) experienced mild adverse reactions. Challenges faced by authors included donor recruitment, lack of regulatory approval for plasmapheresis, revisions of COVID-specific selection criteria, no “anti-COVID-19 antibody” kit, and CCP inventory management. Conclusion: This study provides real-world comprehensive data on process management of CCP donors and their donations. This understanding of the process, its challenges, and their mitigation could be a template for any possible future pandemic.
Keywords: Apheresis, COVID convalescent plasma, COVID-19, donor management, plasma therapy
|How to cite this article:|
Aggarwal G, Tiwari AK, Pabbi S, Marik A, Rawat G, Sharma J, Joseph NP, Vashisth V, Sharma G. Experiences, challenges, and their mitigation during COVID convalescent plasma donation management: Data from a single center in India. Glob J Transfus Med 2022;7:65-70
|How to cite this URL:|
Aggarwal G, Tiwari AK, Pabbi S, Marik A, Rawat G, Sharma J, Joseph NP, Vashisth V, Sharma G. Experiences, challenges, and their mitigation during COVID convalescent plasma donation management: Data from a single center in India. Glob J Transfus Med [serial online] 2022 [cited 2022 Sep 25];7:65-70. Available from: https://www.gjtmonline.com/text.asp?2022/7/1/65/344324
| Introduction|| |
The PLACID trial by ICMR was a “Phase II, open-label, randomized controlled trial to assess safety and efficacy of convalescent plasma to limit COVID-19-associated complications in moderate disease”. COVID convalescent plasma (CCP) therapy involved collecting antibodies-containing plasma, from a person who had recovered from COVID-19. The trial labeled CCP, as an experimental drug, and the authors' institute was a participating center. The authors' center started recruiting CCP donors from May 14, 2020, after necessary regulatory clearances.
Published studies from India either encourage or refute the “therapeutic role” of CCP in the management of COVID-19 patients.,,,, However, besides therapeutic efficacy, the other aspects such as donor recruitment, selection, testing, storage, inventory management, and transfusion are also important and there is sparse literature on these aspects.
Aims and objectives
The authors' would like to share their experiences, challenges, and their mitigation during the entire process in the year 2020 from the time when there was no “anti-COVID-19 antibody” test available to the time that test became available and even beyond when the sample-to-cutoff value of antibody test was validated for neutralizing potential.
| Materials and Methods|| |
This retrospective, observational, descriptive study was conducted over a period of 7 months (May 2020 to December 2020) in the department of transfusion medicine at a tertiary care hospital in North India. The study analyzed all potential CCP donors who were recruited, registered, health-screened, tested, and donated during the study period. COVID-19-recovered patients discharged from the hospital, COVID-19-recovered hospital staff, and home-quarantined patients were encouraged to donate plasma. Voluntary and directed CCP donations were allowed.
Prospective donors were administered medical history questionnaire and underwent a physical examination before CCP donation based on DGHS criteria. Eligibility criteria included age between18 and 60 years, weight >50 kg, hemoglobin ≥12.5 gm%, normal vitals including temperature <98.4°F, pulse 60–100/min, systolic blood pressure 100–140 mmHg, diastolic blood pressure 60–90 mmHg, and overall sense of “well-being.”
Screening based on ICMR selection criteria
A healthy donor who cleared the preliminary screening had to further fulfill the following criteria to be selected for CCP donation:
- All ABO group donations without unexpected antibodies were allowed
- Only males or nulliparous female (to mitigate the risk of TRALI) donors were selected
- Negative for HBsAg, anti-HCV antibody, anti-HIV antibody, malaria parasite, and syphilis
- Total serum protein >6 g/dl
- Evidence of COVID-19 infection and recovery – As the knowledge about COVID-19 increased in the course of time, the selection criteria for CCP donors were revised in accordance with the national regulatory agencies.
The criteria included:
- Prior diagnosis of COVID-19 documented by a laboratory test (RT-PCR)
- Complete resolution of symptoms at least 14 days prior to donation
- Presence of anti-SARS-CoV-2 IgG antibodies.
No history of transfusion including CCP during treatmentSelected donors were advised to donate once every 15 days.
COVID convalescent plasma-specific informed consent
CCP-specific written consent was explained to the donor detailing about eligibility criteria and preprocedure tests, procedure-time, possible adverse events, volume of CCP, storage, and issue to COVID-19 patient(s). CCP was collected from individuals who provided written consent. Donor record sheet (including date of onset, symptoms, severity, hospitalization, history of transfusion, and date of the resolution of symptoms) was completed. Written consent was also obtained from the patient's next-of-kin regarding the off-label clinical use of CCP and possible benefits and risks. This was informed consent regarding the administration of blood component (CCP) to their patient.
Donor testing was performed prior to CCP donation. Test performed at blood center laboratory included blood counts (including hemoglobin, hematocrit, total leucocyte count, and platelet count), blood group, antibody screen, transfusion-transmitted infections (TTI; including HBsAg, anti-HCV antibody, anti-HIV antibody, malaria parasite, and syphilis), and anti-SARS-CoV-2 IgG antibodies. Serum protein was performed at a centralized-hospital biochemistry laboratory.
Anti-SARS-CoV-2 IgG antibodies
During the initial phase (14th May–10th July), since no antibody detection kit was commercially available, donor selection was based solely on ICMR criteria. CCP donations were collected without performing antibody testing and issued to patients. Anti-SARS-CoV-2 IgG antibody detection was subsequently done on stored samples from such donations. After July 10, when the antibody detection kit became available, donor selection was based on the presence of anti-SARS-CoV-2 IgG antibody (S/Co >1.0). In the course of time, the authors established that S/Co of ≥4.96 corresponded with the presence of neutralizing antibodies (protective antibodies against COVID-19), and donor selection for CCP donation was restricted to donors with anti-SARS-CoV-2 IgG antibody S/Co of ≥4.96, thereafter.
The donor who failed to clear initial selection criteria (medical history or physical examination), CCP-specific criteria, or donor testing (including TTI testing or anti-SARS-CoV-2 IgG antibodies) were deferred from donation. The donors were informed if deferral was temporary or permanent with appropriate counseling.
COVID convalescent plasma collection
CCP was collected on the Amicus cell separator machine (Fresenius Kabi, Germany) using plateletpheresis protocol. All donors were observed and monitored for adverse reactions during the procedure and 30 min post procedure in accordance with adverse blood donor reaction reporting form, National Blood Donor Vigilance Programme, National Institute of Biologicals, India. All donors were prophylactically given two oral tablets of calcium carbonate (equivalent to elemental calcium of 500 mg) to prevent citrate-related adverse reactions as per institutional protocol.
COVID convalescent plasma unit storage and issue
The 400 ml CCP collected was divided into two equal doses of 200 ml each using a sterile connecting device. Units were labeled with appropriate information including unique donation number, date of collection, blood group, volume, date of expiry, and patient name (in case of directed donations). ABO compatible CCP unit was thawed; minor cross-match was performed and then issued to the patient.
Donor classification and data collection
Donors were classified in the following manner and data were collected:
Frequency of COVID convalescent plasma donation
- First-time – Donated CCP first-time at authors' center
- Repeat – Donated CCP more than once at the authors' center.
Type of blood donation
- Directed – Donation was made for a specific patient
- Replacement – Donation made to replace blood component already provided to a patient
- Voluntary – Altruistic donation made out of free will.
- Home – Donors isolated at their homes
- Institution – Donors who required institutional/hospital admission for treatment.
- Asymptomatic – History of contact with known COVID-19 positive; experienced no symptoms
- Mild – Had mild symptoms; did not require oxygen
- Moderate – Rrequired oxygen but did not require invasive mechanical ventilation
- Severe – Required invasive mechanical ventilation.
The institutional ethics committee approved the study. The “declaration of Helsinki” guidelines were followed.
| Results|| |
Of the prospective 843 CCP donors registered and screened at the blood center; 742 donors were selected for donation and 101 donors were deferred from donation at various stages of screening on the basis of their medical history, physical examination, or blood testing. Out of 742 donors selected, the donation was initiated for 705 donors. Six out of 705 donors experienced adverse reactions during the procedure. [Figure 1] depicts a flow diagram for donor registration, selection, deferral, apheresis donations, and adverse reactions.
|Figure 1: Flow diagram for donor registration, selection, deferral, apheresis donations, and adverse reactions. *n = 51 can be further divided as medical history (including hemoglobin, blood pressure, etc.; n = 30), history of plasma transfusion (n = 3); poor venous access (n = 7); <14 days post COVID-19 recovery (n = 9); positive repeat RT-PCR for COVID-19 (n = 2). CCP: COVID convalescent plasma; HBV: Hepatitis B virus; HCV: Hepatitis B virus; IAT: Indirect anti-globulin test; TTI: Transfusion transmissible infection; VVR: Vasovagal reflex|
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Male-to-female ratio as 28.4:1 in 705 donors. Donors from all eligible age groups came forward for CCP donations with more than 50% donors from age group 31–45 years (52.2%). The authors' center witnessed huge number of motivated first-time CCP donors (93%). Forty-three donors (7%) donated CCP more than once. Similarly, donation drive among hospital staff including blood centers' staff, and recovered patients resulted in a relatively high percentage of voluntary CCP donations (17.3%). Majority of CCP donors had a history of mild symptoms (86.9%) and were home quarantined (83.8%). Decreasing order for ABO blood group distribution among the CCP donors was B (50.6%) >A (21.2%) >AB (14.4%) >O (13.6%).
Anti-SARS-CoV-2 IgG antibody testing
Retrospective antibody testing on stored samples
Seventy-three CCP donations were collected before the antibody testing kit was available at the authors' center. Retrospective testing revealed that majority of donors (79.5%) had antibodies; antibodies were undetected in 15 donors (20.5%).
Prospective antibody testing of donors
Out of 670 CCP donors tested, 38 (5.6%) donors had antibody S/Co <1.0 (deferred). 632 (94.4%) donors had antibody S/Co >1.0; 103 donors had S/Co between 1.0 and 4.96, and 529 donors had antibody S/Co ≥4.96.
101 donors were deferred from CCP donation due to various reasons. Fifty-one donors were deferred at the stage of initial screening either on basis of their medical history or inability to clear physical examination, for example, medical history including low hemoglobin (n = 15), uncontrolled high blood pressure (n = 10), less than minimum interval of 14 days after recovery and resolution of COVID-19 symptoms (n = 9), history of CCP therapy during their COVID-19 management (n = 3), positive repeat RT-PCR for COVID-19 (n = 2), and others (n = 5). Fifty donors who had cleared initial screening, were deferred on basis of blood testing. Eleven donors were reactive for transfusion transmissible infection markers (six syphilis, four hepatitis B, one hepatitis C); one donor had positive antibody screen (anti-M was identified); and 38 donors were non-reactive for anti-COVID-19 IgG antibodies. Out of these 38 donors, 14 donors had a positive history of COVID-19 infection that presented with mild symptoms and the mean time duration after recovery from symptoms to day of prospective donation was 63 days (range 30–120). The rest, 24 donors, had a history of contact with symptomatic COVID-19-positive family members and had remained asymptomatic. The mean time duration after the last contact to day of prospective donation was 42 days (range 28–70). All donors screened had serum protein >6 g/dL.
The authors' center initiated a total of 748 CCP donations from 705 different donors; 656 donors were first time, and 43 were repeat donors. Out of 748 donations initiated, 740 donations were completed successfully (yielding a total of 1484 CCP units) and six donors had a mild adverse reaction during donation (in four donors, a single unit of 200 ml was collected, while in other two donors, no unit [200 ml] could be collected). The authors' collected a total of 1488 CCP units. [Table 1] and [Table 2] give a detailed demographic distribution of these 705 donors.
|Table 1: Descriptive demographic details of COVID convalescent plasma donations|
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Six donors (0.8%) experienced a mild form of vasovagal reaction (VVR; four donors experienced adverse reactions during the second half of procedure, and one unit CCP (200 ml) each was harvested from these donors. However, two donors had mild reactions soon after initiation of the procedure, and no CCP unit was collected in these donations. All six procedures were stopped immediately after donors complained of symptoms of VVR and donors recovered after conservative management. Red blood cell reinfusion was performed in all the six donors.
Clinical use of COVID convalescent plasma therapy
Moderately affected COVID-19 patients received two units of CCP on consecutive days in accordance with ICMR patient selection guidelines.
| Discussion|| |
The authors' institute was one of the participating centers in the ICMR-initiated PLACID trial and was authorized to recruit, which selects CCP donors and provides CCP therapy to patients who met the ICMR inclusion criteria. The present study analyzed demographic and descriptive details of CCP donors over a period of 7 months. In comparison to previous studies comprising whole blood donors,,, gender and age distribution of CCP donors were similar. Apart from routine blood donor deferral reasons, additional CCP-specific criteria of “history of pregnancy” (HLA sensitization) led to the outright deferral of otherwise motivated and eligible females. Majority of CCP donors had a history of mild symptoms (86.9%) and were home quarantined (83.8%). Mahapatra and Pati et al. also made similar observations. The lack of confidence in the safety measures at the hospitals, fear of COVID-19 reinfection and transmitting infection to family member(s), and subsequent institutional quarantine possibly discouraged many eligible donors to donate CCP, especially those patients who had recovered from moderate to severe symptoms. The authors' center observed only 4.4% (28/632) CCP donations from such donors.
ABO blood group distribution
ABO type distribution among CCP donors (B [50.6%] >A [21.2%] >AB [14.4%] >O [13.6%]) significantly differed from previously published reports on whole blood donors (B [36.4%] >O [30.8%] >A [23.1%] >AB [9.7%]) from the same region.,,, The fact that “AB” blood group is a universal plasma donor resulted in a relatively high percentage of AB group CCP donations. This together with the fact that B blood group plasma is compatible with both B and O group individuals, there was a significantly high number of B group CCP donations and low numbers of O group CCP donations (compatible with only O group patients). The center also encouraged AB and B group CCP donations over O group donors to maintain an inventory of compatible ABO group CCP units.
In the course of time, the authors established that S/Co ≥4.96 as cutoff for the presence of neutralizing antibodies and concluded that this S/Co could be used for selecting suitable plasma donors for CCP therapy. In a large multicentric study using the same immunoassay at Mayo clinic, U. S. A, Joyner et al. classified donors based on levels of neutralizing antibodies. Irrespective of the severity of symptoms or days after recovery from COVID-19, more than 80% of CCP donors had the presence of neutralizing antibodies or S/Co ≥4.96. However, Mahapatra and Pati mentions a high deferral rate among CCP donors due to the absence of adequate neutralizing antibody.
Deferral and adverse events
During the initial screening, majority of CCP donors were temporarily deferred and their inability to donate created anxiety among patients' families. Recruiting volunteer CCP donors mitigated this anxiety. Lack of anti-SARS-CoV-2 IgG antibody was an important reason for deferral in CCP donors. The rate of adverse reactions (0.8%) during apheresis CCP collection was also lower than previously published studies (2.7%–6.06%) from the region.,,,,
Challenges and their mitigation
License to perform plasmapheresis
In accordance with the Drugs and Cosmetics Act, 1940 and Rules, 1945, blood center should possess a valid certified license for the type of intended blood donation and component processing. Most blood centers prepare plasma units from whole blood donations. Since whole blood-derived plasma is usually surplus even after fulfilling all clinical transfusion requirements, most blood centers do not possess the license to prepare plasma via plasmapheresis. This became a major limitation for initiating the collection of plasma (CCP). Blood center received the license, just in time, to initiate the CCP collection.
Lack of dedicated plasmapheresis equipment
Many blood centers including the authors' center did not possess dedicated equipment (for e.g., Autopheresis-C) and specific kit (for e.g., PLS bundled kit, Hemonetics Corporation, USA) to perform donor plasmapheresis. Sankha Datta and Chakrabarty mentions an inadequate number of collection facilities as one of the reasons for failure of plasma therapy. The authors overcame this challenge by performing plasmapheresis on Amicus (Fresenius Kabi, Germany) equipment using plateletpheresis protocol. This ensured that two therapeutic doses of 200 ml plasma (CCP) were obtained and very few platelets (1.5 × 1011) in the belt were discarded. This protocol helped authors' center to collect CCP, without capital expenditure (buying of new apheresis machine), or adding new specific kit to the inventory or compromising donor safety.
Quarantine period (14–28 days), fear of COVID-19 re-infection, lack of awareness, and knowledge about plasmapheresis donation hindered the process of finding eligible donors by the families. Similar observations were noted by other published reports from the region.,, Hospital also distributed “Corona Warrior” certificate to encourage staff members to donate CCP. The authors, themselves, set a precedent by donating CCP, before asking others. In the initial phase, when finding eligible donors was difficult, few NGO and NFP organizations assisted in connecting donors with the patients' families. Donor passes were issued to potential outside/community donors to come forward during the lockdown period. These passes allowed donors to come out of their homes and travel to hospital blood donation centers without police personnel stopping them at check posts. The authors' blood center witnessed multiple voluntary CCP donations.
Multiple revisions of COVID-specific COVID convalescent plasma donor selection criteria
The necessary documentary requirement of COVID reports and multiple revisions of COVID-specific CCP donor selection criteria by the national regulatory bodies (ICMR, DGHS, MOHFW GOI) were unavoidable challenges. Authors abided by these regulatory or guideline-based revisions by regularly updating their standard operating procedure for CCP donor selection criteria and change management protocol.
Neutralizing antibody – a specialized test for quality assurance of COVID convalescent plasma
PLACID trial conducted by ICMR, India, desired the presence of high titers of anti-COVID-19 IgG antibodies (titer ≥1024) or SARS-CoV-2 neutralizing antibodies (titer ≥40) in the CCP donor. Subsequently, MOHFW, GOI, in their COVID Management Protocol, also mentioned that CCP should either be positive for virus-neutralizing antibody (minimal threshold not defined) or positive for anti-COVID-19 IgG antibodies (titer >640).
There are multiple assays that can be used to measure neutralizing antibodies (NAbs). S/Co ratio >4.96 on the chemiluminescent IgG assay showed >30% inhibition on sVNT assay and this correlated with 90% viral neutralization activity.
No “anti-COVID-19 antibody” kit for antibody titer
Although the lack of “titration” testing did not result in donor deferral in the ICMR trial protocol or the MOHFW protocol, titration as a procedure is low throughput, cumbersome, and subjective in interpretation. This correlation negated the need of “titration” and played important role in donor selection.
COVID convalescent plasma Inventory management
Blood centers usually maintain enough inventory of different components such as RBC or platelets to ensure that patients can be provided ABO-compatible components when the need arises. Clinical guidelines on the use of CCP required ABO group and crossmatch compatible unit to be transfused to COVID-19 patients. Patients' families therefore had to arrange directed donors. This was difficult, time consuming, and would cause delay in commencement of CCP therapy. We overcame this challenge by building up a small inventory of CCP units of all ABO groups. This stock allowed authors to provide CCP therapy to patients in time. This also provided a buffer time to families in finding eligible CCP donors as “replacement donors,” instead of “directed donors.” Over time with increase in awareness, and subsequent increase in number of voluntary CCP donations, the authors' center was able to establish rolling stock of CCP units.
| Conclusion|| |
This study provides real-world comprehensive data on the process management of CCP donors and their donations.
Financial support and sponsorship
Conflicts of interest
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[Table 1], [Table 2]