Short report

COVID-19 patients treated with convalescent plasma

Norwegian
    Lise Sofie Haug Nissen-Meyer, Magnhild Eide Macpherson, Linda Gail Skeie, Marte Hvalryg, Abid Hussain Llohn, Tine Torsvik Steinsvåg, Mona Høysæter Fenstad, Anders Tveita, Einar K. Kristoffersen, Tatjana Sundic, Fridtjof Lund-Johansen, John Torgils Vaage, Øystein Flesland, Anne Ma Dyrhol-Riise, Jan Cato Holter, Tor Audun Hervig, Børre Fevang
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    Lise Sofie Haug Nissen-Meyer

    lisoha@ous-hf.no

    Section for Blood Donation

    Department of Immunology

    Oslo University Hospital

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Lise Sofie Haug Nissen-Meyer, PhD, MD, specialist in immunology and transfusion medicine, head of Section for Blood Donation, and head of the NORPLASMA project.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Magnhild Eide Macpherson

    Department of Infection Medicine

    Oslo University Hospital

    Author contribution: data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Magnhild Eide Macpherson, PhD, senior consultant.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Linda Gail Skeie

    Department of Infection Medicine

    Oslo University Hospital

    Author contribution: data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Linda Gail Skeie, Master of nursing (MN in research) and research nurse.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Marte Hvalryg

    Department of Immunology and Transfusion Medicine

    Akershus University Hospital

    Author contribution: data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Marte Hvalryg, specialist in immunology and transfusion medicine, senior consultant.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Abid Hussain Llohn

    Department of Immunology and Transfusion Medicine

    Akershus University Hospital

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, and approval of the manuscript.

    Abid Hussain Llohn, specialist in immunology and transfusion medicine, senior consultant.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Tine Torsvik Steinsvåg

    Department of Immunology and Transfusion Medicine

    Southern Norway Hospital Trust

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Tine Torsvik Steinsvåg, specialist in immunology and transfusion medicine, senior consultant.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Mona Høysæter Fenstad

    Department of Immunology and Transfusion Medicine

    St Olav's Hospital, Trondheim University Hospital

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Mona Høysæter Fenstad, PhD, senior consultant.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Anders Tveita

    Medical Department

    Bærum Hospital

    and

    The KG Jebsen Centre for B-Cell Malignancies

    Oslo University Hospital

    Author contribution: data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Anders Tveita, PhD, specialty registrar and researcher.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Einar K. Kristoffersen

    Department of Immunology and Transfusion Medicine

    Haukeland University Hospital

    and

    Department of Clinical Science

    University of Bergen

    Author contribution: concept, data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Einar K. Kristoffersen, head of Department of Clinical Science and professor.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Tatjana Sundic

    Department of Laboratory Medicine

    Fonna Health Trust

    Author contribution: data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Tatjana Sundic, specialist in immunology and transfusion medicine. Head of Department of Laboratory Medicine.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Fridtjof Lund-Johansen

    Department of Immunology

    Oslo University Hospital

    Author contribution: analysis and interpretation of data, and approval of the manuscript.

    Fridtjof Lund-Johansen, PhD, MD, researcher.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    John Torgils Vaage

    Department of Immunology

    Oslo University Hospital

    Author contribution: concept, structure/design, interpretation of data, and approval of the manuscript.

    John Torgils Vaage, PhD, MD, professor and head of the Department of Immunology, Oslo University Hospital. He is head of the steering group for the NORPLASMA project.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Øystein Flesland

    Department of Quality Improvement and Patient Safety

    Norwegian Directorate of Health

    Author contribution: concept, structure/design, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Øystein Flesland PhD, MD, specialist in immunology and transfusion medicine and senior adviser in the Norwegian Directorate of Health.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Anne Ma Dyrhol-Riise

    Department of Infection Medicine

    Oslo University Hospital

    and

    Institute of Clinical Medicine

    University of Oslo

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Anne Ma Dyrhol-Riise, PhD, MD, senior consultant and head of unit, professor.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Jan Cato Holter

    Department of Microbiology

    Oslo University Hospital

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Jan Cato Holter, PhD, specialist in infectious diseases and medical microbiology, senior consultant. He conducts research on respiratory infections as part of the Clinical Virology Research Group and is head of the Norwegian SARS-CoV-2 study.

    The author has completed the ICMJE form and declares the following conflict of interest: he has received funding from Oslo University Hospital, the Research Council of Norway and Vivaldi Invest.

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    Tor Audun Hervig

    Irish Blood Transfusion Service

    Dublin

    and

    Trinity College

    Dublin

    Author contribution: concept, structure/design, data collection, analysis and interpretation of data, drafting and approval of the manuscript.

    Tor Audun Hervig, specialist in immunology and transfusion medicine, Medical and Scientific Director and Clinical Associate, professor.

    The author has completed the ICMJE form and declares no conflicts of interest.

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    Børre Fevang

    Section for Clinical Immunology and Infectious Diseases

    Oslo University Hospital, Rikshospitalet

    Author contribution: concept, data collection, analysis and interpretation of data, literature search, drafting and approval of the manuscript.

    Børre Fevang, specialist in internal medicine and in infectious diseases, senior consultant. He heads the Norwegian Association for Infection Medicine's expert group for the treatment of COVID-19.

    The author has completed the ICMJE form and declares no conflicts of interest.

    ()

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    Abstract
    BACKGROUND

    BACKGROUND

    In Norway, treatment with COVID-19 convalescent plasma has been given through the NORPLASMA project. The treatment was initially offered to critically ill patients after an individual assessment, but from December 2020, the indication was limited to critically ill, immunocompromised patients. In this article we describe clinical characteristics, comorbidity and mortality in patients who received convalescent plasma in these two periods.

    MATERIAL AND METHOD

    MATERIAL AND METHOD

    From 22 April 2020 to 30 March 2022, a total of 79 patients were included in the observational studies NORPLASMA MONITOR and the Norwegian SARS-CoV-2 study. The patients had received a total of 193 units of convalescent plasma at 15 Norwegian hospitals/nursing homes; 62 in South-Eastern Norway Regional Health Authority, 8 in Western Norway Regional Health Authority and 9 in Central Norway Regional Health Authority. Information on immune status, comorbidity and course of infection was retrieved from the patient records after informed written consent was obtained.

    RESULTS

    RESULTS

    Of 79 patients with a median age of 65 years (interquartile range 51–⁠73) who were treated with convalescent plasma, 31 (39 %) died during hospitalisation. A total of 59 patients were immunocompromised, and of these, 20 died in hospital compared to 11 of 20 who were assumed to be immunocompetent. Median number of comorbidities was 2 (interquartile range 1–4). The patients received a median of two plasma units (min.-max. 1–21). Two of the patients developed mild allergic skin reactions.

    INTERPRETATION

    INTERPRETATION

    Convalescent plasma was well tolerated by patients with COVID-19. Immunocompromised patients may have benefitted from the treatment, with lower mortality than for those assumed to be immunocompetent.

    Main findings

    MAIN FINDINGS

    Treatment with COVID-19 convalescent plasma in 79 patients was well tolerated, and apart from a skin reaction in two of the patients, no serious adverse effects were reported.

    Twenty of the 59 patients with an underlying immunodeficiency died in hospital, while 11 of the 20 patients assumed to be immunocompetent died.

    Article
    Introduction

    COVID-19 convalescent plasma (NORPLASMA) (1) first became available to Norwegian patients in the spring of 2020. The Norwegian Directorate of Health recommended use of the product in patients who were at risk of developing a severe/life-threatening course of COVID-19, where the attending doctor believed there could be clinical benefits for the patient (2). It was also decided to include patients receiving plasma in the observational study NORPLASMA MONITOR (2), but it was not possible to conduct a randomised clinical trial (3).

    All Norwegian hospitals initially conducted clinical studies of COVID-19 patients (4), parallel to inclusion in the observational study Norwegian SARS-CoV-2 (a cohort study), where patients received standard treatment according to consensus-based guidelines. Before 7 December 2020, a small number of patients with an expected severe course of infection were offered experimental treatment with convalescent plasma (5). We have previously discussed the changes in indications for convalescent plasma treatment (3). In the subsequent period (7 December 2020–30 March 2022), treatment with convalescent plasma was limited to critically ill COVID-19 patients where the underlying disease or immunosuppressive treatment was thought to inhibit the immune system/vaccine response. Here we describe the clinical characteristics, comorbidity and mortality in patients who received convalescent plasma at 15 Norwegian hospitals/nursing homes during these two periods.

    Material and method

    Material and method

    NORPLASMA MONITOR is an observational study in which the aim is to collect data from patients who have received COVID-19 convalescent plasma. The protocol, information/consent form and reporting form for patient data collection (REK South-East A, 148622; NCT04463823) are described on the project's website (6). The data protection officers at participating healthcare authorities approved study participation.

    In autumn 2020, the MONITOR study joined forces with the Norwegian SARS-CoV-2 cohort study (REK number 106624; NCT04381819) in a collaboration involving patients recruited at Oslo University Hospital (OUS) and the hospitals in Vestre Viken Hospital Trust. From a total of 15 participating hospitals and nursing homes, 79 patients who had received convalescent plasma were included either in the MONITOR study (n = 55) or via the Norwegian SARS-CoV-2 study (n = 24).

    Fifty-eight patients/next of kin gave written informed consent for inclusion in one of the studies in connection with or after (but independently of) the plasma treatment. Twenty-one deceased patients were later included, after the consent requirement was waived for treated patients who died before inclusion (amendment notification to the Regional Committee for Medical and Health Research Ethics, approved 11 March 2022). Data from participating blood banks showed that 20–25 patients who had received convalescent plasma were not included in the study despite repeated enquiries to the attending doctor. The patients had either declined or had not been asked.

    After separate consent for experimental treatment was obtained, 1–2 units of ABO-compatible COVID-19 convalescent plasma were ordered (1). Some patients received repeated treatments, and a total of 193 plasma units were transfused; 26 in period 1 (22 April 2020–6 December 2020) and 167 in period 2 (7 December 2020–30 March 2022). Antibody content, calculated as the angiotensin-converting enzyme 2 (ACE2) inhibition capacity (1, 3), was measured for 172/193 plasma units (Figure 1). In total, 46 transfused units had an ACE2 inhibition capacity of less than 60 %, either because they were administered early in the pandemic (3) or because they were rare blood types AB or B.

    Figure 1 Antibody content, calculated as the angiotensin-converting enzyme 2 (ACE2) inhibition capacity (1, 3), measured in…
    Figure 1 Antibody content, calculated as the angiotensin-converting enzyme 2 (ACE2) inhibition capacity (1, 3), measured in 172/193 transfused units of COVID-19 convalescent plasma, and time of treatment.
    Collection and storage of patient data

    Collection and storage of patient data

    Health information, including immune status, results of blood tests, vital parameters (respiratory rate, heart rate, oxygen saturation and temperature), treatment and course of infection was obtained from patient records and laboratory data systems according to the protocol (6). It was then de-identified and registered in the project database Ledidi PRJCTS® (Ledidi.com, Oslo). Data from the Norwegian SARS-CoV-2 study were collected from the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) online database using Research Electronic Data Capture (REDCap), version 8.11.11 (Vanderbilt University, Nashville, TN), which is administered by the University of Oxford.

    A comorbidity score was created for all patients by adding the sum of risk factors documented in the patient journal, based on the following list adapted from the Centers for Disease Control and Prevention (7): diabetes, hypertension, heart condition, chronic lung disease, chronic kidney disease, active cancer, rheumatic disease, disease of the central nervous system and body mass index (BMI) > 25 (Figure 2). Patients defined as immunosuppressed have primary or secondary immunodeficiency or receive immunomodulatory treatment. Storage and handling of personal data followed approved procedures at Oslo University Hospital.

    Figure 2 Risk factors included in comorbidity scores (0–9) for 79 patients who received COVID-19 convalescent plasma in the…
    Figure 2 Risk factors included in comorbidity scores (0–9) for 79 patients who received COVID-19 convalescent plasma in the period 22 April 2020–30 March 2022. The figure indicates the number of patients who had each diagnosis/factor. BMI = body mass index.

    The data were processed in Microsoft Excel 2016. Normal distribution (Shapiro-Wilk test) was tested in GraphPad Prism version 9.4.1. Continuous data were predominantly non-parametric and are reported as median (interquartile range) unless otherwise specified.

    Results

    Results

    The study included 79 COVID-19 patients, 51 of whom were men, treated with convalescent plasma in the period 22 April 2020–30 March 2022. The median age was 65 years (51–73). The patients received a median of two (min–max 1–21) units of convalescent plasma.

    A total of 59 patients had immunodeficiency. This was due to immunomodulatory treatment after transplantation, cancer of the blood/immune system or cancer treatment in 38 patients. Patients with immunodeficiency were younger (63 years (46–70)) than those assumed to be immunocompetent (73 years (63–81)). Of the 59 patients with immunodeficiency, 20 died in hospital, compared to 11 out of 20 immunocompetent patients (Table 1).

    Table 1

    Demographic/clinical data for 79 patients who received COVID-19 convalescent plasma in the period 22 April 2020–30 March 2022. 'Immunosuppressed' is defined as patients with primary/secondary immunodeficiency or those receiving immunomodulatory treatment. Number/median with interquartile range is shown in brackets unless otherwise specified.

    Variable

    Immunosuppressed

    Immunocompetent

    Total

    No. of patients

    59

    20

    79

    No. of men

    37

    14

    51

    Age

    63 (46 - 70)

    73 (63–81)

    65 (51–73)

    Comorbidity score1 (0–9)

    3 (2 - 4)

    1.5 (1–3)

    2 (1–4)

    BMI2 (mean ± SD)

    27.6 ± 4.3

    30.7 ± 5.3

    28.7 ± 4.9

    No. of patients receiving intensive care

    25

    11

    36

    Pre-treatment vital parameters:

     

    Respiratory rate

    21 (18–28)

    23 (20–31)

    21,5 (16–28)

     

    Heart rate

    81 (74–96)

    83 (66–91)

    81 (70–95)

     

    Oxygen saturation (SaO2)

    93 (91–96)

    95 (92–96)

    94 (91–96)

     

    Temperature (oC) (mean ± SD)

    37.8 ± 1.0

    37.4 ± 0.8

    37.7 ± 0.9

    Antibody analysis (n = 50 patients):

     

    Positive anti-SARS-CoV-2

    7

    6

    13

     

    Negative anti-SARS-CoV-2

    31

    6

    37

    Course:

     

    Days from positive test to admission

    4 (0–8)

    0 (0–3)

    2 (0–6)

     

    Days from positive test to plasma

    7 (3–16)

    3 (1–6)

    6 (2–13)

     

    Days in hospital after plasma

    11 (5–20)

    10 (3–24)

    10 (4–20)

     

    Days in hospital

    16 (11–30)

    12 (7–24)

    16 (9–30)

     

    No. who died in hospital

    20

    11

    31

    Convalescent plasma transfused:

     

    Units of plasma transfused per patient

    2 (2–3)

    2 (1–2)

    2 (2–3)

     

    ACE2 inhibition capacity, %

    70 (62–80)

    60 (48–80)

    68 (60–80)

     

    No. of transfused units analysed for ACE2 inhibition capacity

    143

    29

    172

    1Comorbidity score 0–9: sum of comorbidities per patient for the following: diabetes, hypertension, heart condition, chronic lung disease, kidney disease, active cancer, rheumatic disease, central nervous system disorder, body mass index > 25.

    2Body mass index: n = 47 (30 immunosuppressed and 17 immunocompetent)

    The patients had a median of two (1–4) comorbidities. The number of patients with each condition included in the calculation of the comorbidity score is shown in Figure 2. Immunocompromised patients had a median of three (2–4) comorbidities, compared to 1.5 (1–3) among the immunocompetent patients. The proportion of patients with heart, kidney or cancer diseases appeared to increase from period 1 to period 2.

    In 21/26 units of convalescent plasma given to 14 patients in period 1, the median ACE2 inhibition capacity was later measured at 48 % (37–83). In period 2, 65 patients received plasma with a median ACE2 inhibition capacity of 70 % (62–80, measured in 151/167 plasma units (Figure 1)). In 50/79 patients, antibody levels against SARS-CoV-2 were measured before they received transfused plasma: 37/50 had no detectable antibodies, and among the 24 who survived the hospital stay, 22 had immunodeficiency. Of the 13 patients with a positive antibody test, 8 survived, and 6 of these had immunodeficiency (further details can be provided upon request to the corresponding author).

    Two patients experienced allergic skin reactions (rash/itchiness) attributed to the plasma treatment, otherwise no adverse effects were reported.

    Discussion

    Discussion

    Convalescent plasma was administered in Norway as an experimental treatment for critically ill COVID-19 patients from 2020 to 2022. This was eventually restricted to critically ill patients with immunodeficiency.

    In our dataset, we found a total mortality of 39 %, which is significantly higher than overall COVID-19 mortality at Norwegian hospitals (4). Figures from the Norwegian Intensive Care and Pandemic Register show a national mortality rate of 6 % among patients hospitalised with COVID-19 in the same period (NIPaR, case number 2022/10466). The high mortality may be due to the strict indication criteria and the fact that it was the most severely ill patients who were included, given the lack of other available treatment options. In international studies, convalescent plasma did not lead to increased mortality (8).

    The lower mortality among patients with immunodeficiency can be explained by the younger age of this patient population compared with the group assumed to be immunocompetent. As at-risk patients started to be identified at an earlier stage, treatment with convalescent plasma could be administered earlier in the course of infection. The ACE2 inhibition capacity in convalescent plasma was generally higher in period 2.

    Convalescent plasma has few adverse effects and is considered safe (8). Possible efficacy in immunocompromised patients is supported by a recently published randomised clinical trial (9). The patient group (n = 50) that underwent SARS-CoV-2 antibody measurement before plasma treatment was too small to analyse the significance of antibody response following previous infection/vaccine. In Norway, the number of patients who received plasma treatment was low. This limited dataset must therefore be interpreted with caution. The fact that it was not possible to carry out a randomised clinical trial is a weakness of the study (3). Nonetheless, our main finding is that convalescent plasma appears to be safe and can be considered for the treatment of COVID-19 patients with immunodeficiency.

    We would like to extend our thanks to Tine Nyberg, Helle B. Hager, Lars Thoresen, Eli Leirdal Hoem, Ingrid Hoff, Aleksander Rygh Holten, Diana Mikova and everyone who contributed to the collection of patient data. We would also like to thank the patients who participated.

    This article has been peer-reviewed.

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    Published: 3 August 2023
    Tidsskr Nor Legeforen 3 August 2023 Vol. 143.
    doi:
    10.4045/tidsskr.22.0577

    Received 8.9.2022, first revision submitted 20.1.2023, accepted 15.5.2023.
    Open access CC-BY-ND
    Copyright: The author(s)
    PlumX
    Published: 3 August 2023
    Tidsskr Nor Legeforen 2023 Vol. 143.
    doi: 10.4045/tidsskr.22.0577

    Received 8.9.2022, first revision submitted 20.1.2023, accepted 15.5.2023.
    Open access CC-BY-ND
    Copyright: The author(s)
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