# Convalescent plasma in patients receiving rituximab or ocrelizumab for multiple sclerosis or neuromyelitis Optica spectrum disorder with Covid-19: A multicenter retrospective study

Tanguy Dequidt, Quentin Richier, Céline Louapre, Florence Ader, Yanis Merad, Nicolas Lauwerier, Christine Jacomet, Michel Carles, Charlotte Biron, Vincent Gendrin, et al.

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Tanguy Dequidt, Quentin Richier, Céline Louapre, Florence Ader, Yanis Merad, et al. Convalescent plasma in patients receiving rituximab or ocrelizumab for multiple sclerosis or neuromyelitis Optica spectrum disorder with Covid-19: A multicenter retrospective study. International Journal of Infectious Diseases, 2025, 151, pp.107323. 10.1016/j.ijid.2024.107323. hal-05047050

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# Convalescent plasma in patients receiving rituximab or ocrelizumab for multiple sclerosis or neuromyelitis Optica spectrum disorder with Covid-19: A multicenter retrospective study

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Tanguy Dequidt<sup>1,*</sup>, Quentin Richier<sup>2</sup>, Céline Louapre<sup>3</sup>, Florence Ader<sup>4</sup>, Yanis Merad<sup>4</sup>, Nicolas Lauwerier<sup>5</sup>, Christine Jacomet<sup>6</sup>, Michel Carles<sup>7</sup>, Charlotte Biron<sup>8</sup>, Vincent Gendrin<sup>9</sup>, Clément Marlat<sup>10</sup>, François Danion<sup>11</sup>, Tristan M Lepage<sup>12</sup>, Albert Sotto<sup>13</sup>, Loïc Bourdellon<sup>14</sup>, Alexandre Mania<sup>15</sup>, Martin Martinot<sup>16</sup>, Georges Le Falher<sup>17</sup>, Alexis Ferre<sup>18</sup>, Benoit Pilmis<sup>19</sup>, Guillaume Gondran<sup>20</sup>, Pierre Simeone<sup>21</sup>, Matthieu Henry<sup>22</sup>, Toufik Kamel<sup>23</sup>, Simon Ray<sup>24</sup>, Sophie Ancellin<sup>25</sup>, Nicolas Mélé<sup>26</sup>, Fabrice Camou<sup>27</sup>, Marjolaine Destremau<sup>27</sup>, Jeremy Sellenet<sup>28</sup>, Noémie Zucman<sup>29</sup>, Marion Le Maréchal<sup>30</sup>, Khawla Mellouki<sup>31</sup>, Marie-Elodie Langlois<sup>32</sup>, David Luque Paz<sup>33</sup>, Maud Mousset<sup>34</sup>, Catherine Leclerc<sup>35</sup>, Agnès Sommet<sup>36</sup>, Karine Lacombe<sup>37</sup>, Guillaume Martin-Blondel<sup>38,39</sup>

<footnote n="1"><sup>1</sup> Department of Infectious Diseases, Guadeloupe University hospital, Pointe-à-Pitre, France</footnote>

<footnote n="2"><sup>2</sup> Sorbonne University, Department of Infectious Diseases, Saint Antoine Hospital, APHP, Paris, France</footnote>

<footnote n="3"><sup>3</sup> Sorbonne University, Department of Neurology, Pitié Salpêtrière Hospital, APHP, CIC neurosciences, Paris Brain Institute, Paris, France</footnote>

<footnote n="4"><sup>4</sup> Department of Infectious Diseases, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote n="5"><sup>5</sup> Department of Infectious Diseases, Lille University Hospital, Lille, France</footnote>

<footnote n="6"><sup>6</sup> Department of Infectious Diseases, Clermont-Ferrand University Hospital, Clermont-Ferrand, France</footnote>

<footnote n="7"><sup>7</sup> Department of Infectious Diseases, Nice University Hospital, Nice, France</footnote>

<footnote n="8"><sup>8</sup> Department of Infectious Diseases, Nantes University Hospital, Nantes, France</footnote>

<footnote n="9"><sup>9</sup> Department of Infectious Diseases, Nord Franche-Comté Hospital, Belfort, France</footnote>

<footnote n="10"><sup>10</sup> Department of Infectious Diseases, Rouen University Hospital, Rouen, France</footnote>

<footnote n="11"><sup>11</sup> Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France</footnote>

<footnote n="12"><sup>12</sup> Department of Infectious Diseases, Montpellier University Hospital, Montpellier, France</footnote>

<footnote n="13"><sup>13</sup> Department of Infectious Diseases, Nimes University Hospital, Nimes, France</footnote>

<footnote n="14"><sup>14</sup> Medicine A unit, Emile Durkheim Hospital, Epinal, France</footnote>

<footnote n="15"><sup>15</sup> Department of Internal Medicine, Henri Mondor Hospital, Aurillac, France</footnote>

<footnote n="16"><sup>16</sup> Department of Infectious Diseases, Colmar Hospital, Colmar, France</footnote>

<footnote n="17"><sup>17</sup> Department of Internal Medicine, Béziers Hospital, Béziers, France</footnote>

<footnote n="18"><sup>18</sup> Intensive Care Unit, Versailles Hospital, Le Chesnay, France</footnote>

<footnote n="19"><sup>19</sup> Antimicrobial Stewardship Team, Microbiology Unit, Groupe Hospitalier Paris Saint Joseph, Paris, France</footnote>

<footnote n="20"><sup>20</sup> Department of Internal Medicine, Limoges University Hospital, Limoges, France</footnote>

<footnote n="21"><sup>21</sup> Department of Anesthesiology and Critical Care Medicine, University Hospital Timone, APHM, Marseille, France</footnote>

<footnote n="22"><sup>22</sup> Medical-Surgical Intensive Care Unit, District Hospital Center, La Roche sur Yon, France</footnote>

<footnote n="23"><sup>23</sup> Intensive Care Unit, Orléans University Hospital, Orléans, France</footnote>

<footnote n="24"><sup>24</sup> Department of Infectious Diseases, Rodez Hospital, Rodez, France</footnote>

<footnote n="25"><sup>25</sup> Department of Infectious Diseases, Auch Hospital, Auch, France</footnote>

<footnote n="26"><sup>26</sup> Department of Neurology, GHU Paris Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France</footnote>

<footnote n="27"><sup>27</sup> Intensive Care and Infectious Disease Unit, Groupe Saint-André, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote n="28"><sup>28</sup> Department of Internal Medicine, Saint Jean Sud de France Clinic, Saint-Jean-de-Vedas, France</footnote>

<footnote n="29"><sup>29</sup> Intensive Care Unit, CH Annecy Genevois, Epagny Metz-Tessy, France</footnote>

<footnote n="30"><sup>30</sup> Univ. Grenoble Alpes, Infectious Diseases Department, CHU Grenoble Alpes, Grenoble, France</footnote>

<footnote n="31"><sup>31</sup> Department of Infectious Diseases, Claude Bernard University Lyon 1, Valence Hospital Center, Valence, France</footnote>

<footnote n="32"><sup>32</sup> Department of Internal Medicine and Infectious Diseases, Saint Joseph Saint Luc Hospital, Lyon, France</footnote>

<footnote n="33"><sup>33</sup> Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France</footnote>

<footnote n="34"><sup>34</sup> Intensive Care Unit, Comminges Pyrénées Hospital, Saint-Gaudens, France</footnote>

<footnote n="35"><sup>35</sup> Department of Infectious Diseases, CHI Poissy - Saint-Germain-en-Laye, Saint-Germain-en-Laye, France</footnote>

<footnote n="36"><sup>36</sup> Clinical Investigation Center, Toulouse University Hospital, Toulouse, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: tanguy.dequidt@gmail.com (T. Dequidt).</footnote>
ARTICLE INFO

Article history:

Received 10 September 2024

Revised 28 November 2024

Accepted 29 November 2024

Keywords:

SARS-CoV-2

Protracted COVID-19

Convalescent plasma

Anti-CD20 antibodies

Multiple sclerosis

Neuromyelitis optica

A B S T R A C T

**Background:** Despite vaccination, patients receiving anti-CD20 monoclonal antibodies (mAbs) for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) have an increased risk of developing severe or protracted COVID-19. The aim of this study was to describe the effect of COVID-19 convalescent plasma (CCP) in patients with MS or NMOSD exposed to anti-CD20 and infected by SARS-CoV-2.

**Methods:** This French national, retrospective cohort study was conducted between November 2020 and June 2023. Patients with MS or NMOSD, under anti-CD20 mAbs, with symptomatic COVID-19 and treated by CCP were screened. Protracted COVID-19 was defined by a duration of symptoms >21 days. The primary endpoint was the overall survival 30 days after CCP administration.

**Results:** Ninety-two patients from 34 hospitals were included, 84 (91%) with MS and 8 (9%) with NMOSD. Overall, 30-day survival was 97% (IC95%: 91-99). SARS-CoV-2 viremia was positive in 47/75 (61%) patients before CCP versus 9/59 (15%) seven days post-CCP. In the 52 patients (57%) with protracted COVID-19, the duration of symptoms before CCP was 51 [28-69] days, including fever in 75% of cases, which disappeared in 100% of patients 7 days post-CCP.

**Conclusions:** CCP could be a therapeutic option in patients exposed to anti-CD20 mAbs for inflammatory demyelinating disease, particularly in those with protracted COVID-19.

© 2024 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Introduction

Anti-CD20 monoclonal antibodies (mAbs) such as rituximab and
ocrelizumab are now widely used for the treatment of inflamma-
tory demyelinating diseases (IDD) including multiple sclerosis (MS)
and neuromyelitis optica spectrum disorders (NMOSD) [1]. Since
the first outbreak of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2), several studies have shown that patients treated
with anti-CD20 mAbs can develop severe or protracted coronavirus
disease 2019 (COVID-19), with symptoms lasting up to 1 year with-
out adequate treatment [2]. Exposure to anti-CD20 mAbs leads to
complete B-cell depletion, resulting in impaired humoral immu-
nity due to reduced neutralizing antibody titer, which in turn leads
to reduced viral clearance and protracted clinical manifestations of
SARS-CoV-2 infection [3].

Convalescent plasma therapy is a passive hyperimmune poly-
clonal antibody transfusion to provide prompt humoral immunity,
already used in the past for other viral epidemics such as Span-
ish flu, Argentinian fever, SARS-CoV and Ebola. In immunocompe-
tent patients, while early administration appears to be beneficial
in mild to severe infections, COVID-19 convalescent plasma (CCP)
remains controversial due to a large number of clinical trials with
conflicting results [4–6]. However, following reports of case series
showing clinical efficacy, CCP therapy has attracted renewed inter-
est in immunocompromised patients exposed to anti-CD20 mAbs
[7]. Hueso et al. [8] even showed that patients pre-exposed to anti-
CD20 mAbs for B-cell lymphoid disease and treated with CCP ex-
hibited a significantly better survival probability than those who
did not receive CCP.

Patients with MS or NMOSD exposed to anti-CD20 mAbs have a reduced humoral immune response to SARS-CoV-2, as reported in hematological malignancies [9]. Although CCP has been less studied in patients with MS, some cases exposed to mAbs have reported rapid clinical improvement after CCP administration [10]. In contrast, there are no reports of COVID-19 treated with CCP in patients with NMOSD exposed to anti-CD20 mAbs.

The aim of our study was to describe clinical, biological and vi-
rological outcomes in a homogeneous population of MS or NMOSD

patients exposed to anti-CD20 mAbs and treated with CCP for
symptomatic COVID-19.

Methods

Hospital setting and study design

This nationwide, multicenter and retrospective cohort study was conducted between November 2020 and June 2023. In France, the CCP administration must be assessed after consulting a regional multidisciplinary expert groups (here located in Paris, Lyon, Rennes or Bordeaux) who manage the French CCP Early Access Program. All symptomatic COVID-19 patients for whom CCP is requested are registered in databases from which patients with MS or NMOSD and anti-CD20 mAbs were screened for eligibility criteria. Inclusion criteria were adult patients (age ≥18 years) with an established diagnosis of MS or NMOSD, exposed to anti-CD20 mAbs, and effectively treated with CCP for symptomatic COVID-19. Symptomatic SARS-CoV-2 infection was proven by positive RT-PCR in one respiratory sample (nasopharyngeal or bronchoalveolar lavage). Noninclusion criteria were refusal of CCP transfusion by the multidisciplinary expert group, no effective CCP administration, lack of access to clinical record and patient refusal to participate.

Convalescent plasma collection

Convalescent donors were eligible for plasma donation if
COVID-19 symptoms had been resolved for at least 15 days. Col-
lected apheresis plasma underwent pathogen reduction (Intercept
blood system; Cerus, Concord, CA) and standard testing, in compli-
ance with French regulations.

Convalescent plasma infusion

All patients received two units per day over 2 days of ABO-compatible CCP (200–220 mL each). Before mid-January 2022, patients received CCP predating the emergence of omicron, and from mid-January and onward, mostly omicron CCP has been transfused.

<footnote n="37"><sup>37</sup> Sorbonne University, IPLESP Inserm, Infectious Diseases Department, Saint Antoine Hospital, APHP, Paris, France</footnote>

<footnote n="38"><sup>38</sup> Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France</footnote>

<footnote n="39"><sup>39</sup> Toulouse Institute for Infectious and Inflammatory Diseases, INSERM UMR1291 - CNRS UMR5051 - Toulouse III University, Toulouse, France</footnote>
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Flow chart.</figcaption></figure>

The anti-SARS-CoV-2 antibody content was assessed for each do-
nation, with the requirement of a SARS-CoV-2 seroneutralization
titer ≥40. Additionally, antibody content was determined by IgG
enzyme-linked immunosorbent assay (ELISA EUROIMMUN, Bussy-
Saint-Martin, France) [11]. All collected plasma yielded a mean
ELISA ratio of 6.1 (s.d.: 2.9, IQR: 5.4, min. 0.4, max: 13.0).

Data collection

After identification of the patients using data from the experts'
groups in France, we contacted requesting clinicians to obtain ad-
ditional information. Medical records of included patients were re-
viewed retrospectively by the requesting clinician from each cen-
ter. Data were collected via an online LimeSurvey. Baseline char-
acteristics were age, sex, body mass index (BMI), hypertension,
Charlson comorbidity index, time since inflammatory demyelinat-
ing diseases diagnosis, multiple sclerosis subtype, Expanded Dis-
ability Status Scale (EDSS) score [12], prior disease-modifying ther-
apy (DMT) use, anti-CD20 agent, time from anti-CD20 start to
COVID-19, number of anti-CD20 cycles, time from last anti-CD20
infusion to COVID-19, data related to vaccination against COVID-19,
SARS-CoV-2 serostatus and specific treatments for COVID-19 prior
to CCP. Clinical (fever, oxygen requirement, WHO severity scale
[13]), biological (C-reactive protein (CRP) and ferritin) and virologi-
cal (RT-PCR in respiratory and blood samples, cycle threshold when
available and SARS-CoV-2 variant identification) parameters were
recorded at day 0 and day +7 after CCP. Serological and RT-PCR
methods were not gathered (Supplementary methods). All grade
3-4 adverse events were reported.

Definitions

Acute and protracted forms of COVID-19 were defined by symp-
toms lasting ≤ and >21 days after the first SARS-CoV-2 RT-PCR,
respectively, according to the Dioverti *et al.* [14] definition.

SARS-CoV-2 serology was considered positive when the anti-
spike antibody threshold was >264 BAU/mL, which is associated
with a COVID-19 vaccine efficacy of 80% against symptomatic in-
fection [15].

Viremia referred to a positive SARS-CoV-2 RT-PCR on blood
sample.

COVID-19 relapse corresponded to the need for a new hospital-
ization due to a recurrence of COVID-19 symptoms and confirmed
by a new positive SARS-CoV-2 RT-PCR on respiratory or blood sam-
ples.

Primary and secondary endpoints

The primary outcome was 30-day overall survival after CCP
treatment. Secondary endpoints were 7 and 90-day overall sur-
vival, occurrence of COVID-19 relapse at 30 and 90 days, and kinet-
ics of clinical, biological, and virological parameters between day 0
and day 7 after CCP transfusion. Clinical improvement was defined
as a loss of 1 point or more on the WHO severity scale between
day 0 and day 7 after CCP transfusion.

Statistical analysis

Data were expressed as median with interquartile (IQR) range for quantitative variables, and numbers and percentage for qualitative variables. Continuous variables were compared using Student's t-tests or Mann-Whitney tests and categorical variables were compared using Chi-square tests or Fisher's exact tests. All tests were 2-tailed and P values ≤ 0.05 were used for statistical significance testing. Analyses were performed using STATA® software (version 18, StataCorp, College Station, Texas).
## Ethics

The study was approved by the French national infectious diseases ethical committee (N°IRB00011642). All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments. According to French legislation, participants received an information notice mentioning their participation to the study and giving the possibility of objecting.

## Results

### Baseline characteristics and disease features

Over a 32-months period, 112 MS or NMOSD patients were presented to the French multidisciplinary expert groups. Ninety-two individuals from 34 hospitals (Table S1) were included in the final study analysis, of whom 84 patients (91%) had MS and 8 patients (9%) suffered from NMOSD (Figure 1, also including grounds for eligibility). Baseline characteristics are summarized in Table 1. Our population was relatively young with a median age of 49 [43-59] years, predominantly female (66%), with moderate disability (median EDSS [IQR]: 4.5 [3-6]) and with few other comorbidities (median Charlson index [IQR]:1 [0-2]). Among patients who presented a previous COVID-19, a median of 269 days [IQR 253-564] separated the former from the current COVID-19 episode. Of the three patients treated prophylactically with Cilgavimab – Tixagevimab, with a median delay of 386 days [IQR 326-446] between the injection and the current COVID-19 infection, two had a positive serology. Monoclonal curative therapy with Casirivimab - Imdevimab was given to two patients in combination with CCP. Forty patients (43%) had an acute form of COVID-19, while fifty-two patients (57%) presented with a protracted COVID-19. Many variants of SARS-CoV-2 were observed in our study, with a predominance of Omicron (29/92, 31%) and Delta (12/92, 13%). Most patients had fever (68/92, 74%) and required oxygen therapy (58/92, 63%), while a small part needed intensive care (17/92, 18%) (Figure 2a). Patients with NMOSD are described in Table S2.

### Clinical and biological outcomes

Overall survival at 30 days after CCP treatment was 89/92 (97% [IC95%: 91-99]) for the whole cohort (Table 2). Two patients presented a COVID-19 relapse, at day 20 and day 82 after CCP infusion. Overall survival at 7 and 90 days after CCP was 92/92 (100% [IC95%: 96-100]) and 87/92 (95% [IC95%: 88-98]), respectively. All deaths were related to worsening of COVID-19. Evolution of clinical status, assessed by the WHO severity scale, is illustrated in Figure 3. Clinical improvement at 7 and 30 days post-CCP was achieved in 71/92 (77% [IC95%: 67-85]) and in 86/92 (93% [IC95%: 86-98]) of patients. Of the 75 patients initially hospitalized on a conventional ward (WHO scale 4-5), eight patients (11% [IC95%: 5-20]) were admitted to the intensive care unit after a median [IQR] 1.5 [1-2] days post-CCP. Among the 17 patients hospitalized in the intensive care unit, 8 (47% [IC95%: 23-72]) were discharged within the first week after CCP administration. Kinetics of inflammatory parameters between Day 0 and Day 7 are shown in Figure 4. C-reactive protein (CRP) and ferritin were halved in 54 out of 75 patients (72%) and 15 out of 45 patients (33%), respectively.

### Virological kinetics

Median cycle thresholds (Ct) on SARS-CoV-2 RT-PCR in respiratory samples were 26 [20-31] at baseline (n=51) and increased to 30 [25-33] on day 7 post-CCP (n=28). Forty-six patients (61%) had a detectable viremia before CCP infusion, of whom 9 (15%) stayed

detectable on day 7 post-CCP. Median Ct [IQR] of SARS-CoV-2 RT-PCR in blood samples was 33 [30-36] prior to CCP (n=28) and elevated to 38 [32-38] after CCP (n=5).

### Subgroup analysis for protracted COVID-19

Among the 52 patients with protracted COVID-19, the most represented variant was Omicron (35%). The most frequent symptom was persistent fever (75%), with a median duration [IQR] of symptoms at 51 [28-69] days and a maximum of 184 days. Prior to CCP, CRP and ferritin were statistically lower in the protracted group (respectively 53 [40-116] vs 84 [60-155] p=0.022, and 732 [418-1446] vs 1574 [723-2668], p=0.010) and SARS-CoV-2 RT-PCR performed on respiratory and blood samples showed significantly higher Ct (respectively 29 [28-35] vs 22 [19-25] p<0.001, and 35 [33-37] vs 32 [28-35] p=0.040) (Table 3).

By day 7 after CCP, apyrexia was obtained in 100% of patients (Figure 2c). Clinical improvement was achieved in 44/52 (85% [IC95%: 72-93]) patients. Clinical outcomes were not significantly different between acute and protracted COVID-19, although clinical improvement tended to be numerically higher in patients with protracted COVID-19 (85% vs 67%, p=0.052) (Table 2). CRP and ferritin were halved in 32/42 patients (76%) and 7/17 patients (29%), respectively. Twenty-three patients (57%) were viremic before CCP, and 3/35 (9%) remained viremic on day 7 after CCP.

By day 30 after CCP, only one patient, on mechanical ventilation prior to CCP, died. All other patients (98% [IC95%: 90-100]) experienced clinical improvement.

By day 90 after CCP, no further patients had died.

### Adverse effects

One anaphylactic shock and one non-severe allergic skin reaction related to CCP were reported. Symptoms disappeared rapidly after adrenaline in the first patient and antihistamines in the second. No other adverse effects were reported.

## Discussion

To the best of our knowledge, this original study is the first to describe the effect of CCP in a homogeneous population with inflammatory demyelinating diseases treated with anti-CD20 mAbs. The study's main findings show a high 30-day survival rate as well as a major clinical improvement after CCP, notably apyrexia, particularly highlighted in patients with protracted COVID-19 who presented symptoms from weeks to months and who no longer had symptoms within 2 days after CCP administration.

Since the beginning of the COVID-19 pandemic, several antiviral drugs have been studied in COVID-19 immunocompromised patients. Among them, convalescent plasma has been shown to be very active in vitro, notably in comparison with the antiviral drug remdesivir [16] but no randomized trials have been conducted exclusively in immunocompromised patients. However, a recent meta-analysis confirmed the potential benefit of CCP in a large number of immunocompromised individuals with mild-to-moderate COVID-19 disease [17]. B-cell depletion induced by anti-CD20 mAbs leads to a deficit of humoral immunity. From a pathophysiological approach, the addition of antispike IgG antibodies contained in CCP could therefore appear relevant in this target group. Additionally, CCP enhances the magnitude of the T cell response, essential for ensuring adequate control of viral replication [18]. In patients with B-cell lymphoid malignancy, CCP showed an improvement in 90-day survival in patients on anti-CD20 mAbs versus those who were not (77% vs. 35%) (8). In another series of B-cell depleted COVID-19 patients receiving a single CCP transfusion for haematological (n=15) or autoimmune disorder (n=9), the
<table><caption>**Table 1**
Baseline characteristics.</caption><thead><tr><th>Characteristics</th><th>Total<br>(n = 92)</th><th>Acute<br>(n = 40)</th><th>Protracted<br>(n = 52)</th></tr></thead><tbody><tr><td>Age, years</td><td>49 [42-58]</td><td>50 [43-59]</td><td>48 [38-54]</td></tr><tr><td>Female</td><td>61 (66)</td><td>27 (67)</td><td>34 (65)</td></tr><tr><td>Body mass index</td><td>24 [21-28]</td><td>25 [24-31]</td><td>23 [20-26]</td></tr><tr><td>Obesity</td><td>17 (18)</td><td>10 (25)</td><td>7 (13)</td></tr><tr><td>Hypertension</td><td>9 (10)</td><td>3 (7)</td><td>6 (11)</td></tr><tr><td>Charlson comorbidity index</td><td>1 [0-2]</td><td>1 [0-2]</td><td>1 [0-2]</td></tr><tr><td>IDDs</td><td></td><td></td><td></td></tr><tr><td>Multiple sclerosis</td><td>84 (91)</td><td>38 (95)</td><td>46 (88)</td></tr><tr><td>Neuromyelitis optica spectrum disorders</td><td>8 (9)</td><td>2 (5)</td><td>6 (12)</td></tr><tr><td>Time from MS or NMOSD diagnosis to COVID-19, year</td><td>13 [8-20]</td><td>16 [8-19]</td><td>13 [6-22]</td></tr><tr><td>Multiple sclerosis subtype</td><td></td><td></td><td></td></tr><tr><td>Relapsing-remitting</td><td>32 (38)</td><td>12 (32)</td><td>20 (44)</td></tr><tr><td>Secondary progressive</td><td>36 (43)</td><td>18 (47)</td><td>18 (39)</td></tr><tr><td>Primary progressive</td><td>16 (19)</td><td>8 (21)</td><td>8 (17)</td></tr><tr><td>EDSS score</td><td>4.5 [3-6]</td><td>5.5 [4-6]</td><td>4 [2-6.5]</td></tr><tr><td>Prior DMT use (before anti-CD20)</td><td></td><td></td><td></td></tr><tr><td>Natalizumab</td><td>29 (31)</td><td>10 (25)</td><td>19 (36)</td></tr><tr><td>Fingolimod</td><td>22 (24)</td><td>8 (32)</td><td>14 (27)</td></tr><tr><td>Mitoxantrone</td><td>6 (6)</td><td>4 (10)</td><td>2 (4)</td></tr><tr><td>Cyclophosphamide</td><td>10 (11)</td><td>4 (10)</td><td>6 (11)</td></tr><tr><td>Azathioprine</td><td>8 (9)</td><td>5 (12)</td><td>3 (6)</td></tr><tr><td>Mycophenolate mofetil</td><td>6 (6)</td><td>2 (5)</td><td>4 (8)</td></tr><tr><td>Others*</td><td>46 (50)</td><td>21 (52)</td><td>25 (48)</td></tr><tr><td>Anti-CD20 agent</td><td></td><td></td><td></td></tr><tr><td>Rituximab</td><td>56 (61)</td><td>26 (65)</td><td>30 (58)</td></tr><tr><td>Ocrelizumab</td><td>36 (39)</td><td>14 (35)</td><td>22 (42)</td></tr><tr><td>Time from anti-CD20 start to COVID-19, years</td><td>4 [3-5]</td><td>4 [3-5]</td><td>4 [3-6]</td></tr><tr><td>Number of anti-CD20 cycles</td><td>7 [5-9]</td><td>7 [4-9]</td><td>7 [6-10]</td></tr><tr><td>Time from last anti-CD20 infusion to COVID-19, days</td><td>127 [74-187]</td><td>113 [72-177]</td><td>132 [89-191]</td></tr><tr><td>Previous history of COVID-19</td><td>14 (15)</td><td>4 (10)</td><td>10 (19)</td></tr><tr><td>Vaccination against SARS-CoV-2</td><td>57 (62)</td><td>25 (62)</td><td>32 (61)</td></tr><tr><td>Number of vaccine doses received</td><td>3 [2-4]</td><td>3 [2-3]</td><td>3 [2-4]</td></tr><tr><td>Time between last vaccination and COVID-19, days</td><td>108 [59-232]</td><td>113 [72-177]</td><td>101 [59-349]</td></tr><tr><td>SARS-CoV-2 serostatus before CCP</td><td></td><td></td><td></td></tr><tr><td>Positive</td><td>8 (9)</td><td>1 (2)</td><td>7 (13)</td></tr><tr><td>Negative</td><td>75 (81)</td><td>35 (88)</td><td>40 (77)</td></tr><tr><td>Unknown</td><td>9 (10)</td><td>4 (10)</td><td>5 (10)</td></tr><tr><td>If positive, number of BAU/mL</td><td>604 [272-1135]</td><td>1135</td><td>438 [269-1552]</td></tr><tr><td>Specific treatments for COVID-19 prior to CCP</td><td></td><td></td><td></td></tr><tr><td>Corticotherapy</td><td>61 (66)</td><td>34 (85)</td><td>27 (52)</td></tr><tr><td>Tocilizumab</td><td>4 (4)</td><td>3 (7)</td><td>1 (2)</td></tr><tr><td>Baricitinib</td><td>0 (0)</td><td>0 (0)</td><td>0 (0)</td></tr><tr><td>Remdesivir</td><td>6 (6)</td><td>1 (2)</td><td>5 (10)</td></tr><tr><td>Nirmatrelvir</td><td>1 (1)</td><td>0 (0)</td><td>1 (2)</td></tr><tr><td>Anti-Spike monoclonal antibodies</td><td>5 (5)</td><td>3 (7)</td><td>2 (4)</td></tr><tr><td>Cilgavimab/Tixagevimab (prophylactic therapy)</td><td>3 (3)</td><td>1 (2)</td><td>2 (4)</td></tr><tr><td>Casirivimab/Imdevimab (curative therapy)</td><td>2 (2)</td><td>2 (5)</td><td>0 (0)</td></tr><tr><td>Variant</td><td></td><td></td><td></td></tr><tr><td>D614G</td><td>8 (9)</td><td>1 (3)</td><td>7 (13)</td></tr><tr><td>Alpha</td><td>7 (8)</td><td>2 (5)</td><td>5 (10)</td></tr><tr><td>Beta</td><td>2 (2)</td><td>2 (5)</td><td>0 (0)</td></tr><tr><td>Delta</td><td>12 (13)</td><td>9 (22)</td><td>3 (6)</td></tr><tr><td>Omicron</td><td>29 (31)</td><td>11 (28)</td><td>18 (35)</td></tr><tr><td>Omicron BA.1</td><td>5 (5)</td><td>1 (3)</td><td>4 (8)</td></tr><tr><td>Omicron BA.2</td><td>2 (2)</td><td>0 (0)</td><td>2 (4)</td></tr><tr><td>Omicron BA.4/5</td><td>3 (3)</td><td>1 (3)</td><td>2 (4)</td></tr><tr><td>Omicron BQ.1</td><td>1 (1)</td><td>0 (0)</td><td>1 (2)</td></tr><tr><td>Omicron unspecified</td><td>18 (20)</td><td>9 (22)</td><td>9 (17)</td></tr><tr><td>Others</td><td>3 (3)</td><td>2 (5)</td><td>1 (2)</td></tr><tr><td>Unknown</td><td>31 (34)</td><td>13 (32)</td><td>18 (34)</td></tr><tr><td>Time from COVID-19 symptoms onset to CCP, days</td><td>26 [16-55]</td><td>15 [10-20]</td><td>51 [28-69]</td></tr></tbody></table>

Data are presented as median [IQR] or count (%).

IDDs = inflammatory demyelinating disease. MS = multiple sclerosis. NMOSD = Neuromyelitis optica spectrum disorders. EDSS = Expanded Disability Status Scale;

DMT = disease-modifying therapy. CCP = COVID-19 convalescent plasma. BAU/mL = Binding Antibody Units (international standard unit).

* Interferon-beta-1a, glatiramer acetate, teriflunomide or dimethyl fumarate.

survival rate was 84% [19]. In our study, the 90-day survival rate was higher (95%), but patients with IDD are probably less immunocompromised than patients with haematological malignancies, irrespective of anti-CD20 mAbs. In opposition, Kasten et al. found no benefit of CCP versus standard of care on 30-day mortality in various B-cell depleted COVID-19 patients. However, the study had nu-

merous biases, was underpowered (n=19 vs n=31) and contained two unbalanced groups [20]. Nevertheless, comparing outcomes from use of CCP between studies remains challenging, as CCP titers may have been obtained using different nonstandardized methods.

In MS, two small studies have outlined the efficacy of COVID-19 passive antibody therapy in patients receiving anti-CD20 mAbs.
<figure><img src="image_4.png" /><figcaption>**Figure 2.** Clinical characteristics and respiratory parameters of all patients (a) then separated according to the acute (b) or protracted (c) form of COVID-19 between day 0 and day 7 after CCP.</figcaption></figure>

<table><caption>**Table 2**
Clinical outcomes.</caption><thead><tr><th>Variables</th><th>Total<br>(n = 92)</th><th>Acute<br>(n = 40)</th><th>Protracted<br>(n = 52)</th></tr></thead><tbody><tr><td>Clinical status 7 days after CCP</td><td></td><td></td><td></td></tr><tr><td>Clinical improvement</td><td>71 (77)</td><td>27 (67)</td><td>44 (85)</td></tr><tr><td>Duration before apyrexia</td><td>1.5 [1-3.5]</td><td>2 [1-5]</td><td>1 [1-2]</td></tr><tr><td>Respiratory worsening</td><td>13 (14)</td><td>9 (22)</td><td>4 (8)</td></tr><tr><td>Overall mortality</td><td>0 (0)</td><td>0 (0)</td><td>0 (0)</td></tr><tr><td>Clinical status 30 days after CCP</td><td></td><td></td><td></td></tr><tr><td>Clinical improvement</td><td>86 (93)</td><td>35 (87)</td><td>51 (98)</td></tr><tr><td>COVID-19 relapses</td><td>1 (1)</td><td>0 (0)</td><td>1 (2)</td></tr><tr><td>Overall mortality</td><td>3 (3)</td><td>2 (5)</td><td>1 (2)</td></tr><tr><td>COVID-19 relapses between 30 and 90 days</td><td>1 (1)</td><td>1 (2)</td><td>0 (0)</td></tr><tr><td>90-day overall mortality</td><td>5 (5)</td><td>4 (10)</td><td>1 (2)</td></tr><tr><td>Time between CCP and death, days</td><td>21 [13-39]</td><td>26 [10-41]</td><td>21 [21-21]</td></tr></tbody></table>

Data are presented as median [IQR] or count (%). CCP = COVID-19 convalescent plasma.
Clinical improvement was defined as a loss of 1 point or more on the WHO severity scale after CCP transfusion.

The first was a series of five patients who reported satisfactory symptomatic improvement after CCP (10). The second described 22 MS patients who evolved positively after infusion of anti-SARS-CoV-2 monoclonal antibodies, with a 90-day survival rate of 100%, which is close to our results [21].

In our work, two-thirds of patients were vaccinated, with a median of 3 doses. Despite vaccination, 81% of patients remained seronegative, which is in line with the low seroconversion rates already described in MS patients treated with anti-CD20 mAbs [22].

Moreover, antibody levels remained very low in our responding patients, which drastically reduced the protection against COVID-19 [23]. Lack of ability to produce antibodies can lead to failure to clear SARS-CoV-2, resulting in a protracted clinical course of COVID-19. The definition of the protracted form of COVID-19 is not consensual. In this study, we defined protracted form as symptoms lasting more than 21 days after the first positive SARS-CoV-2 RT-PCR which is consisting with the Dioverti et al. [14] definition. Protracted COVID-19 had a long median duration of symptoms of 51
<figure><img src="image_5.png" /><figcaption>**Figure 3.** Clinical status of the total population, acute and protracted forms of COVID-19 on day 0, day 7 and day 28 after CCP. Patients were classified according to the WHO scale (23): Ambulatory mild disease or uninfected (0 to 3), hospitalised without oxygen therapy (4), hospitalised with mask oxygen or nasal prongs (5), hospitalised with high-flow nasal cannula (6), hospitalised with mechanical ventilation (7 to 9) and dead (10).</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Figure 4.** Kinetics of inflammatory parameters (A) C-reactive protein (mg/L) and (B) Ferritin (ng/mL) between day 0 and day 7 after CCP transfusion in acute and protracted forms of COVID-19.</figcaption></figure>

[28-69] days, including one patient who had been ill for around 6 months. In this population, the effect of CCP was clear, with apyrexia in 100% of patients by day 7. Furthermore, apyrexia appeared within 48 hours of CCP in most cases, in patients who were symptomatic for weeks to months. Given that fever aggravates neurological symptoms in patients with IDD (Uhthoff's phenomenon), treatment of protracted COVID-19 with passive antibody therapy may also be beneficial for the neurological disease [24]. Regarding virological analysis, viremia was detected in 57% (23/40) of patients before CCP, which is significantly higher than in the population without C-cell depletion infected with SARS-CoV-2, where

the proportion ranged from 10% to 33% [25]. In immunocompetent patients, it is now clearly established that CCP is effective if administered early [4,5]. Among mild-to-moderate protracted COVID-19 in B-cell depleted patients, the effect is still present when CCP is administered late, whatever the time since onset of symptoms.

Despite initial clinical improvement, two patients relapsed after CCP. Several hypotheses may explain COVID-19 recurrences. First, the content of CCP can be widely heterogeneous, leading to variable efficacy. Hence, CCP must contain a high antibody titer to be successful [26]. Subsequently, Gachoud et al. described a boosted efficacy of CCP when collected from patients who had also been
<table><caption>**Table 3**
Subgroup analysis of biological and virological parameters in acute and protracted forms of COVID-19.</caption><thead><tr><th>Variables</th><th>Acute (n = 40)</th><th>Protracted (n = 52)</th></tr></thead><tbody><tr><td>Biological parameters prior to CCP</td><td></td><td></td></tr><tr><td>CRP (mg/L)</td><td>84 [60-155]</td><td>53 [40-116]</td></tr><tr><td>Ferritin (ng/mL)</td><td>1574 [2723-2668]</td><td>732 [418-1446]</td></tr><tr><td>SARS-CoV-2 RT-PCR results prior to CCP</td><td></td><td></td></tr><tr><td>Respiratory sample Ct</td><td>22 [19-25]</td><td>29 [29-32]</td></tr><tr><td>Viremia</td><td>23/35 (66)</td><td>23/40 (57)</td></tr><tr><td>Blood sample Ct</td><td>32 [28-35]</td><td>35 [33-37]</td></tr><tr><td>Biological parameters 7 days after CCP</td><td></td><td></td></tr><tr><td>CRP</td><td>20 [10-52]</td><td>8 [4-18]</td></tr><tr><td>Ferritin</td><td>1192 [772-2314]</td><td>760 [391-1154]</td></tr><tr><td>CRP halved</td><td>22/30 (67)</td><td>32/42 (76)</td></tr><tr><td>Ferritin halved</td><td>8/21 (38)</td><td>7/17 (29)</td></tr><tr><td>SARS-CoV-2 RT-PCR results 7 days after CCP</td><td></td><td></td></tr><tr><td>Respiratory sample Ct</td><td>30 [25-34]</td><td>30 [27-33]</td></tr><tr><td>Viremia</td><td>6/24 (25)</td><td>3/35 (9)</td></tr><tr><td>Blood sample Ct</td><td>35 [31-38]</td><td>40 [40-40]</td></tr></tbody></table>

Data are presented as median [IQR] or count (%). CCP = COVID-19 convalescent plasma. Ct = Cycle threshold. CRP = C-reactive protein.

vaccinated against COVID-19 [27]. The same team also showed a progressive decrease in anti-spike IgG titres after CCP in patients who had received B-cell depleting agents, compared to controls. In this study, patients with antibody titres decay also experienced prolonged clinical symptoms and SARS-CoV-2 viral loads [28]. In the context of inadequate immune response, sustained viral replication is the breeding ground for a high mutation rate, which may facilitate the emergence of divergent escape variants [28,29].

Our study has some limitations. First, this was a retrospective observational study with the inherent biases of such studies, and without a control group. Second, although our study contains the largest number of patients treated with anti-CD20 mAbs for IDD and affected by COVID-19, the sample size remains small. In contrast to previous studies, this low number is counterbalanced by the high homogeneity of the population, including patients with similar neurological disorders and immunosuppression mechanisms. This is also the first study to describe the outcomes of CCP in patients with NMOSD. Third, the study design was not well adapted to intensive care patients. Indeed, many key parameters concerning the proper monitoring of critical care patients were not collected. Fourth, we unfortunately did not record the origin of the respiratory samples on which SARS-CoV-2 RT-PCR was performed. Description of this item would have been relevant, as it has been shown that SARS-CoV-2 RT-PCR on nasopharyngeal swab was often negative in patients treated with anti-CD20 mAbs [30]. In such cases, diagnosis could only be carried out on bronchoalveolar fluid. Fifth, grade 1-2 adverse events were not systematically recorded, which may have underestimated nonsevere side effects due to the retrospective nature of the data analysis. In our study, one center reported anaphylactic shock following drug administration in one patient. Thus, comprehensive safety assessment in our immunocompromised population might have been pertinent.

In conclusion, our results suggest that CCP could be a therapeutic option for patients treated with anti-CD20 mAbs for IDD and suffering from COVID-19, especially in those with a protracted form of COVID-19. Knowledge of this therapy by neurologists and infectious could help reduce the lengthy duration of symptoms in these patients and decrease the impact of the COVID-19 on the underlying neurological disease. Further controlled research is needed to investigate our findings.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Ethical approval statement

The study was approved by the French national infectious diseases ethical committee (N°IRB00011642). All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments. According to French legislation, participants received an information notice mentioning their participation to the study and giving the possibility of objecting.

## Author contributions

TD, KL, GM-B, CL and QR contributed to the conception and design of the study. TD, QR, FA, YM, NL, CJ, MC, CB, VG, CM, FD, TML, AS, LB, AM, MM, GLF, AF, BP, GG, PS, MH, TK, SR, SA, NM, FC, MD, JS, NZ, MLM, KM, M-EL, DLP, MM, CL, AS, KL and GM-L contributed to the acquisition and analysis of data. TD, GM-B and QR contributed to drafting the text and preparing the figures. All authors contributed to the critical revision of the final manuscript.

## Declarations of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

KL has received funds from Gilead, MSD, Janssen, ViiV Healthcare and Abbvie for expert boards and travel grants. None of those funds target COVID-19. CL has received compensation for travel fees, consulting services or speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi and Roche and IIT Research grant from Biogen. AF reports honorariat by Fisher & Paykel for a lecture during SFMU Congress 2022, outside the submitted work. AM is president of an association that has received funding from GSK and Blueprint, hospitality from GSK, Novartis, Sanofi, Janssen, Teva, Shire, Ipsen, training funding from Novartis, LFB, Leo Pharma, and has a contract to speak at scientific events from Leo Pharma.

The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ijid.2024.107323.
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