key: cord-0910834-e75qsrst
authors: Clark, E.; Guilpain, P.; Filip, L.; Pansu, N.; Le Bihan, C.; Cartron, G.; Tchernonog, E.; Roubille, Camille; Morquin, D.; Makinson, A.; Tuaillon, E.; Le Moing, V.
title: Convalescent plasma for persisting Covid‐19 following therapeutic lymphocyte depletion: a report of rapid recovery
date: 2020-06-27
journal: Br J Haematol
DOI: 10.1111/bjh.16981
sha: 42a8a150b2bffde9bbd96573287afacd73da7224
doc_id: 910834
cord_uid: e75qsrst

We read with deep interest the report by Tepasse and colleagues(1) , concerning two cases of persisting viremia in Covid‐19 with fatal outcome. Whilst SARS‐CoV‐2 infection in the early stages of infection has been well described, less is known about the development of antibodies to SARS‐CoV‐2, clearance of RNA shedding and clinical outcome of COVID‐19.

We read with deep interest the report by Tepasse and colleagues 1 , concerning two cases of persisting viremia in Covid-19 with fatal outcome. Whilst SARS-CoV-2 infection in the early stages of infection has been well described, less is known about the development of antibodies to SARS-CoV-2, clearance of RNA shedding and clinical outcome of COVID-19. In addition, the impact of immunosuppressive treatments on disease severity is not yet established, but several reports suggest a more prolonged disease in patients under rituximab, a B cell depleting drug. [2] [3] [4] Here we report a case of persisting COVID-19, following combined treatment with rituximab and bendamustine for lymphoma, which immediately recovered after convalescent plasma transfusion. We think that this case raises promising perspectives for immunocompromised patients with persisting Covid-19. 

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To date, treatment of Covid-19 is still challenging and there is no specific recommended therapy. Despite the sequential introduction of different treatments, our patient experienced an unusual delayed clinical worsening, a persisting clinical infection and a prolonged viral shedding. Such a course is unusual, since the median time to clinical worsening is approximately 8-10 days. Furthermore, the median time until viral RNA clearance attested by PCR on a nasopharyngeal swab, is estimated around 17-24 days in hospitalized patients. 5 Prolonged viral RNA shedding over 15 days is not infrequent, especially in elderly and severe COVID-19 cases. 6 In patients with prolonged viral shedding, the symptoms had retrieved whilst SARS-COV-2 RNA remained detectable in pharyngeal swabs at day 54. Furthermore, in our patient, persistent pneumonia, abnormalities in the CT scan, and the levels of PCR CT values suggested a persisting viral replication and possible infectiousness. Seroconversion occurs after 7 days in 50% of patients and IgG are detected in more than 90% of patients after day 14. 7 High viral loads are reported during the first week of COVID-19 when viral isolation of SARS-CoV-2 is possible.

Herein, spontaneous seroconversion never occurred, suggesting that the combination of bendamustine and rituximab induced an impairment of humoral and cellular response against SARS-CoV-2 due to persisting depletion of circulating CD4+ T and B cells. Indeed, bendamustine preferentially inhibits CD4+ lymphocytes, 8 while rituximab deeply depletes humoral and B cell responses to infections. 9 Despite its reputation for good tolerance, rituximab may even induce severe life-threatening infections. 10 Although rituximab does not directly affect CD20 negative plasma cells producing antibodies, the antibody production can be impaired as well as the antibody response after vaccination. Other B cell functions may be altered by rituximab, notably the antigen presentation and cellular interactions with T cells and monocytes/macrophages through IL-6 production. 4 Thus, B-cell depleting drugs may delay the inflammatory response in Covid-19, which is tragically illustrated by a cytokine storm in the most severe cases, as illustrated by those reported by Tepasse and coll. 1 We think that hyperimmune plasma from convalescent patients could provide a valuable input against SARS-Cov-2 infection in patients immunosuppressed with rituximab.

This article is protected by copyright. All rights reserved Herein, the rapid clinical improvement followed by viral clearance after administration of hyperimmune plasma argue that passively-transfer antibodies played a key role in COVID-19 recovery. Convalescent plasma extracted from patients recovering from diverse infections contains neutralizing antibodies against specific agents, and its efficacy has been diversely evaluated in patient with of severe and acute COVID-19

infection. 11 In the present case, the transfusion was well tolerated and no transfusionrelated acute lung injury (TRALI) was observed. 12 To the best of our knowledge, we describe the first case of favorable outcome following convalescent plasma transfusion, in an immunocompromised patient with persisting Covid-19. Administration of neutralizing antibodies may be a possible therapeutic approach in patients with persisting Covid-19 symptomatology in the context of deep immunosuppression. 

Persisting SARS-CoV-2 viraemia after rituximab therapy: two cases with fatal outcome and a review of the literature

Severe COVID-19-associated pneumonia in 3 patients with systemic sclerosis treated with rituximab

Rituximab for granulomatosis with polyangiitis in the pandemic of covid-19: lessons from a case with severe pneumonia

Accepted Article This article is protected by copyright. All rights reserved

Response to: « Severe COVID-19 associated pneumonia in 3 patients with systemic sclerosis treated with rituximab

Temporal dynamics in viral shedding and transmissibility of COVID-19

Factors associated with prolonged viral RNA shedding in patients with COVID-19

Detection of SARS-CoV-2 antibodies using commercial assays and seroconversion patterns in hospitalized patients

Bendamustine associated immune suppression and infections during therapy of hematological malignancies

The effect of rituximab on vaccine responses in patients with immune thrombocytopenia

Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease

Research reported in this publication included work performed in Montpellier University.The authors declare no competing financial interests.Evangéline CLARK, Ionut Laurentiu Filip and Philippe Guilpain designed and wrote the paper. Edouard Tuaillon extracted virology data.All the authors revised the paper.