Case Report: Convalescent Plasma Achieves SARS-CoV-2 Viral Clearance in a Patient With Persistently High Viral Replication Over 8 Weeks Due to Severe Combined Immunodeficiency (SCID) and Graft Failure

We describe the unique disease course and cure of SARS-CoV-2 infection in a patient with SCID and graft failure. In absence of a humoral immune response, viral clearance was only achieved after transfusion of convalescent plasma. This observation underscores the necessity of the humoral immune response for SARS-CoV-2 clearance.


INTRODUCTION
We describe a 25-year-old female patient with severe combined immunodeficiency (SCID) due to a RAG1 variant (1,2) with persistently high SARS-CoV-2-RNA concentrations in respiratory samples over 60 days. Immunocompromised patients have not only an increased risk of acquiring severe Corona virus disease 2019 (COVID-19) (3,4) but may fail to achieve viral clearance with prolonged shedding of viable virus (5,6).
Our patient was first treated with remdesivir and subsequently received convalescent plasma (CP), which achieved sustained viral clearance.

CASE DESCRIPTION AND DIAGNOSTIC ASSESSMENT
The patient was diagnosed with T -/B -/NK + SCID and received unconditioned haploidentical hematopoietic stem cell transplantation (HSCT) from her father at 4 months of age (7). Due to incomplete immune reconstitution with poor T celland no B cell-engraftment she received a stem cell boost without preconditioning at 4 years of age, repetitive donor lymphocyte infusions (5 times, last infusion 11/2019) and regular immunoglobulin substitution therapy.
She suffered from recurrent bronchopulmonary infections and chronic obstructive pulmonary disease. Due to progressive graft failure she was scheduled for another HSCT.
After a close friend tested positive for SARS-CoV-2, testing was performed while she was asymptomatic and results were positive for SARS-CoV-2 on 30 th of April 2020 (day 0). Since patients with SCID are prone to severe systemic viral infections (e.g. cytomegalovirus, adenovirus, parainfluenza virus) (8)(9)(10) she was admitted for clinical observation.
Upon admission, her physical examination, vital signs, chest radiography and a CT scan were unremarkable ( Figure 1). The patient experienced a mild headache for one day but no other COVID-19 associated symptoms. The initial SARS-CoV-2-RNA concentration in the nasopharyngeal swab was 4.89 x 10 8 copies/ml. SARS-CoV-2 could not be PCR-amplified from the patient's EDTA blood, bone marrow, urine and stool samples. Over the course of 30 days, the patient did not develop any overt symptoms despite persistent high-level viral replication.

DISCUSSION
This unique case illustrates the course of COVID-19 in a situation where the functionality of innate and especially adaptive humoral and cellular immunity is severely limited. Development of COVID-19 pneumonia was significantly delayed despite high viral concentrations and only developed after partial recovery of the cellular immune response. As expected, viral clearance is not achieved with severely impaired T-cell and absent B-cell mediated responses (13,14). This case and the detection of viral replication in cell culture beyond d50 highlights the need for prolonged quarantine measures and monitoring in patients with immune defects (6).
While remdesivir treatment reduced virus concentrations by 2.6-log, however, after stopping of the drug virus concentrations quickly recovered. CP administration from two different donors achieved sustained viral clearance even after anti-SARS-CoV-2 antibodies dropped below the detection limit, which is in line with reports from patients with primary and secondary immunodeficiency as well as with hematological malignancies (15)(16)(17). This therapeutic effect was retained even during a second HSCT on day 138. This case report underscores the importance of the humoral immune response, substituted here by CP transfusions, to successfully clear SARS-CoV-2 infection.

DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online repositories. Consensus Sequences are available on GISAID: EPI_ISL_572330, EPI_ISL_572331, EPI_ISL_572333, EPI_ISL_573152, EPI_ISL_574259, EPI_ISL_572397. See also Supplementary Material.

ETHICS STATEMENT
The examinations were carried out in accordance with the Declaration of Helsinki and the patient gave written informed consent for use of CP as well as for publication of the pseudonymized results and patient history.

ACKNOWLEDGMENTS
Expert technical assistance by Lisa Knopp is thankfully acknowledged.