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We read with great interest the recent article by Fiedman and Winthrop reporting a patient with granulomatosis with polyangiitis (GPA) being treated with rituximab (RTX), recurrent SARS-CoV-2 disease 2019 (COVID-19) and no detectable SARS-CoV-2 seroresponse after recovery.1 Anti-CD20 therapy impairs humoral response, theoretically increasing the risk of prolonged SARS-CoV-2 infection and shedding as well as subsequent reinfection.1–3 We have recently reported a patient with GPA under maintenance therapy with RTX and SARS-CoV-2 infection.4 Here, we report further details on anti-CD20 therapy with RTX, serological response to SARS-CoV-2 infection, virus elimination and corresponding B cell numbers. This case highlights that B cell numbers in patients with rheumatic diseases treated with RTX could associate with serological response to SARS-CoV-2 infection, which is particularly relevant as RTX may also impair the immunogenicity of SARS-CoV-2 vaccines.
An 80-year-old man had received a diagnosis of GPA in 2014 with biopsy-confirmed renal vasculitis and no history of pulmonary manifestation. After remission induction therapy, he received RTX at a dose of 500 mg every 6 months as maintenance therapy. The last infusion was in March 2019 with persistent B cell depletion: 0% CD19+ B cells in September 2019, 0,13% CD19+ B cells in December 2019, 2,7% CD19+ B cells in February 2020 (normal range 6%–19%). In March 2020, the patient presented to the emergency department with a 2-week history of productive cough and his oxygenation was 85% on room air (figure 1A). An initial nasopharyngeal swab was negative for SARS-CoV-2 RNA but positive for influenza A RNA. Because of worsening respiratory failure, the patient required mechanical ventilation. A tracheal aspirate was tested positive for SARS-CoV-2 RNA. Subsequently, the patient expired due to multiorgan failure. Serological response to SARS-CoV-2 infection was confirmed at day 29 after admission revealing serum levels of 2.16 for IgA and 8.21 for IgG (reference ratios <0.8, EUROIMMUN, Lübeck, Germany), associated with tracheal aspirate tested negative for SARS-CoV-2 RNA (figure 1A). Urinary measurements of SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N, KIT40588, Sino Biological, Beijing, China) confirmed systemic viral infection with decreasing levels during course of disease (figure 1B).5 Serological response to confirmed SARS-CoV-2 infection and attenuated systemic viral spread correlated with B cell reconstitution (17.73% CD19+ B cells, figure 1C). These observations indicate that B cell numbers in patients with rheumatic diseases treated with RTX could associate with SARS-CoV-2 serological response and virus elimination.
(A) Timeline of COVID-19 clinical course, SARS-CoV-2 RNA testing and serological response. (B) ELISA measurements of urinary SARS-CoV-2 N during disease course of COVID-19 (measurements were done in triplicates, mean values are shown). (C) Timeline of corresponding B cell numbers (normal range: 6%–19%) in September 2019, December 2019, February 2020 and April 2020 (day 25 after admission). SARS-CoV-2 N, SARS-CoV-2 nucleocapsid protein.
To our knowledge, this is the first report of a relationship between B cell numbers, SARS-CoV-2 serological response and virus elimination in a patient with GPA on anti-CD20 therapy with RTX. It remains unclear why initial nasopharyngeal swabs for SARS-CoV-2 RNA were negative in our case, possibly attributed to the patient’s immunocompromised state. However, COVID-19 was confirmed in the tracheal aspirate. Anti-CD20 therapies prevent the formation of protective antibodies, leading to an increased risk of prolonged SARS-CoV-2 infection or even reinfection.1 2 This has implications for SARS-CoV-2 vaccination, which may not be effective in RTX-treated patients. Therefore, clinicians using RTX may consider delaying RTX application or testing for reconstitution of B cells to allow for vaccination, although both may not always be feasible.6 Finally, further studies are necessary to determine the exact effect of anti-CD20 therapy on SARS-CoV-2 vaccines and whether delayed dosing improves vaccine immunogenicity. Our observation that seroresponse to SARS-CoV-2 infection correlated with the reconstitution of B cells is of importance and implicates that assessment of B cell numbers in patients with rheumatic diseases treated with RTX could further improve the timing of SARS-CoV-2 vaccination. This underscores the need for further studies to investigate the effects of specific rheumatic diseases and anti-CD20 therapy on the efficacy and durability of the antibody response to SARS-CoV-2.
Ethics statements
Ethics approval
The institutional ethical board of the University Medical Center Göttingen, Germany approved the study (reference number 25/4/19Ü) and informed written consent was obtained. All data were anonymized to comply with the provisions of personal data protection legislation.
Footnotes
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Contributors BT conceived the correspondence and wrote the first draft. DT performed urinary SARS-CoV-2 N measurements. PK and MSW provided clinical data. All authors participated in the construction and editing of the manuscript.
Funding BT was supported by the Research program, University Medical Center, University of Göttingen (1403720). The funding sources had no involvement in the design, collection, analysis, interpretation, writing or decision to submit the article.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; internally peer reviewed.