The Longest Persistence of Viable SARS-CoV-2 With Recurrence of Viremia and Relapsing Symptomatic COVID-19 in an Immunocompromised Patient-A Case Study

Chiara Sepulcri; Chiara Dentone; Malgorzata Mikulska; Bianca Bruzzone; Alessia Lai; Daniela Fenoglio; Federica Bozzano; Annalisa Bergna; Alessia Parodi; Tiziana Altosole; Emanuele Delfino; Giulia Bartalucci; Andrea Orsi; Antonio Di Biagio; Gianguglielmo Zehender; Filippo Ballerini; Stefano Bonora; Alessandro Sette; Raffaele De Palma; Guido Silvestri; Andrea De Maria; Matteo Bassetti

doi:10.1093/ofid/ofab217

The Longest Persistence of Viable SARS-CoV-2 With Recurrence of Viremia and Relapsing Symptomatic COVID-19 in an Immunocompromised Patient-A Case Study

Open Forum Infect Dis. 2021 Apr 28;8(11):ofab217. doi: 10.1093/ofid/ofab217. eCollection 2021 Nov.

Authors

Chiara Sepulcri¹, Chiara Dentone², Malgorzata Mikulska^{1

2}, Bianca Bruzzone³, Alessia Lai⁴, Daniela Fenoglio^{5

6}, Federica Bozzano², Annalisa Bergna⁴, Alessia Parodi⁶, Tiziana Altosole⁵, Emanuele Delfino², Giulia Bartalucci⁷, Andrea Orsi^{3

8}, Antonio Di Biagio^{1

2}, Gianguglielmo Zehender⁹, Filippo Ballerini¹⁰, Stefano Bonora¹¹, Alessandro Sette^{12

13}, Raffaele De Palma^{6

14}, Guido Silvestri^{15

16}, Andrea De Maria^{1

2}, Matteo Bassetti^{1

2}

Affiliations

¹ Infectious Diseases Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
² Infectious Diseases Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neurosciences, Genoa, Italy.
³ Hygiene Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neurosciences, Genoa, Italy.
⁴ Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy.
⁵ Center of Excellence for Biomedical Research, Cytofluorimetry Unit, University of Genoa, Genoa, Italy.
⁶ Biotherapy Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neurosciences, Genoa, Italy.
⁷ Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.
⁸ Hygiene Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁹ Hygiene Unit, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy.
¹⁰ Hematology Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neurosciences, Genoa, Italy.
¹¹ Infectious Diseases Unit, Ospedale Amedeo di Savoia, University of Turin, Turin, Italy.
¹² Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA.
¹³ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
¹⁴ Immunology Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neurosciences, Genoa, Italy.
¹⁵ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁶ Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, Georgia, USA.

Abstract

Background: Immunocompromised patients show prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs. We report a case of prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of coronavirus disease 2019 (COVID-19) in a patient with mantle cell lymphoma who underwent treatment with rituximab, bendamustine, cytarabine with consequent lymphopenia and hypogammaglobulinemia.

Methods: Nasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR). On 5 positive nasopharyngeal swabs, we performed viral culture and next-generation sequencing. We analyzed the patient's adaptive and innate immunity to characterize T- and NK-cell subsets.

Results: SARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive for 268 days. All 5 performed viral cultures were positive, and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in 3 out of 4 COVID-19 clinical relapses and cleared each time after remdesivir treatment. The T- and NK-cell dynamic was different in aviremic and viremic samples, and no SARS-CoV-2-specific antibodies were detected throughout the disease course.

Conclusions: In our patient, SARS-CoV-2 persisted with proven infectivity for >8 months. Viremia was associated with COVID-19 relapses, and remdesivir treatment was effective in viremia clearance and symptom remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood; these are probably recruited in inflammatory tissue for viral eradication. In addition, we found a high level of NK-cell repertoire perturbation with relevant involvement during SARS-CoV-2 viremia.

Keywords: SARS-CoV-2; hematological; immunological response; viral shedding; viremia.