Clinical and molecular landscape of prolonged SARS-CoV-2 infection with resistance to remdesivir in immunocompromised patients
Chisako Iriyama, Takaya Ichikawa, Tomokazu Tamura, Mutsumi Takahata, Takashi Ishio, Makoto Ibata, Ryuji Kawai, Mitsunaga Iwata, Masahiro Suzuki, Hirokazu Adachi, Naganori Nao, Hikoyu Suzuki, Akito Kawai, Akifumi Kamiyama, Tadaki Suzuki, Yuichiro Hirata, Harutaka Katano, Yasushi Ishii, Takahiro Tsuji, Yoshitaka Oda, Shinya Tanaka, Nanase Okazaki, Yuko Katayama, ， Shimpei Nakagawa, Tetsuya Tsukamoto, Yohei Doi, M.D Takasuke Fukuhara, Takayuki Murata, M.D Akihiro Tomita
doi:10.1093/pnasnexus/pgaf085/8083008
Patients with hematologic diseases have experienced COVID-19 with prolonged, progressive course. Here we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high SARS-CoV-2 levels persisted for more than 4 weeks, and two of them succumbed to COVID-19. Autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping CMV, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in
Significance statement In immunocompromised patients with hematological malignancies, prolonged/progressive course of COVID-19 is still a critical problem, even in an era when vaccines and several antiviral therapeutics have been developed. Here we analyzed serial viral specimens of three B-cell lymphoma patients undergoing immuno-chemotherapies who experienced prolonged/progressive course of COVID-19 and demonstrated that diverse genetic mutations on SARS-CoV-2 accumulated on therapy within each individual. In vitro drug susceptibility assay revealed that specific genetic alterations on NSP12 (V792I and M794I) were responsible for acquisition of remdesivir resistance. These findings indicate that mutations related to drug resistance accumulate in SARS-CoV-2 in immunocompromised patients, suggesting the importance of treatment strategies that can eradicate the virus at an early stage of COVID-19 onset. (116 words)
Authorship contribution
Sequence data availability The RNAseq data of case #1 specimens 1 to 12 in Figure 1A will be available from NCBI SRA (PRJNA1049969). The data of case #1 specimen 13 in Figure 1A and Supplementary Figure S2 (at autopsy) will be available from DDBJ DRA (DRA017735). The sequence data of case #2 and 3 are available from DDBJ (accession numbers: case #2. LC798944, LC753061, LC753062; case #3. LC798945, LC798946, LC798947).
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Patients with hematologic diseases have experienced COVID-19 with prolonged, progressive course. Here we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high SARS-CoV-2 levels persisted for more than 4 weeks, and two of them succumbed to COVID-19. Autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping CMV, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in variant allele frequencies over time. NSP12 mutations V792I and M794I appeared independently in two cases as COVID-19 progressed. In vitro drug susceptibility analysis and animal experiment using recombinant SARS-CoV-2 demonstrated that each mutation, V792 and M794I, was independently responsible for remdesivir resistance and attenuated pathogenicity. E340A, E340D and F342INS mutations in the spike protein were found in one case, which may account for the sotrovimab resistance. Analysis of autopsy specimens indicated heterogeneous distribution of these mutations. In summary, we demonstrated temporal and spatial diversity in SARS-CoV-2 that evolved resistance to various antiviral agents in malignant lymphoma patients under immunodeficient conditions caused by certain types of immunochemotherapies. Strategies may be necessary to prevent acquisition of drug resistance and improve outcome, such as selection of appropriate treatment strategies for lymphoma considering patients’ immune status and institution of early intensive antiviral therapy.</jats:p>",
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