Successful Treatment of Persistent Symptomatic Coronavirus Disease 19 Infection With Extended-Duration Nirmatrelvir-Ritonavir Among Outpatients With Hematologic Cancer

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Abstract

Persistent symptomatic coronavirus disease 2019 (COVID-19) is a distinct clinical entity among patients with hematologic cancer and/or profound immunosuppression. The optimal medical management is unknown. We describe 2 patients who had symptomatic COVID-19 for almost 6 months and were successfully treated in the ambulatory setting with extended courses of nirmatrelvir-ritonavir.

Abstract

Persistent COVID-19 infection is a challenging management dilemma among immunosuppressed individuals, particularly those with B-cell dysfunction. We describe 2 patients with symptomatic COVID-19 for almost 6 months who were successfully treated in the ambulatory setting with extended courses of nirmatrelvir/ritonavir.

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Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Bina Choi, Manish C. Choudhary, James K. Regan … (2020)

To the Editor: A 45-year-old man with severe antiphospholipid syndrome complicated by diffuse alveolar hemorrhage, 1 who was receiving anticoagulation therapy, glucocorticoids, cyclophosphamide, and intermittent rituximab and eculizumab, was admitted to the hospital with fever (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). On day 0, Covid-19 was diagnosed by SARS-CoV-2 reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of a nasopharyngeal swab specimen, and the patient received a 5-day course of remdesivir (Fig. S2). Glucocorticoid doses were increased because of suspected diffuse alveolar hemorrhage. He was discharged on day 5 without a need for supplemental oxygen. From day 6 through day 68, the patient quarantined alone at home, but during the quarantine period, he was hospitalized three times for abdominal pain and once for fatigue and dyspnea. The admissions were complicated by hypoxemia that caused concern for recurrent diffuse alveolar hemorrhage and was treated with increased doses of glucocorticoids. SARS-CoV-2 RT-PCR cycle threshold (Ct) values increased to 37.8 on day 39, which suggested resolving infection (Table S1). 2,3 On day 72 (4 days into another hospital admission for hypoxemia), RT-PCR assay of a nasopharyngeal swab was positive, with a Ct value of 27.6, causing concern for a recurrence of Covid-19. The patient again received remdesivir (a 10-day course), and subsequent RT-PCR assays were negative. On day 105, the patient was admitted for cellulitis. On day 111, hypoxemia developed, ultimately requiring treatment with high-flow oxygen. Given the concern for recurrent diffuse alveolar hemorrhage, the patient’s immunosuppression was escalated (Figs. S1 through S3). On day 128, the RT-PCR Ct value was 32.7, which caused concern for a second Covid-19 recurrence, and the patient was given another 5-day course of remdesivir. A subsequent RT-PCR assay was negative. Given continued respiratory decline and concern for ongoing diffuse alveolar hemorrhage, the patient was treated with intravenous immunoglobulin, intravenous cyclophosphamide, and daily ruxolitinib, in addition to glucocorticoids. On day 143, the RT-PCR Ct value was 15.6, which caused concern for a third recurrence of Covid-19. The patient received a SARS-CoV-2 antibody cocktail against the SARS-CoV-2 spike protein (Regeneron). 4 On day 150, he underwent endotracheal intubation because of hypoxemia. A bronchoalveolar-lavage specimen on day 151 revealed an RT-PCR Ct value of 15.8 and grew Aspergillus fumigatus. The patient received remdesivir and antifungal agents. On day 154, he died from shock and respiratory failure. We performed quantitative SARS-CoV-2 viral load assays in respiratory samples (nasopharyngeal and sputum) and in plasma, and the results were concordant with RT-PCR Ct values, peaking at 8.9 log10 copies per milliliter (Fig. S2 and Table S1). Tissue studies showed the highest SARS-CoV-2 RNA levels in the lungs and spleen (Figs. S4 and S5). Phylogenetic analysis was consistent with persistent infection and accelerated viral evolution (Figures 1A and S6). Amino acid changes were predominantly in the spike gene and the receptor-binding domain, which make up 13% and 2% of the viral genome, respectively, but harbored 57% and 38% of the observed changes (Figure 1B). Viral infectivity studies confirmed infectious virus in nasopharyngeal samples from days 75 and 143 (Fig. S7). Immunophenotyping and SARS-CoV-2–specific B-cell and T-cell responses are shown in Table S2 and Figures S8 through S11. Although most immunocompromised persons effectively clear SARS-CoV-2 infection, this case highlights the potential for persistent infection 5 and accelerated viral evolution associated with an immunocompromised state.

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SARS-CoV-2 evolution during treatment of chronic infection

Steven A Kemp, Dami A. Collier, Rawlings P Datir … (2021)

Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

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SARS-CoV-2 Variants in Patients with Immunosuppression

Lawrence Corey, Chris Beyrer, Myron S Cohen … (2021)

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Author and article information

Contributors

Catherine Liu:

ORCID: https://orcid.org/0000-0002-7532-4822

Leah H Yoke

Pooja Bhattacharyya

Ryan D Cassaday

Guang-Shing Cheng

Zahra Kassamali Escobar

Cristina Ghiuzeli

Denise J McCulloch

Steven A Pergam

Pavitra Roychoudhury

Frank Tverdek

Joshua T Schiffer

Emily S Ford

Journal

Journal ID (nlm-ta): Open Forum Infect Dis

Journal ID (iso-abbrev): Open Forum Infect Dis

Journal ID (publisher-id): ofid

Title: Open Forum Infectious Diseases

Publisher: Oxford University Press (US )

ISSN (Electronic): 2328-8957

Publication date Collection: June 2023

Publication date (Electronic): 06 June 2023

Publication date PMC-release: 06 June 2023

Volume: 10

Issue: 6

Electronic Location Identifier: ofad306