Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2.

BACKGROUND: Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended for high-risk patients, but the potential for the development of multidrug-resistant mutations in immunocompromised patients is unclear. METHODS: To investigate the treatment course in cases of prolonged viral shedding in an immunocompromised patient with SARS-CoV-2 infection, we conducted longitudinal measurements of laboratory tests, chest computed tomography (CT) image evaluations, antibody titers, and antigen levels in nasopharyngeal swabs. Furthermore, we performed whole-genome sequencing and digital PCR analysis to examine the mechanisms of drug resistance. FINDINGS: We present a case of a 65-year-old man with a history of malignant lymphoma who was treated with multiple antiviral and antibody therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), and molnupiravir. Initially, viral antigen levels decreased after treatments. However, after the virus rebounded, the patient showed no virologic response. The viral genome analysis revealed a single Omicron subvariant (BA.1.1), which evolved within the host during the disease progression. The viruses had acquired multiple resistance mutations to nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L and E340K), and remdesivir (RNA-dependent RNA polymerase [RdRp] V166L). CONCLUSIONS: Our results indicate that viruses with multidrug-resistant mutations and survival fitness persist in the infected subpopulation after drug selection pressure. FUNDING: This study was supported by the JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid for Scientific Research (B) 20H03668 and 23H02955 (Y.H.), the YASUDA Medical Foundation (Y.H.), the Uehara Memorial Foundation (Y.H.), the Takeda Science Foundation (Y.H.), and Kato Memorial Bioscience Foundation (Y.H.).

Lung tropism in hospitalized patients following infection with SARS-CoV-2 variants from D614G to Omicron BA.2.

BACKGROUND: The genetic and pathogenic characteristics of SARS-CoV-2 have evolved from the original isolated strains; however, the changes in viral virulence have not been fully defined. In this study, we analyzed the association between the severity of the pathogenesis of pneumonia in humans and SARS-CoV-2 variants that have been prevalent to date. METHODS: We examined changes in the variants and tropism of SARS-CoV-2. A total of 514 patients admitted between February 2020 and August 2022 were included and evaluated for pneumonia by computed tomography (CT) as a surrogate of viral tropism. RESULTS: The prevalence of pneumonia for each variant was as follows: D614G (57%, 65/114), Alpha (67%, 41/61), Delta (49%, 41/84), Omicron BA.1.1 (26%, 43/163), and Omicron BA.2 (11%, 10/92). The pneumonia prevalence in unvaccinated patients progressively declined from 70% to 11% as the variants changed: D614G (56%, 61/108), Alpha (70%, 26/37), Delta (60%, 38/63), BA.1.1 (52%, 15/29), and BA.2 (11%, 2/19). The presence of pneumonia in vaccinated patients was as follows: Delta (16%, 3/19), BA.1.1 (21%, 27/129), and BA.2 (11%, 8/73). Compared with D614G, the areas of lung involvement were also significantly reduced in BA.1.1 and BA.2 variants. CONCLUSIONS: Compared with previous variants, there was a marked decrease in pneumonia prevalence and lung involvement in patients infected with Omicron owing to decreased tropism in the lungs that hindered viral proliferation in the alveolar epithelial tissue. Nevertheless, older, high-risk patients with comorbidities who are infected with an Omicron variant can still develop pneumonia and require early treatment.

The SARS-CoV-2 virus changes over time with the differing viruses described as variants. The different variants of SARS-CoV-2 have an impact on how easily they infect people and the effects they have on infected individuals. Here, we examined images of the lungs of patients hospitalized with COVID-19 to investigate whether they had pneumonia, a type of swelling in the lung. Compared with the variant found early in the pandemic, the more recent Omicron variant led to a decreased rate of pneumonia in infected individuals. Our findings emphasize the need for early treatment, as pneumonia may progress in older patients or those with other illnesses.