土井 洋平

Patients with hematologic diseases have experienced coronavirus disease 2019 (COVID-19) with a 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) levels persisted for >4 weeks, and two of them succumbed to COVID-19. The autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping cytomegalovirus, 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 an 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 the acquisition of drug resistance and improve outcomes, such as the selection of appropriate treatment strategies for lymphoma considering patients' immune status and the institution of early intensive antiviral therapy.

BACKGROUND AND OBJECTIVES: Carbapenem-resistant Gram-negative bacilli (CRGNB), especially Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii, are critical pathogens associated with excess morbidity and mortality. To elucidate their molecular epidemiology and clinical outcomes in Japan, patients with CRGNB were enrolled in the MDR organisms clinical research network (MDRnet) consisting of eight tertiary care facilities. METHODS: Between 2019 and 2022, 246 unique patients with carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant P. aeruginosa (CRPA) and carbapenem-resistant A. baumannii (CRAB) isolates were prospectively enrolled. RESULTS: A total of 246 isolates were collected from 246 patients, including 78 (31.7%) CRE, 167 (67.9%) CRPA and 1 (0.4%) CRAB. For CRE, 74.4% of the isolates carried carbapenemase genes with predominance of bla IMP (64.1%). Only 2.4% of CRPA had carbapenemase genes, which was lower than CRE. Among the infected patients, 20.0% and 12.5% died of CRE and CRPA within 30 days, respectively. In patients with CRE, the mortality rate within 30 days for those without carbapenemase-producing Enterobacterales (CPE) was higher compared with those with CPE (22.2% compared with 18.8%). CONCLUSIONS: Our study highlights the unique molecular epidemiology and clinical outcomes of CRGNB in Japan.

Several Ephedra Herb-containing Kampo medicines are common initial treatments for various infections; however, the ephedrine alkaloids in Ephedra Herb can cause side effects by stimulating adrenergic receptors. Accordingly, an ephedrine alkaloids-free Ephedra Herb Extract (EFE) has been developed. This study aimed to evaluate whether EFE can be used effectively and safely in patients with mild coronavirus disease 2019 (COVID-19). We randomized patients with mild COVID-19 to receive EFE equivalent to 6 g of Ephedra Herb per day or a placebo for 14 days. The primary efficacy endpoint was the non-aggravation rate up to Day 15. We allocated 41 and 40 patients to the EFE and placebo groups, respectively. All participants were included in the mITT and safety analysis populations [male ratio, mean age: 31.7%, 42.0 years (EFE); 17.5%, 43.2 years (placebo)]. The non-aggravation rate up to Day 15 for the primary endpoint was 100.0% and 94.6% in the EFE and placebo group, respectively, with no between-group difference. The number of days to the improvement in nausea symptoms was significantly shorter in the EFE group. One patient in the placebo group discontinued the trial due to a side effect. Although EFE demonstrated safety in patients with mild COVID-19, it did not show superior efficacy compared to placebo for symptoms other than nausea.

BACKGROUND: With progressive accumulation of knowledge on SARS-CoV-2 infection clinical management, treatment guidelines recommended several options including remdesivir (RDV), a broad-spectrum antiviral. Given the evolving nature of COVID-19, capturing the totality of scientific evidence from clinical trials and observational studies is critical to inform clinical decision making. We conducted a systematic literature review (SLR) with meta-analysis (MA) to summarize RDV effectiveness among hospitalized adults. METHODS: We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining RDV efficacy. A rigorous double-reviewer approach was used for source identification, screening, data extraction and risk of bias assessment. A hierarchical random-effects model MA was used, with subgroup analyses for randomized controlled trials (RCT) and real-world (RW) studies. RESULTS: From January 2019 to December 2023 over 18,000 sources were screened and 122 unique studies were identified, reporting on 25,174 participants in RCTs and 1,279,859 in RW studies. Remdesivir significantly increased survival in the overall population [OR: 0.69 (0.55-0.86); p=0.001] across SARS-CoV-2 variants and disease severity levels: no supplemental oxygen [OR: 0.81 (0.75-0.88)], low-flow oxygen [OR: 0.71 (0.64-0.79)], high-flow oxygen [OR: 0.87 (0.83-0.91)] and invasive mechanical ventilation [OR: 0.78 (0.68-0.90)]. Rehospitalization risk was significantly reduced in patients receiving remdesivir [OR: 0.72 (0.64-0.81)]. CONCLUSION: Our comprehensive SLR, capturing the totality of evidence, showed a significant survival benefit among patients hospitalized for SARS-CoV-2 infection receiving RDV across all disease severity levels. To assure that healthcare providers are aware of and deploy evidence-based optimal care, recommendations should rely on both RCT and RW data.