Patients after allogeneic hematopoietic SCT (HSCT) are at risk of malnutrition. To assess the impact of malnutrition after allogeneic HSCT on transplant outcomes, we conducted a retrospective study. Adult patients who received allogeneic HSCT from 2000 to 2009 for standard-risk leukemia and achieved disease-free survival up to 3 months after allogeneic HSCT were included. From participating centers, 145 patients were enrolled. Median age was 46 years (19-68). Patients were classified based on weight loss during 3 months after allogeneic HSCT as follows: normal group (weight loss o 5%, n = 53), mild malnutrition group (5% ⩽ weight loss o 10%, n = 47), severe malnutrition group (10% ⩽ weight loss, n = 45). The cumulative incidences of 2-year nonrelapse mortality (NRM) were 3.8% in the normal group, 8.5% in the mild malnutrition group and 27.3% in the severe malnutrition group. The probabilities of a 2-year OS were 73.2% in the normal group, 74.5% in the mild malnutrition group and 55.3% in the severe malnutrition group. In multivariate analysis, severe malnutrition was associated with an increased risk of NRM and a worse OS. In conclusion, weight loss ⩾ 10% was associated with a worse clinical outcome. Prospective studies that identify patients at risk of malnutrition and intervention by a nutritional support team are warranted.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

In a previous study, we noted wide inter-individual variability in drug interactions between voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7-10 days after, initiating voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6-1110.7) to 537.5 (range 127.8-1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of voriconazole; the median increase was 138.8 % (range -32.0 to 685.7 %). The plasma concentration of voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of voriconazole. Other possible mechanisms should be explored in future studies.

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