Although previous authors have reported single data point, yearly changes in respiratory function have not been examined in combined pulmonary fibrosis and emphysema (CPFE). To quantify the annual changes in respiratory function of patients with CPFE and to examine the difference in survival between CPFE patients and patients with idiopathic pulmonary fibrosis without emphysema (IPF alone), 26 patients with CPFE and 33 IPF alone patients, whose respiratory function had been monitored for at least a year, were selected. The baseline of vital capacity percent predicted (VC% pred) in CPFE patients was greater than that in IPF-alone patients (86.6+/-24.0% vs. 72.8+/-19.4%, p=0.018). The annual decrease in VC% pred was significantly less in CPFE patients than in IPF-alone patients (-1.2+/-4.8% vs. -8.0+/-7.4%, p<0.001). Baseline ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC%) in CPFE patients was lower than that in IPF-alone patients (76.6+/-8.5% vs. 85.2+/-6.7%, p<0.001). In the CPFE group, FEV(1)/FVC% tended to decrease with time (-0.5+/-2.2% per year), but, in contrast, it increased in IPF-alone patients (+1.1+/-3.4% per year) (p=0.036). Baseline of diffusing capacity percent predicted (DLco% pred) was significantly lower in CPFE patients than in IPF-alone patients (45.3+/-15.0% vs. 60.7+/-19.8%, p=0.003). The annual decrease in DLco% pred was lower in CPFE patients than in IPF-alone patients (-3.7+/-7.9% vs. -10.7+/-8.8%, p=0.042). There was no significant difference in the survival duration between 26 CPFE and 33 IPF-alone patients according to Kaplan-Meier analysis. Ventilatory and gas-exchange deterioration during the course of IPF became mild when emphysema was coexistent.

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.

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Patients with chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, often contract recurrent life-threatening bacterial and fungal infections. CGD is considered to arise from a functional defect of the O(2)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. To determine whether or not NADPH oxidase is crucial to the host defence against Mycobacterium avium, we investigated the response against M. avium using CGD model mice (gp91-phox(-)) of C57BL/6 strain. A tracheal injection of 1 x 10(7) colony-forming units (CFU)/head of M. avium strain FN into the CGD mice resulted in a pulmonary infection, while also increasing the mortality rate. In contrast, normal C57BL/6 mice injected with same dose of the organisms did not develop severe pulmonary infection and were able to survive through 2 months of observation. The macrophages obtained from the CGD mice were observed to have a higher burden of the bacterial growth than macrophages from normal C57BL/6 mice. These results suggest that the defect of the NADPH oxidase function impairs the host defence against M. avium infection.