In the treatment of asthma and chronic obstructive pulmonary disease (COPD), errors in handling and wrong techniques in using inhalation devices are associated with poor disease control. The aim of this study was to evaluate the number of instructions that are necessary to minimize errors in using pressurized metered-dose inhaler (pMDI), soft mist inhaler (SMI), and dry powder inhaler (DPI). Among 216 patients with asthma (n = 135) and COPD (n = 81), we studied 245 cases that used different types of inhalation devices. After initial guidance, 145 of 245 cases (59%) made at least one error that could affect efficacy. For every device, at least three instructions were required to achieve entirely no errors or less than 10% errors in total. The most common error on the use of pMDI was device handling, whereas that of DPI was inhalation manner. Both errors were associated with low peak flow rate. In both patients with asthma and in patients with COPD, the most common error was inhalation manner. We concluded that it is necessary to repeat at least three times of instructions to achieve effective inhalation skills in both asthma and COPD patients.

The incidence and risk factors of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated.We conducted a retrospective study of 632 patients with IPF to assess the incidence and risk factors of lung cancer development.Seventy patients developed lung cancer over a median follow-up period of 3.8 years. The incidence density of lung cancer development was 25.2 cases per 1000 person-years. The most frequent type was squamous cell carcinoma (30%), the majority developed lung cancer in the peripheral lung (82.9%) and adjacent to usual interstitial pneumonia (75.7%). In a multivariate Cox regression hazard model, pack-years of smoking ≥35 and coexisting emphysema were associated with lung cancer development. The 1-, 3- and 5-year all-cause mortality rates after lung cancer diagnosis were 53.5%, 78.6% and 92.9%, respectively.The incidence density of lung cancer is high in IPF patients and occurs more frequently in patients with smoking history of pack-years of smoking ≥35 and with coexisting emphysema. The majority of lung cancers develop adjacent to usual interstitial pneumonia. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

Objective Community-acquired pneumonia (CAP) remains a major cause of death. No studies have reported the use of rapid influenza diagnostic tests (RIDT) for the etiological diagnosis, and the factors contributing to severity and mortality have not yet been fully investigated. The aim of this study was to review the etiologies of CAP using RIDT and to identify risk factors related to the severity and mortality of the disease. Methods This retrospective study assessed these factors in hospitalized patients, with special emphasis on microbial etiology. Results A total of 1,032 patients aged 63.9±18.3 years were studied, 66.2% of whom were men. Microbial identification was obtained in 57.0% of the cases. The most frequent causative microbial agents were Streptococcus pneumoniae, Mycoplasma pneumoniae and the influenza virus, and the second most frequent pathogens in the patients with severe CAP and the non-survivors were S. pneumoniae and the influenza virus. Age (! 65 years), chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, dementia and Legionella spp. infection and polymicrobial infection were each found to be independent factors related to severity in the multivariate analysis, whereas "unidentified pathogen" was found to be an independent factor for non-severe CAP. Age (! 65 years), chronic pulmonary aspergillosis, post-lung cancer surgery and severe CAP were found to be independent factors for non-survival according to a multivariate analysis. Conclusion In addition to S. pneumoniae, the influenza virus was a frequent cause of CAP overall and a frequent causative pathogen in both severe cases of CAP and non-survivors. Legionella spp. infection and polymicrobial infection were found to be an independent factor for the severity of CAP along with advanced age and certain comorbidities. An advanced age, certain respiratory comorbidities and severe CAP were found to be important independent factors for the mortality of CAP.

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.

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Objective The long-term clinical course and prognosis of patients with chronic eosinophilic pneumonia (CEP) including factors predictive of the relapse of CEP have not been fully investigated. The aim of the present study was to investigate these issues. Methods We retrospectively investigated the rate of relapse and prognosis in 73 patients diagnosed as having CEP. Results Systemic corticosteroid therapy was administered at a prednisolone dose of 29.4±7.6 mg/day. During a median follow-up period of 1,939 days, 27 patients suffered from relapse of CEP. Two patients developed steroid-induced diabetes mellitus, and 1 patient developed pulmonary nontuberculous mycobacteriosis. Five patients died; however, none died of CEP. A history of smoking was the only independent negative risk factor for relapse of CEP [hazard ratio, 0.37 (0.14-0.98)]. Conclusion Patients with CEP frequently relapse. During the follow-up, metabolic and infectious complications under prolonged corticosteroid therapy are problematic. A history of smoking was a negative factor for predicting the risk of CEP relapse.

BackgroundEosinophils play an important role in the pathogenesis of bronchial asthma and its exacerbation. Recent reports suggest the involvement of IFN-γ-inducible protein of 10 kDa (IP-10) in virus-induced asthma exacerbation. The objective of this study was to examine whether CXCR3 ligands including IP-10 modify the effector functions of eosinophils.MethodsEosinophils isolated from the blood of healthy donors were stimulated with CXCR3 ligands and their adhesion to rh-ICAM-1 was then measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O2-) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) release was evaluated to determine whether CXCR3 ligands induced eosinophil degranulation. Cytokine and chemokine production by eosinophils was examined using a Bio-plex assay.ResultsEosinophil adhesion to ICAM-1 was significantly enhanced by IP-10, which also significantly induced eosinophil O2- generation in the presence of ICAM-1. Both the enhanced adhesion and O2- generation were inhibited by an anti-β2 integrin mAb or an anti-CXCR3 mAb. Other CXCR3 ligands, such as monokine induced by IFN-γ (Mig) and IFN-inducible T cell α chemoattractant (I-TAC), also induced eosinophil adhesion and O2- generation in the presence of ICAM-1. IP-10, but not Mig or I-TAC, increased the release of EDN. IP-10 increased the production of a number of cytokines and chemokines by eosinophils.ConclusionsThese findings suggest that CXCR3 ligands such as IP-10 can directly upregulate the effector functions of eosinophils. These effects might be involved in the activation and infiltration of eosinophils in the airway of asthma, especially in virus-induced asthma exacerbation.

Background: Omalizumab, an anti-immunoglobulin E monoclonal antibody, has shown an inhibitory effect on airway inflammation, which may be associated with clinical improvement of severe asthma. This study evaluated changes in airway inflammation and cytokine release by the peripheral blood mononuclear cells (PBMCs) of Japanese patients with severe asthma after administration of omalizumab. Methods: Sixteen Japanese patients with severe asthma who were allergic to house-dust mites were enrolled in this study. Eight received omalizumab every 2 or 4 weeks for 16 weeks, and 8 control subjects were treated with conventional drug treatment. Changes in clinical scores for sputum eosinophils and levels of fraction of exhaled nitric oxide (FeNO) were measured at the time of enrollment and at week 16. Cytokines from PBMCs stimulated by house-dust mite (Dermatophagoides farinae) or ionomycin/phorbol myristate acetate (PMA) were measured at baseline and at week 16. Results: In the omalizumab-treated group, decreases in sputum eosinophils and FeNO were observed following treatment. Furthermore, the ex vivo production of interleukin (IL)-5 by PBMCs in response to both mite allergen and ionomycin/PMA decreased significantly. In contrast, interferon (IFN)-γ production was unchanged. There were no changes in any of the parameters observed in the control group. Conclusion: Omalizumab exerts inhibitory effects on airway inflammation in Japanese patients with severe allergic asthma. This treatment attenuates production of IL-5 by PBMCs stimulated with both a specific allergen and a nonspecific activator. Reduction of the Th2 inflammatory cascade likely contributes to clinical benefits; however, further studies are required to clarify these results due to the small sample size in this study.