Published papers

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

Background: Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods: We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFX-containing regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive sputum cultures for >6 months of macrolide-based standard therapy. Results: Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative sputum culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative sputum culture conversion. Conclusions: Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.

Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

BACKGROUND: Biological agents inhibiting TNF-α and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. CASE PRESENTATION: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. CONCLUSION: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.

Obesity is a risk factor for disease severity in individuals with coronavirus disease (COVID-19). However, the increased susceptibility of this population to COVID-19 is unclear. We outline several underlying mechanisms that may explain the relationship between obesity and COVID-19 severity. Obesity has an adverse effect on respiratory physiology because increased intra-abdominal adipose tissue can interfere with lung expansion, resulting in reduced lung compliance. Further, fat accumulation in the soft tissue of the pharynx can increase inspiratory resistance, and obesity may be associated with sleep apnea. Obesity is associated with several defects in cell-mediated immunity, including increased levels of pro-inflammatory cytokines. Impaired adipocyte-mediated immune function results in chronically high leptin levels, low adiponectin levels, and anti-inflammatory adipokines. Reduced physical activity can impair several steps of the immune response to viruses. Obesity also promotes a hypercoagulable state, leading to severe consequences. These factors may synergistically play a role in promoting the severity of the disease in obese individuals. A better understanding of the mechanisms by which obesity contributes to the severity of COVID-19 is important for developing more effective treatments.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. There is a rank order of the efficacy and safety of treatment options, including immune checkpoint inhibitors (ICIs), bevacizumab (Bev), and cytotoxic drugs. When patients have low programmed death-ligand 1 (PD-L1) expression, there are multiple options for treatment. In this study, we focused on ICI regimens in patients with non-squamous NSCLC with low PD-L1 expression and no driver alterations and assessed the efficacy of the regimens using network meta-analysis. Methods: Randomized trials for incurable chemo-naïve non-squamous NSCLC were collected through electronic searches. The data were independently extracted and cross-checked by two investigators. The primary outcome of this analysis was overall survival (OS). A frequentist weighted least-squares approach random-model network meta-analysis was applied. Results: Sixty-eight eligible studies and 22,619 patients were identified. Using a platinum + third-generation cytotoxic agent regimen (platinum regimen) as a reference, the platinum regimen + pembrolizumab (Pemb) [hazard ratio (HR) =0.55, 95% confidence interval (CI): 0.34-0.89, P=0.015] showed the best OS, followed by the platinum regimen + nivolumab (Niv) + ipilimumab (Ipi) (HR =0.61, 95% CI: 0.44-0.84, P=0.003) with no heterogeneity (I2=0%, P=0.348). Conclusions: The addition of Pemb or Niv/Ipi to platinum-based chemotherapy seems to be a good therapeutic option for non-squamous NSCLC with a PD-L1 tumor proportion score (TPS) of 1-49%.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for solid tumours; however, treatment-related adverse events, including pneumonitis, sometimes disrupt the ongoing treatment. To evaluate the impact of ICI addition on the risk of pneumonitis, a meta-analysis was conducted. METHODS: Phase III randomised controlled trials comparing ICIs and conventional therapy with conventional therapy alone were selected by searching databases, including PubMed, Embase, Web of Science and Cochrane Library. The odds ratio (OR) of any grade and grade III-V pneumonitis was calculated. Meta-analysis was performed to compare the incidence of pneumonitis between the treatment arm with additional ICIs and the arm with conventional therapy. RESULTS: A total of 25 randomised controlled trials (RCTs) representing 16,343 patients for grade I-V and 23 RCTs with 15,006 patients for grade III-V pneumonitis were analysed. Adding ICIs was associated with a significant increase in pneumonitis (grade I-V: OR, 2.67, 95% confidence interval [CI]: 2.12-3.37, grade III-V: OR, 1.83, 95% CI: 1.26-2.65). In subgroup analyses based on the mechanism of action of ICIs, cancer types (lung and non-lung cancer) and each ICI, no significant difference in heterogeneity was observed. CONCLUSIONS: Adding ICIs to the conventional treatment for solid tumours significantly increased both grade I-V and grade III-V pneumonitis regardless of the mechanisms of ICIs and cancer type. These results would be helpful for oncologists to choose the appropriate treatment options using ICIs, particularly for patients with known risk factors of pneumonitis or interstitial lung disease.