Published papers

Pulmonary manifestations in patients with allergic bronchopulmonary aspergillosis (ABPA) and nontuberculous mycobacterial-pulmonary disease (NTM-PD) include bronchiectasis and mucus plugging. A 68-year-old woman, treated with antibiotics and inhaled corticosteroids for NTM-PD and asthma, presented with fever and wheezing. ABPA was diagnosed based on laboratory findings (elevated peripheral blood eosinophil counts and serum total IgE levels and positive Aspergillus-specific IgE and IgG) and imaging observation of a high-attenuation mucus plug. Systemic prednisolone was avoided to prevent NTM-PD progression. Dupilumab, a monoclonal antibody that blocks IL-4/13, was introduced to improve the clinical findings. Herein, we discuss the pathophysiological mechanisms underlying this rare comorbidity.

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently admi-nistered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019 as an outbreak of pneumonia of unknown origin. Previous studies have suggested the utility of chest computed tomography (CT) in the diagnosis of COVID-19 because of its high sensitivity (93%–97%), relatively simple procedure, and rapid test results. This study, performed in Japan early in the epidemic when COVID-19 prevalence was low, evaluated the diagnostic accuracy of chest CT in a population presenting with lung diseases having CT findings similar to those of COVID-19. We retrospectively included all consecutive patients (≥18 years old) presenting to the outpatient department of Keio University Hospital between March 1 and May 31, 2020, with fever and respiratory symptoms. We evaluated the performance of diagnostic CT for COVID-19 by using polymerase chain reaction (PCR) results as the reference standard. We determined the numbers of false-positive (FP) results and assessed the clinical utility using decision curve analysis. Of the 175 patients, 22 were PCR-positive. CT had a sensitivity of 68% and a specificity of 57%. Patients with FP results on CT diagnosis were mainly diagnosed with diseases mimicking COVID-19, e.g., interstitial lung disease. Decision curve analysis indicated that the clinical utility of CT imaging was limited. The diagnostic performance of CT for COVID-19 was inadequate in an area with low COVID-19 prevalence and a high prevalence of other lung diseases with chest CT findings similar to those of COVID-19. Considering this insufficient diagnostic performance, CT findings should be evaluated in the context of additional medical information to diagnose COVID-19.

Objectives: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. Results: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97–39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. Conclusions: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

No clinical studies to date have compared the airway luminal area between supine and standing positions. Our aim was therefore to compare the airway luminal area between these two positions on computed tomography (CT) and to determine its correlation with forced expiratory volume in 1 s (FEV1). Thirty-two asymptomatic volunteers underwent both conventional (supine position) and upright (standing position) CT during deep inspiration breath-holding. Pulmonary function tests were conducted on the same day. We measured the airway luminal area on CT in each position. Paired t-tests and Pearson's correlation coefficients were used for statistical analysis. The average luminal areas of the trachea, right and left main bronchi, and average third-generation airway were greater in the standing than the supine position by 3.4%, 6.1%, 5.5%, and 5.2%, respectively. The correlation coefficients between airway luminal areas and FEV1 tended to be higher in the standing than the supine position; this correlation was highest for the average third-generation airway (r = 0.70, P < 0.0001). The airway luminal areas of the trachea, bilateral main bronchi, and average third-generation airway were greater in the standing than the supine position. The average third-generation airway area in the standing position had the highest correlation with FEV1.

Background: No clinical studies to date have compared the inspiratory and expiratory airway lumen area between supine and standing positions. Thus, the aims of this study were twofold: (1) to compare inspiratory and expiratory airway lumen area (IAA and EAA, respectively) on computed tomography (CT) among supine and standing positions; and (2) to investigate if IAA and EAA are associated with lung function abnormality in patients with chronic obstructive pulmonary disease (COPD). Methods: Forty-eight patients with COPD underwent both low-dose conventional (supine position) and upright CT (standing position) during inspiration and expiration breath-holds and a pulmonary function test (PFT) on the same day. We measured the IAA and EAA in each position. Results: For the trachea to the third-generation bronchi, the IAA was significantly larger in the standing position than in the supine position (4.1–4.9% increase, all p < 0.05). The EAA of all bronchi was significantly larger in the standing position than in the supine position (9.7–62.5% increases, all p < 0.001). The correlation coefficients of IAA in the standing position and forced expiratory volume in 1 s were slightly higher than those in the supine position. The correlation coefficients of EAA or EAA/IAA in the standing position and residual volume, and the inspiratory capacity/total lung capacity ratio were higher than those in the supine position. Conclusions: Airway lumen areas were larger in the standing position than in the supine position. IAAs reflect airway obstruction, and EAAs reflect lung hyperinflation. Upright CT might reveal these abnormalities more precisely. Trial registration University Hospital Medical Information Network (UMIN 000026587), Registered 17 March 2017. URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000030456.

No clinical study has compared lung or lobe volumes on computed tomography (CT) between the supine and standing positions in patients with idiopathic lung fibrosis (IPF). This study aimed to compare lung and lobe volumes between the supine and standing positions and evaluate the correlations between the supine/standing lung volumes on CT and pulmonary function in patients with IPF. Twenty-three patients with IPF underwent a pulmonary function test and both low-dose conventional (supine position) and upright CT (standing position) during inspiration breath-holds. The volumes of the total lungs and lobes were larger in the standing than in the supine position in patients with IPF (all p < 0.05). Spearman's correlation coefficients between total lung volumes on chest CT in supine/standing positions and vital capacity (VC) or forced VC (FVC) were 0.61/0.79 or 0.64/0.80, respectively. CT-based volumes on upright CT were better correlated with VC and FVC than those on supine CT. Lung and lobe volumes in the standing position may be useful biomarkers to assess disease severity or therapeutic effect in patients with IPF.

Background: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients. Methods: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared. Results: The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (KCO). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores. Conclusion: FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.

Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.

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: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. Methods: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. Results: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27–0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19–0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission. Conclusions: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation. Trial Registration None.

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

Lung fibrosis is a progressive fatal disease, and the underlying mechanisms remain unclear. These involve a combination of altered fibroblasts, excessive accumulation of extracellular matrix, inflammation, and aberrant activation of epithelial cells. Previously, we showed that high-fat diet (HFD) induces lung inflammation, aberrant activation of stem cells, and lung mitochondria impairment. Therefore, we hypothesized that HFD-induced changes would influence lung fibrosis. Mice were fed standard diet (SD) or HFD, administered bleomycin, then examined for fibrosis severity and the start of repair 3 weeks after injury, and for fibrosis repair/resolution 6-9 weeks after injury. At 3 weeks, no significant differences in inflammation and fibrosis severity were observed between SD-and HFD-fed mice. However, infiltration of alveolar type (AT)-2 cells and bronchioalveolar stem cells (BASCs) into the fibrotic areas (the start of repair) was impaired in HFD-fed mice. At 6 weeks, SD-fed mice showed near-complete resolution/repair of fibrosis and inflammation, while HFD-fed mice still showed residual fibrosis and inflammation. Infiltration of the fibrotic areas with AT2 cells was observed, but very few BASCs were detectable. At 9 weeks, mice from both groups showed complete resolution/repair of fibrosis and inflammation, indicating that HFD induced delayed, rather than failed, resolution of fibrosis and alveolar repair. To further confirm the direct role of enhanced fatty-acid oxidation (FAO) in delayed resolution/repair, we administered etomoxir, a FAO inhibitor, to HFD-fed mice for 3-6 weeks after bleomycin injury. Inhibition of FAO abolished the HFD-induced delay in alveolar repair and fibrosis resolution at both time points. In conclusion, after a fibrosis-inducing injury, HFD slows resolution of fibrosis/inflammation and delays alveolar repair by slowing the contribution of AT2 stem cells and abolishing the contribution of BASCs in the repair process. FAO activation appears to be involved in this delay mechanism; thus, inhibiting FAO may be useful in the treatment of lung injury and fibrosis.

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20-2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19-2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11-1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

Background: Obesity is reported to be a risk factor for severe disease in patients with coronavirus disease 2019 (COVID-19). However, there are no specific reports on the risk of severe disease according to body mass index (BMI) in Japan. Thus, this study aimed to investigate the effect of obesity stratified by BMI on the severity of COVID-19 in the general Japanese population. Methods: From February 2020 to May 2021, 1 837 patients aged ≥18 years were enrolled in the Japan COVID-19 Task Force. Patients with known BMI and disease severity were analyzed. Severity was defined as critical if the patient was treated in the intensive care unit, required invasive mechanical ventilation, or died. Results: Class 1 obesity (25.0 ≤ BMI < 30.0 kg/m2), class 2 obesity (30.0 ≤ BMI < 35.0 kg/m2), and class 3 or 4 obesity (BMI ≥ 35 kg/m2) were present in 29%, 8%, and 3% of the cases, respectively. Multiple logistic regression analysis with known risk factors for critical illness indicated that class 2 obesity was an independent risk factor for oxygenation (adjusted odds ratio, 4.75) and critical cases (adjusted odds ratio, 1.81). Class 1 obesity and class 3 or 4 obesity were independent risk factors for oxygen administration (adjusted odds ratios 2.01 and 3.12, respectively), but not for critical cases. However, no differences in the mortality rates were observed between the BMI classes (P = 0.5104). Conclusion: Obesity is a risk factor for respiratory failure in Japanese patients with COVID-19, regardless of the degree of obesity. However, it may not cause severe COVID-19 in a dose–response relationship with BMI. COVID-19 patients with mild obesity may benefit from aggressive intensive care.

Dysregulated fatty acid metabolism is clinically associated with eosinophilic allergic diseases, including severe asthma and chronic rhinosinusitis. This study aimed to demonstrate the role of 12/15-lipoxygenase (12/15-LOX) in interleukin (IL)-33-induced eosinophilic airway inflammation; to this end, we used 12/15-LOX-deficient mice, which displayed augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells (ILC2s) in the airway. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics revealed that the levels of a series of 12/15-LOX-derived metabolites were significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid (HDoHE), a major 12/15-LOX-derived product, suppressed IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. Using bioactive lipid screening, we found that 14(S)-HDoHE and 10(S),17(S)-diHDoHE markedly attenuated ILC2 proliferation and cytokine production at micromolar concentration in vitro. In addition, maresin 1 (MaR1) and resolvin D1 (RvD1), 12/15-LOX-derived specialized proresolving mediators (SPMs), inhibited cytokine production of ILC2s at nanomolar concentration. These findings demonstrate the protective role of endogenous 12/15-LOX-derived lipid mediators in controlling ILC2-mediated eosinophilic airway inflammation and related diseases. Thus, 12/15-LOX-derived lipid mediators may represent a potential therapeutic strategy for ameliorating airway inflammation-associated conditions.

Case Presentation: A 70-year-old woman who had received a diagnosis of pneumonia in the right lower lobe was treated with antibiotics at a general practitioner's clinic 9 months earlier. Her pneumonia had improved, but the cough and lung infiltrates persisted for > 6 months, so the patient was referred to our hospital. She had undergone surgery for breast cancer 30 years earlier but had no other medical history. She was not taking any medications and had no history of smoking, including passive smoking.

Background: Asthma, chronic obstructive pulmonary disease (COPD), and asthma–COPD overlap (ACO) are complex and heterogeneous diseases that share clinical characteristics (phenotypes) and molecular mechanisms (endotypes). Whilst physicians make clinical decisions on diagnostic groups, for some such as ACO there is no commonly accepted criteria. An alternative approach is to evaluate phenotypes and endotypes that are considered to respond well to a specific type of treatment (“treatable traits”) rather than diagnostic labels. Purpose: The prospective, longitudinal, and observational TRAIT study will evaluate disease characteristics, including both phenotypes and endotypes, in relation to the presentation of obstructive respiratory disease characteristics in patients diagnosed with asthma, COPD, or ACO in Japan, with the aim of further understanding the clinical benefit of a treatable traits-based approach. Patients and Methods: A total of 1500 participants will be enrolled into three cohorts according to their treating physician’s diagnosis of asthma, COPD, or ACO at screening. Part 1 of the study will involve cross-sectional phenotyping and endotyping at study enrollment. Part 2 of the study will evaluate the progression of clinical characteristics, biomarker profiles, and treatment over a 3-year follow-up period. The follow-up will involve three annual study visits and three telephone calls scheduled at 6-month intervals. A substudy involving 50 participants from the asthma cohort (in which the ratio will be approximately 1:1 including 25 participants with a smoking history of ≥10 pack-years and 25 participants with no smoking history), 100 participants from the ACO cohort, and 100 participants from the COPD cohort will evaluate disease phenotypes using inspiratory and expiratory computed tomography scans. Conclusion: TRAIT will describe clinical characteristics of patients with obstructive respiratory diseases to better understand potential differences and similarities between clinical diagnoses, which will support the improvement of personalized treatment strategies.

Background: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. Materials and Methods: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. Results: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. Conclusions: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10DLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10DLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10DLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10DLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10DLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.