Exacerbation rates in Japanese patients with obstructive lung disease: A subanalysis of the prospective, observational NOVELTY study.

BACKGROUND: Although clinical trials including asthma and COPD patients have revealed much about exacerbation frequencies, most studies are limited in that they recruited patients only with a clear diagnosis of one disease or the other, based on conventional diagnostic criteria, which may exclude many real-world patients with mixed symptoms. METHODS: NOVELTY is a global prospective observational study of patients with asthma and/or COPD from real-world practice. In this subanalysis, we compared patient characteristics of obstructive pulmonary diseases between the Japanese population (n = 820) and the overall population excluding Japanese patients (n = 10,406). RESULTS: The Japanese population had fewer exacerbations than the overall population across most of the physician-assessed disease severities and all diagnoses. The difference in exacerbation frequencies was more prominent in patients with COPD and asthma + COPD. The Japanese population was older, had higher former smoking rates, lower BMI, fewer respiratory symptoms, and better health-related quality of life compared with the overall population across all diagnoses. CONCLUSIONS: We clarified differences in patient characteristics among patients with asthma and/or COPD in Japan compared with non-Japanese patients. Importantly, we found that Japanese patients with asthma and/or COPD had significantly fewer exacerbations compared with patients overall. The results from our study may contribute to the development of precision medicine and guidelines specific to Japan.

Sputum Neurturin Levels in Adult Asthmatic Subjects.

Background: Neurturin (NRTN) is a neurotrophic factor that was originally identified in the development and maintenance of neural cells. Recent studies involving NRTN knockout mice have reported its anti-inflammatory effects in allergic airway conditions. However, the role of NRTN in human asthma has not yet been identified. Objective: The purposes of the present study were to confirm the presence of NRTN in the airways and to investigate the clinical and pathogenetic roles of NRTN in asthma. Methods: The NRTN levels in the induced sputum were measured by enzyme-linked immunosorbent assay (ELISA). Relationships between NRTN and clinical characteristics, asthma control status, and airway inflammation were assessed. Results: Sixty-four asthmatic subjects were enrolled in the study. All asthmatic subjects had detectable sputum NRTN levels, with a mean (SD) level of 2.03 (1.29) ng/mL. The sputum NRTN levels had significant positive correlations with sputum eosinophil and exhaled nitric oxide levels and were significantly higher in the atopic subjects than in the non-atopic subjects. No significant difference in sputum NRTN levels were observed for asthma control status and asthma exacerbation. In sputum inflammatory analyses, sputum NRTN level was positively correlated with interleukin (IL)-5 and IL-13 levels, and negatively correlated with matrix metalloproteinase (MMP)-9 level. Conclusion: It is plausible that sputum NRTN could serve as a new marker for Type 2 airway inflammation, implicating its role in the process of airway remodeling in asthma. Future studies should investigate the clinical relevance of sputum NRTN level in prospective analyses.

Ultrasonic Debridement of Fournier Gangrene.

Ultrasonic debridement devices are minimally invasive and effective for biofilm removal, allowing for debridement of necrotic tissue while minimizing damage to normal tissues, such as the blood vessels and nerves. The use of ultrasonic debridement has been reported for foot ulcers and pressure ulcers but not Fournier gangrene. The perineal area, which is difficult to surgically debride using electrocautery, is a suitable site for the use of an ultrasonic debridement device because of its proximity to vital organs. We report here a case of Fournier gangrene that healed with testicular sparing using an ultrasonic debridement device.

Reconstruction of necrotizing soft tissue infection in the auricle and temporal region: a case report.

A 43-year-old female patient had a necrotizing soft tissue infection in the temporal region. Because of the necrotic temporoparietal fascia, auricular reconstruction was attempted using the temporalis muscle flap; the flap was successfully placed. The use of the temporalis muscle flap was considered a treatment option for salvaging the auricle.

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic.

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase.

Impact of depressed state on attention and language processing during news broadcasts: EEG analysis and machine learning approach.

While information enriches daily life, it can also sometimes have a negative impact, depending on an individual's mental state. We recorded electroencephalogram (EEG) signals from depressed and non-depressed individuals classified based on the Beck Depression Inventory-II score while they listened to news to clarify differences in their attention to affective information and the impact of attentional bias on language processing. Results showed that depressed individuals are characterized by delayed attention to positive news and require a more increased load on language processing. The feasibility of detecting a depressed state using these EEG characteristics was evaluated by classifying individuals as depressed and non-depressed individuals. The area under the curve in the models trained by the EEG features used was 0.73. This result shows that individuals' mental states may be assessed based on EEG measured during daily activities like listening to news.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

Development of dermatomyositis after anti-transcriptional intermediary factor 1-γ antibody seroconversion during treatment for small cell lung cancer.

BACKGROUND: Inflammatory myositis, such as dermatomyositis, is sometimes complicated by cancer and is recognized as cancer-associated myositis. Although some autoimmune antibodies are considered to be involved in the development of myositis in cancer patients, the precise mechanism has not been clarified. The findings of the present case shed light on the mechanism by which anti-transcriptional intermediary factor 1 (TIF1)-γ Ab was produced and the pathogenesis of cancer-associated myositis. CASE PRESENTATION: We describe a case of dermatomyositis that developed in a 67-year-old man who had been diagnosed with small cell lung cancer of clinical T4N3M0 stage IIIB/limited disease during treatment. He received systemic chemotherapy and radiation therapy, and dermatomyositis developed along with a significant decrease in tumor size. TIF1-γ Ab, which is one of the myositis-specific antibodies, was found to be seroconverted. In addition, immunohistochemical analysis showed that cancer cells were positive for the TIF1-γ antigen. CONCLUSION: The findings of the present case suggest that transcriptional intermediary factor 1-γ, which is released from tumor cells, induces the production of TIF1-γ Ab, leading to the development of dermatomyositis.

Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough.

BACKGROUND: The purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3 versus P2X2/3. METHODS: In a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2-3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated. RESULTS: Of 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks of treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary end-point) and over 24 h (secondary end-point) were -31.6% (p=0.0546) and -30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration. CONCLUSIONS: Sivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.

Usefulness of diurnal variation of fractional exhaled nitric oxide for predicting early therapeutic response to asthma treatment.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is considered to be an adjunct for asthma management, although its usefulness remains controversial. Therefore, it may be necessary for new approaches to use FeNO for asthma management. We evaluated whether diurnal variations of FeNO can predict response to asthma treatment. METHODS: This pilot study consisted of 22 uncontrolled asthmatics and 16 healthy subjects. FeNO and peak expiratory flow (PEF) were measured by themselves twice daily at home for three weeks (asthmatics) or two weeks (healthy subjects), and daily mean and diurnal variations of FeNO and PEF levels were calculated. In uncontrolled asthmatics, treatment was intensified a week after study entry, and then control status was reevaluated after three to four weeks. Asthmatics were then divided into two groups; good or poor responders. RESULTS: Diurnal variations of FeNO levels, as well as daily mean FeNO and PEF levels, in uncontrolled asthmatics before intensive treatment were significantly higher than those in healthy subjects, regardless of treatment response (p < 0.01). Furthermore, in the good responders, diurnal variations of FeNO levels were significantly decreased in the 1st week (p < 0.05) of intensive treatment, whereas the daily mean FeNO levels significantly dropped in the 2nd week (p < 0.05). In the poor responders, no such changes were observed in FeNO levels. In terms of PEF, only the daily mean levels were significantly elevated after the initiation of intensive treatment, regardless of treatment response. CONCLUSIONS: Diurnal variations of FeNO may contribute to predicting early therapeutic response to asthma treatment.

Association Between Sleep Characteristics and Asthma Control in Middle-Aged and Older Adults: A Prospective Cohort Study.

BACKGROUND: Nocturnal asthma symptoms are a well-known feature of sleep disturbance. However, there are few reports on the association between sleep-related characteristics and asthma exacerbation. The aim of the current prospective observational study was to explore the factors while sleeping associated with future asthma exacerbation. MATERIALS AND METHODS: At baseline, adult asthmatics underwent home sleep monitoring by a Watch-PAT instrument and then they were prospectively followed-up for the occurrence of exacerbations. The number of asthma exacerbation was observed over a period of one year, and multivariable analyses of the factors associated with asthma exacerbation were performed. RESULTS: A total of 62 asthmatic subjects were enrolled (mean age 62.1 years), 59 of whom were finally included in the prospective observational study. Obstructive sleep apnea (defined by an apnea-hypopnea index based on peripheral arterial tone more than 5 times/hour) were observed in 81% of the subjects. During the one-year monitoring period, 14 of the 59 subjects (24%) used occasional systemic corticosteroids for their exacerbation asthma (worsened group) while the other 45 subjects did not experience asthma exacerbation (stable group). A comparison of the baseline clinical characteristics and sleep-related data between the two groups, mean forced expiratory volume one second percent (FEV1/FVC), mean baseline Asthma Control Test (ACT) score, median pAHI value, and median oxygen desaturation index value were significantly lower in the worsened group than those in the stable group. Additionally, mean prevalence of the left lateral decubitus (LLD) position in sleep monitoring were significantly higher in the worsened group than that in the stable group. Among the independent variables, baseline asthma severity, ACT score, and the LLD position showed significant associations with asthma exacerbation. DISCUSSION/CONCLUSION: The present study identified that sleeping in the LLD position was also associated with asthma exacerbation.

Hydrogen sulfide as a novel biomarker of asthma and chronic obstructive pulmonary disease.

Hydrogen sulfide (H2S) has recently been recognised as the third important gas-signalling molecule, besides nitric oxide and carbon monoxide. H2S has been reported to be produced by many cell types in mammalian tissues and organs throughout the actions of H2S-generating enzymes or redox reactions between the oxidation of glucose and element of sulfur. Although the pathological role of H2S has not yet been fully elucidated, accumulative data suggest that H2S may have biphasic effects. Briefly, it mainly has anti-inflammatory and antioxidant roles, although it can also have pro-inflammatory effects under certain conditions where rapid release of H2S in tissues occur, such as sepsis. To date, there have been several clinical studies published on H2S in respiratory disorders, including asthma and chronic obstructive pulmonary disease (COPD). According to previous studies, H2S is detectable in serum, sputum, and exhaled breath, although a gold standard method for detection has not yet been established. In asthma and COPD, H2S levels in serum and sputum can vary depending on the underlying conditions such as an acute exacerbation. Furthermore, sputum H2S in particular correlates with sputum neutrophils and the degree of airflow limitation, indicating that H2S has potential as a novel promising biomarker for neutrophilic airway inflammation for predicting current control state as well as future risks of asthma. In the future, concurrent measures of H2S with conventional inflammatory biomarkers (fractional exhaled nitric oxide, eosinophils etc) may provide more useful information regarding the identification of inflammatory phenotypes of asthma and COPD for personalised treatment.

An official JRS statement: The principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice.

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma Involving the Lung and Brain: A Rare Case Study.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma and other organ involvement is very rare. A rare case of MEITL involving the lung and brain is herein reported. The patient developed panperitonitis with a small intestinal perforation, and emergency surgery was performed. The pathological findings from the surgical specimens demonstrated atypical lymphoid cells which were positive for CD3, CD8, and CD56. Moreover, the pathological findings of lung specimens taken by bronchoscopy were consistent with those of the small intestine. It is therefore important to include the possibility of MEITL in the differential diagnosis of cancer patients.

Clinical significance of thyroid hormone and antibodies in patients with idiopathic interstitial pneumonia.

BACKGROUND: Hypothyroidism was recently reported to be common and to predict mortality in patients with idiopathic pulmonary fibrosis (IPF). In addition, a high prevalence of hypothyroidism was shown in patients with idiopathic pleuroparenchymal fibroelastosis. However, in idiopathic interstitial pneumonia (IIP), a clinical significance of thyroid function has not been clarified in detail. The goal of this study was to investigate the clinical significance of thyroid function and the presence of thyroid antibodies in IIP. METHODS: We have reviewed IIP patients, and analyzed the positivity of thyroid antibodies at first. Next, the relationship of clinical characteristics with thyroid function and the positivity of thyroid antibodies was analyzed. Lastly, the positivity of thyroid antibodies and other autoantibodies was evaluated. RESULTS: In IIP patients, thyroglobulin and thyroid peroxidase antibodies were positive in 17 and 16%, respectively, and 22% of patients had either or both antibodies. Subclinical and/or overt hypothyroidism was confirmed in 7% of IIP patients. The free thyrotropin level had a significant positive correlation with vital capacity and a significant negative correlation with the C-reactive protein and surfactant protein-A levels, and erythrocyte sedimentation ratio (ESR). In addition, autoantibodies suggestive of connective tissue diseases (CTDs) were positive in more than two thirds of IIP patients with the thyroid antibody, and the positive rate of antinuclear and proteinase-3 anti-neutrophil cytoplasmic antibodies was significantly higher in IIP patients with thyroid antibodies than those without the antibodies. CONCLUSIONS: Although thyroid dysfunction is not frequent, thyroid hormones and thyroid antibodies are possibly involved in the pathogenesis of IIP and their evaluation may be clinically useful to identify the clinical phenotype of IIP with autoimmune features.

Comparison of fractional exhaled nitric oxide levels measured by different analyzers produced by different manufacturers.

Objective: Fractional exhaled nitric oxide (FeNO) is widely used as a biomarker of allergic airway inflammation. At present, both stationary chemiluminescence and portable electrochemical analyzers produced by different manufacturers are available. However, it remains debatable whether those analyzers are comparable to each other. We compare FeNO levels obtained by different analyzers.Methods: For the first study, 153 subjects were enrolled to compare differences in FeNO levels measured using three analyzers (NA623NP®, NObreath®, and NIOX MINO®) which were produced by different manufacturers. For the second study, 30 subjects were recruited to compare FeNO levels obtained by the two analyzers (NIOX MINO® and NIOX VERO®) produced by the same manufacturer. FeNO was measured twice using each analyzer in random order.Results: FeNO levels obtained using the NIOX MINO® and NObreath® were more variable than those measured using the NA623NP®. There were strong positive correlations in FeNO levels measured by the NA623NP®, NIOX MINO®, and NObreath® (p < 0.001). The NA623NP® and NIOX MINO® provided the highest and lowest FeNO levels, respectively; whereas, those obtained by NObreath® were intermediate. No significant differences were observed in FeNO levels obtained using the NIOX MINO® and NIOX VERO®.Conclusions: FeNO levels measured by the NIOX MINO® and NIOX VERO®, both of which were produced by the same manufacturer, have comparability. However, significant differences in FeNO levels exist when measured by analyzers manufactured by different manufacturers. This should be taken into account for FeNO measurement.

Clinical Characteristics of Cough Frequency Patterns in Patients with and without Asthma.

BACKGROUND: Cough is a frequent symptom of asthma. Cough frequency (CoFr) monitoring devices are now available to objectively measure cough counts and offer a novel endpoint to assess asthma. However, little is known about CoFr in asthma. OBJECTIVE: The aims were, first, to determine whether unique features of CoFr exist in asthmatic and nonasthmatic patients and, secondly, to evaluate relationships between CoFr and pathophysiological parameters of asthma. METHODS: In the current study, 73 asthmatic and 63 nonasthmatic patients suffering from persistent cough were enrolled. At study entry, the Leicester Cough Questionnaire (LCQ health status), cough visual analog scale (VAS), Leicester Cough Monitor (LCM), fractional exhaled nitric oxide (FeNO) measurements, and spirometry were performed. In asthmatic patients, the bronchial hyperresponsiveness (BHR) test was conducted if applicable. In 28 asthmatic and 17 nonasthmatic patients, LCQ, VAS, and LCM were examined before and after treatment. RESULTS: CoFr during nighttime (asleep) was significantly higher in asthmatic patients than in nonasthmatic patients. Twenty-four-hour CoFr significantly decreased after appropriate treatment and was correlated with changes in VAS and LCQ in all patients. The improvement in cough in asthmatic patients was greater during nighttime than during daytime (awake). CoFr in asthmatic patients was significantly correlated with BHR, but not with FeNO. CONCLUSIONS: In asthmatic patients, nocturnal CoFr can be associated with BHR, was significantly higher before treatment, but improved more after treatment compared with nonasthmatic patients. Monitoring nocturnal CoFr may provide unique and valuable information on making an early prediction of therapeutic effects in asthma.

A case of primary lung squamous cell carcinoma mimicking malignant mesothelioma producing granulocyte colony stimulating factor with chemotherapy (cisplatin and gemcitabine)-associated thrombotic thrombocytopenic purpura (TTP); An autopsy case report.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy. In recent years, an extensive variety of drugs, including certain cytotoxic agents, have been reported to be associated with TTP. Additionally, several studies have reported that granulocyte colony-stimulating factor (G-CSF) was produced by lung carcinoma. G-CSF-producing carcinoma also produces various other cytokines, which may cause vascular endothelial damage and trigger TTP development. However, there has been no report describing G-CSF-producing carcinoma combined with TTP. We report a rare case of pseudomesothliomatous squamous cell lung carcinoma producing G-CSF along with chemotherapy associated TTP. MATERIALS AND METHODS: A 66-year-old man with pseudomesotheliomatous primary squamous cell lung carcinoma was treated with chemotherapy consisting of cisplatin and gemcitabine as the first line treatment. However, thrombocytopenia, acute renal dysfunction and acute respiratory failure occurred after starting the first chemotherapy cycle. As a result, the patient died, and an autopsy was performed. RESULTS: According to the autopsy findings, a diagnosis of primary lung squamous cell carcinoma producing G-CSF associated with TTP was made. CONCLUSION: Chemotherapy-related TTP should be considered when anemia and thrombocytopenia progress rapidly in patients who are under chemotherapy treatment. Furthermore, the current case may provide a possible link between TTP and G-CSF-producing tumor.