Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.

Background/Objectives: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. Methods: Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. Results: Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. Conclusions: In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.

Pulmonary function and chest CT abnormalities 3 months after discharge from COVID-19, 2020-2021: A nation-wide multicenter prospective cohort study from the Japanese respiratory society.

BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.

Clinical characteristics and cytokine profiles of adult obese asthma with type2 inflammation.

Obesity-related non-eosinophilic asthma has been identified as a phenotype of asthma. However, mepolizumab and omalizumab improve asthma control in severe asthma with obesity, implying that type-2 cytokines may be involved in the deterioration of control in obese asthma. Despite this, the clinical details of obese asthma with positive type-2 inflammation markers have not yet been reported. The objective of this study was to investigate the clinical characteristics of patients with obese asthma with positive type-2 inflammation markers. Adult obese asthmatic patients were enrolled and were classified into two groups: obese asthma with positive type-2 inflammation markers (T2) and obese asthma with negative type-2 inflammation markers (NT2), then data were compared. In total, 434 patients were enrolled (85% of patients were at GINA therapy step 4-5). The T2 group had a higher proportion of patients with persistent asthma since childhood and with allergic rhinitis. A higher percentage of patients used high-dose inhaled corticosteroids (ICS) and experienced acute exacerbations (annual exacerbation ratio ≥ 1) in the T2 group. Multivariate logistic regression analysis showed that the T2 group was independently associated with younger age, comorbidity of allergic rhinitis, persistent asthma since childhood, use of high-dose ICS, and acute exacerbation rate ≥ 1. Adipocytokine levels were similar between the groups. Collectively, obese asthma with positive type-2 inflammation markers is characterised by a higher percentage of persistent asthma since childhood and more severe asthma.

Relationship between Anti-SARS-CoV-2 S Abs and IFN-λ3 Levels in the Administration of Oxygen following COVID-19 Vaccination.

Although the effectiveness of vaccination at preventing hospitalization and severe coronavirus disease (COVID-19) has been reported in numerous studies, the detailed mechanism of innate immunity occurring in host cells by breakthrough infection is unclear. One hundred forty-six patients were included in this study. To determine the effects of vaccination and past infection on innate immunity following SARS-CoV-2 infection, we analyzed the relationship between anti-SARS-CoV-2 S Abs and biomarkers associated with the deterioration of COVID-19 (IFN-λ3, C-reactive protein, lactate dehydrogenase, ferritin, procalcitonin, and D-dimer). Anti-S Abs were classified into two groups according to titer: high titer (≥250 U/ml) and low titer (<250 U/ml). A negative correlation was observed between anti-SARS-CoV-2 S Abs and IFN-λ3 levels (r = -0.437, p < 0.001). A low titer of anti-SARS-CoV-2 S Abs showed a significant association with oxygen demand in patients, excluding aspiration pneumonia. Finally, in a multivariate analysis, a low titer of anti-SARS-CoV-2 S Abs was an independent risk factor for oxygen demand, even after adjusting for age, sex, body mass index, aspiration pneumonia, and IFN-λ3 levels. In summary, measuring anti-SARS-CoV-2 S Abs and IFN-λ3 may have clinical significance for patients with COVID-19. To predict the oxygen demand of patients with COVID-19 after hospitalization, it is important to evaluate the computed tomography findings to determine whether the pneumonia is the result of COVID-19 or aspiration pneumonia.

Impact of inhaled ciclesonide on asymptomatic or mild COVID-19: A randomized trial.

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms.

[Drug-repositioning indicates a way to conquest corticosteroid-insensitivity].

Recent advance of medications and devices brings more effective treatment intervention to the patients with asthma. As far as obeying guidelines, approximately 90% of patients with asthma acquire good control. However, there are still small number of patients with asthma who resist conventional treatment. Most of them are corticosteroid-insensitive. It would be thought that there are two ways to deal with this problem. The first one is biologics. However, these are very expensive. The second way is a treatment intervention focusing on cancellation of corticosteroid-resistance. In early 2010s, a new-intracellular signaling pathway (phosphatydilinositol-3-kinese: PI3K pathway) is proven to be closely associated with corticosteroid-resistance. PI3K-inhibitor should be one of the promising candidates to attenuate corticosteroid-resistance. But PI3K-inhibitor also has a toxicity when given systemically. Drug-repositioning (DR) is a good option to deal with it. To find out PI3K-inhibitor from numerous medicines gives an answer how to inhibit PI3K pathway. The presenter has found both low-dose theophylline and long-acting beta-2 agonist have a potential to antagonize PI3K. These medicines have been prescribed for decades and their safety has already been proved. It is possible for clinicians to inhibit PI3K activation in patients with asthma associated with corticosteroid-resistance using these medicines without waiting for development of bran-new PI3K inhibitors. DR revealed that nortriptyline acts as a steroid-enhancer via its anti-PI3K activity. Calcium-channel blocker saves lung function in patients with asthma in long-term observation. DR promises us to find cheap and safe options to treat difficult asthma by inhibiting specific intracellular signaling pathways.

Development of a novel score model to predict hyperinflammation in COVID-19 as a forecast of optimal steroid administration timing.

Objectives: This study aims to create and validate a useful score system predicting the hyper-inflammatory conditions of COVID-19, by comparing it with the modified H-score. Methods: A total of 98 patients with pneumonia (without oxygen therapy) who received initial administration of casirivimab/imdevimab or remdesivir were included in the study. The enrolled patients were divided into two groups: patients who required corticosteroid due to deterioration of pneumonia, assessed by chest X-ray or CT or respiratory failure, and those who did not, and clinical parameters were compared. Results: Significant differences were detected in respiratory rate, breaths/min, SpO2, body temperature, AST, LDH, ferritin, and IFN-λ3 between the two groups. Based on the data, we created a corticosteroid requirement score: (1) the duration of symptom onset to treatment initiation ≥ 7 d, (2) the respiratory rate ≥ 22 breaths/min, (3) the SpO2 ≤ 95%, (4) BT ≥ 38.5°C, (5) AST levels ≥ 40 U/L, (6) LDH levels ≥ 340 U/L, (7) ferritin levels ≥ 800 ng/mL, and (8) IFN-λ3 levels ≥ 20 pg/mL. These were set as parameters of the steroid predicting score. Results showed that the area under the curve (AUC) of the steroid predicting score (AUC: 0.792, 95%CI: 0.698-0.886) was significantly higher than that of the modified H-score (AUC: 0.633, 95%CI: 0.502-0.764). Conclusion: The steroid predicting score may be useful to predict the requirement of corticosteroid therapy in patients with COVID-19. The data may provide important information to facilitate a prospective study on a larger scale in this field.

Real-world treatment and health care resource use among severe asthma patients in Japan.

BACKGROUND: There are limited studies on healthcare resource use (HCRU) among adult asthma patients in Japan using real-world evidence, and analysis on acute treatment and associated costs stratified by disease severity is further limited. This study aimed to characterize the disease burden of severe asthma patients in Japan in terms of HCRU and comorbid medical conditions, with particular interest in oral corticosteroid (OCS) dependency. METHODS: This retrospective cohort study of asthma patients used data from a claims database of diagnosis procedure combination hospitals in Japan. The severe asthma cohort included patients treated with OCS for more than 180 days in one year before the index date, with at least one asthma diagnosis claim. Comorbidity and drug use in the look-back period, HCRU, assumed OCS-related adverse events, and asthma exacerbations in the follow-up period were analyzed. RESULTS: Costs associated with the treatment of severe asthma were approximately twice that of mild/moderate asthma, and the annual median cost of patients hospitalized due to asthma reached ¥448,000 (USD $4073). Annual asthma exacerbation rate was higher in the severe asthma cohort than in the mild/moderate cohort. Patients with longer OCS use in the previous year had higher risks of secondary adrenal insufficiency, osteoporosis, and pneumonia in the following year. CONCLUSIONS: OCS use among asthma patients in Japan incurred greater medical and economic burden. Better understanding of the disease characteristics including the severity of asthma and appropriate management of disease burden will lead to more optimal use of healthcare resources in Japan.

Cigarette smoke-induced impairment of autophagy in macrophages increases galectin-8 and inflammation.

Cigarette smoke impairs autophagy, an intracellular protein degradation system, but the consequences of this defect have not been fully elucidated, especially in macrophages. Dysfunctional alveolar macrophages play an important role in chronic obstructive pulmonary disease (COPD). Here we show that galectin-8, a danger receptor that identifies damaged intracellular host vesicles and initiates autophagosome engulfment, is elevated due to activation of autophagy by cigarette smoke extract (CSE) in macrophages. CSE impaired autophagic flux in PMA-differentiated U937 macrophage-like cells, resulting in intracellular accumulation of galectin-8 and the autophagic adaptor protein NDP52. COPD patients showed elevated levels of galectin-8 and NDP52 in the lung homogenates with significant increase in the serum galectin-8 levels in patients with frequent acute exacerbations. Soluble galectin-8 induced interleukin (IL)-6 release in bronchial epithelial cells via PI3Kα signalling. Thus, increased galectin-8 due to CSE-induced impaired autophagy may be involved in the pathogenesis of COPD and may be a biomarker of this disease.

Pulmonary emphysema is associated with fungal sensitization in asthma.

BACKGROUND: Fungal sensitization is a risk factor for severe asthma. Colonization in the lower respiratory tract is one of the forms of fungal exposure, and it is related to fungal sensitization. Pulmonary emphysema was recently reported to be an underlying disease of fungal colonization. The aim of study was to evaluate the prevalence of pulmonary emphysema in asthmatic patients with and without fungal sensitization. METHODS: We enrolled 108 patients with allergic asthma and divided them into the patients sensitized to Aspergillus and/or Candida (n=56) and those not sensitized to both Aspergillus and Candida (n=52). The presence of pulmonary emphysema on chest CT was evaluated retrospectively. RESULTS: The frequency of pulmonary emphysema was significantly higher in the patients sensitized to Aspergillus and/or Candida compared to the patients not sensitized to both fungi (P=0.0040). The frequency of pulmonary emphysema was also significantly higher in the patients sensitized to either Aspergillus or Candida compared to the patient not sensitized to the fungi (P=0.0398 and P=0.0198, respectively). A multivariate logistic regression analysis demonstrated that the presence of pulmonary emphysema was independently associated with the sensitization to Aspergillus and/or Candida (OR 7.84, 95% CI: 1.20-51.10). CONCLUSIONS: Pulmonary emphysema is associated with sensitization to Aspergillus and/or Candida.

Persistent Asthma from Childhood to Adulthood Presents a Distinct Phenotype of Adult Asthma.

BACKGROUND: In approximately 30% of children with asthma, the condition persists into adulthood. The longer duration of asthma in these patients is a risk factor for poor asthma control. However, the characteristics of adult patients with asthma that has persisted since childhood are not well documented. OBJECTIVE: We sought to compare the clinical characteristics among patients with adult-onset asthma, patients who outgrew childhood asthma but relapsed, and patients with persistent asthma since childhood. METHODS: We conducted a cross-sectional study of adult patients with asthma who visited our hospital. We classified them into 3 groups: those with adult-onset asthma (adult-onset), those who had remitted childhood asthma that relapsed (relapsed), and those who had asthma that had persisted since childhood (persistent). The clinical characteristics of these groups were compared. RESULTS: A total of 1443 patients were enrolled. The persistent group was younger and included fewer patients with a smoking history. There were statistically significant differences among the 3 groups in the percentages of patients with a family history of asthma and comorbidities of allergic rhinitis and atopic dermatitis. The proportion of patients with severe asthma differed among the 3 groups (31% in the adult-onset group, 34% in the relapsed group, and 40% in the persistent group; P = .015). The values of forced expiratory flow at 75% of vital capacity were lower in the persistent group than the relapsed or adult-onset group. A multivariable logistic regression analysis (dependent variable: severe asthma) in each group revealed that the factors associated with severe asthma differed among the adult-onset, relapsed, and persistent groups. When we established an overall model that included interaction terms of cohort-by-other factors, there was a trend that comorbidity of allergic rhinitis affected the severity of asthma differently in the relapsed group compared with the other groups. CONCLUSION: The clinical phenotype of asthma that persists from childhood to adulthood seems to be a distinct phenotype of adult asthma.

Obesity-associated severe asthma in an adult Japanese population.

BACKGROUND: Severe asthma is increasingly being recognized as an important public health issue. Obesity has been identified as a risk factor for poor asthma control and for worsening of asthma severity. However, most studies investigating obese patients with asthma have been performed in Western countries. Reports on the characteristics of obese Japanese individuals with severe asthma are lacking. Herein, we investigated the clinical characteristics of patients with obesity-associated severe asthma in a Japanese population and the association between obesity and poor asthma control. METHODS: We conducted a retrospective observational study of adult patients with severe asthma. Patients were classified into two groups based on the definition of obesity recommended by the Japan Society for the Study of Obesity: obese (OB) group (body mass index [BMI] ≥25 kg/m2) and non-obese (NOB) group (BMI <25 kg/m2). The two groups were compared. The characteristics of obesity and the metabolic functions are known to differ between males and females; therefore, we analyzed male-only and female-only cohorts separately. RESULTS: A total of 492 patients were enrolled. Age, smoking history in terms of number of pack-years, daily controller medications use, and spirometric data were not significantly different between the OB and NOB groups in either cohort. In the female cohort, the annual exacerbation ratio and the percentage of frequent exacerbators were significantly higher in the OB group compared to the NOB group. A multivariate logistic regression analysis showed that obesity was independently associated with frequent asthma exacerbations in the female cohort. CONCLUSIONS: Our study revealed that obesity, defined as a BMI ≥25 kg/m2, was independently associated with poor asthma control (including acute exacerbations) in adult Japanese females with severe asthma.