Prognostic significance of antifibrotic agents in idiopathic pulmonary fibrosis after initiation of long-term oxygen therapy.

BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive interstitial lung disease with varying degrees of hypoxemia. Long-term oxygen therapy (LTOT) is frequently used to treat hypoxemia, however the prognostic factors for better survival in IPF patients after initiation of LTOT remain unknown. METHODS: We retrospectively investigated favorable factors of survival in consecutive 55 IPF patients with chronic respiratory failure who were introduced LTOT. RESULTS: The 6-, 12-, 18-, and 24-month survival rates in IPF patients after introduction of LTOT were 70.9%, 49.0%, 45.2%, and 32.3%, respectively. Univariate analysis demonstrated that low Glasgow Prognostic Score (GPS) (hazard ratio [HR] 0.482, p=0.043) and treatment with antifibrotic agents (HR 0.401, p=0.013) were associated with favorable survival, while multivariate analysis revealed that treatment with antifibrotic agents was the independent predictor (HR 0.449, p=0.032). Moreover, IPF patients treated with antifibrotic agents with LTOT had significantly longer survival than those without antifibrotic agents (p = 0.0106). CONCLUSION: In IPF patients who were introduced LTOT, treatment with antifibrotic agents was the independent factor for favorable survival. Treatment with antifibrotic agents may improve prognosis of IPF even after initiation of LTOT.

Surfactant protein D: A useful biomarker for distinguishing COVID-19 pneumonia from COVID-19 pneumonia-like diseases.

Introduction: Computed tomography is useful for the diagnosis of coronavirus disease (COVID-19) pneumonia. However, many types of interstitial lung diseases and even bacterial pneumonia can show abnormal chest shadows that are indistinguishable from those observed in COVID-19 pneumonia. Thus, it is necessary to identify useful biomarkers that can efficiently distinguish COVID-19 pneumonia from COVID-19 pneumonia-like diseases. Herein, we investigated the usefulness of serum Krebs von den Lungen 6 (KL-6) and surfactant protein D (SP-D) for identifying patients with COVID-19 pneumonia among patients with abnormal chest shadows consistent with COVID-19 pneumonia. Method: This was a retrospective cohort study of consecutive patients who underwent evaluation of serum KL-6 and SP-D at a single center from February 2019 to December 2020. A total of 54 patients with COVID-19 pneumonia and 65 patients with COVID-19 pneumonia-like diseases were enrolled in this study from the source population. Serum KL-6 and SP-D levels in both groups were analyzed. Result: The serum levels of KL-6 and SP-D in patients with COVID-19 pneumonia were significantly lower than those in patients with COVID-19 pneumonia-like disease (median [interquartile range]: 208.5 [157.5-368.5] U/ml vs. 430 [284.5-768.5] U/ml, p < 0.0001 and 24.7 [8.6-51.0] ng/ml vs. 141 [63.7-243.5] ng/ml, p < 0.0001, respectively). According to receiver operating characteristic (ROC) analysis, the areas under the ROC curves (95% confidence intervals) of serum KL-6 and SP-D levels for distinguishing COVID-19 pneumonia from COVID-19 pneumonia-like diseases were 0.761 (0.675-0.847) and 0.874 (0.812-0.936), respectively. The area under the ROC curve of serum SP-D was significantly larger than that of serum KL-6 (p = 0.0213), suggesting that serum SP-D can more efficiently distinguish COVID-19 pneumonia from COVID-19 pneumonia-like diseases. Conclusion: Serum SP-D is a promising biomarker for distinguishing COVID-19 pneumonia from COVID-19 pneumonia-like diseases. Serum SP-D can be useful for the management of patients with abnormal chest shadow mimicking COVID-19 pneumonia.

Impact of sarcopenia on chemotherapy-triggered exacerbation of interstitial lung disease in patients with non-small cell lung cancer.

BACKGROUND: While recent evidence has suggested that sarcopenia could predict chemotoxicity, its association with chemotherapy-triggered interstitial lung disease (ILD) exacerbations has yet to be investigated. Thus, the present study sought to determine whether sarcopenia could predict ILD exacerbations and overall survival (OS) in patients with ILD-complicated non-small cell lung cancer (NSCLC). METHODS: From January 2010 to July 2020, 74 patients with ILD-complicated NSCLC who received chemotherapy were retrospectively investigated. After categorizing patients according to the presence or absence of sarcopenia based on the psoas muscle index, ILD exacerbation rates and OS were evaluated. RESULTS: Among the patients in the study, 39 were included in the sarcopenia group. Moreover, 17 (22.9%) patients developed ILD exacerbations, with the sarcopenia and nonsarcopenia groups having an exacerbation rate of 33.3% and 11.4%, respectively (p = 0.025). Multivariate analysis identified sarcopenia as an independent predictor of ILD exacerbations (p = 0.039). Furthermore, patients with sarcopenia demonstrated a significantly shorter median OS compared to those without the same (9.2 vs. 13.3 months; p = 0.029). CONCLUSIONS: Sarcopenia predicted chemotherapy-triggered ILD exacerbation and OS in patients with ILD-complicated NSCLC, suggesting its utility in determining treatment approaches.

Early intervention of plasma exchange combined with intensive immunosuppressive treatment for anti-MDA-5 antibody-positive rapidly progressive interstitial pneumonia: Two case reports.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) has to be reported to often cause rapidly progressive interstitial lung disease (RP-ILD) especially in East Asian countries. Even with the recommended rapid administration of immunosuppressive agents with high-dose corticosteroids, intravenous pulse cyclophosphamide, and calcineurin inhibitors, the prognosis of anti-MDA5 Ab-related RP-ILD is poor. Plasma exchange (PE) has been reported to be effective for steroid-refractory RP-ILD with anti-MDA5 Ab. However, the timing, frequency, and interval of PE for the treatment of RP-ILD with anti-MDA5 Ab have not yet been established. CASE PRESENTATION: We report two cases of RP-ILD with anti-MDA5 Ab treated by early intervention of PE combined with immunosuppressive treatment. Blood biomarkers including titers of anti-MDA5 Ab, serum KL-6 and ferritin were promptly decreased after each session of PE. Clinical symptoms, oxygenation and chest computed tomography abnormalities were completely improved after immunosuppressive treatment with PE. CONCLUSION: Early intervention of PE combined with immunosuppressive treatment may prevent the development to lethal severe respiratory failure in RP-ILD with anti-MDA5 Ab.

Differential effects of dexamethasone and roflumilast on asthma in mice with or without short cigarette smoke exposure.

Appropriate drug treatment for smoking asthmatics is uncertain because most smokers with asthma are less sensitive to treatment with glucocorticoids compared with non-smokers with asthma. We hypothesized that roflumilast (Rof), a selective phosphodiesterases-4 inhibitor regarded as an add-on therapy for chronic obstructive pulmonary disease, might be more effective than glucocorticoids for improving asthma in smokers. To investigate this hypothesis, we compared the therapeutic effects of dexamethasone (Dex) and Rof in a mouse model of ovalbumin-induced asthma with or without concurrent cigarette smoke (CS) exposure for 2 weeks. We found that recurrent asthma attacks increased lung tissue resistance. CS exposure in asthmatic mice decreased the central airway resistance, increased lung compliance, and attenuated airway hyper-responsiveness (AHR). CS exposure in asthmatic mice also increased the number of neutrophils and macrophages in the bronchoalveolar fluid. Treatment with Dex in asthmatic mice without CS exposure reduced airway resistance, AHR and airway eosinophilia. In asthmatic mice with CS exposure, however, Dex treatment unexpectedly increased lung tissue resistance and restored AHR that had been otherwise suppressed. Dex treatment in asthmatic mice with CS exposure inhibited eosinophilic inflammation but conversely exacerbated neutrophilic inflammation. On the other hand, treatment with Rof in asthmatic mice without CS exposure reduced airway resistance and airway eosinophilia, although the inhibitory effect of Rof on AHR was unremarkable. In asthmatic mice with CS exposure, Rof treatment did not exacerbate lung tissue resistance but modestly restored AHR, without any significant effects on airway inflammation. These results suggest that CS exposure mitigates sensitivity to both Dex and Rof. In asthmatic mice with CS exposure, Dex is still effective in reducing eosinophilic inflammation but increases lung tissue resistance, AHR and neutrophilic inflammation. Rof is ineffective in improving lung function and inflammation in asthmatic mice with CS exposure. This study did not support our initial hypothesis that Rof might be more effective than glucocorticoids for improving asthma in smokers. However, glucocorticoids may have a detrimental effect on smoking asthmatics.

Glasgow prognostic score for prediction of chemotherapy-triggered acute exacerbation interstitial lung disease in patients with small cell lung cancer.

BACKGROUND: Predicting the incidence of chemotherapy-triggered acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer is important because AE-ILD confers a poor prognosis. The Glasgow prognostic score (GPS), which is an inflammation-based index composed of serum levels of C-reactive protein and albumin, predicts prognosis in patients with small cell lung cancer (SCLC) without ILD. In this study, we investigated AE-ILD and survival outcome based on the GPS in patients with ILD associated with SCLC who were receiving chemotherapy. METHODS: Medical records of patients who received platinum-based first-line chemotherapy between June 2010 and May 2019 were retrospectively reviewed to compare the incidence of AE-ILD and overall survival (OS) between GPS 0, 1, and 2. RESULTS: Among our cohort of 31 patients, six (19.3%) experienced chemotherapy-triggered AE-ILD. The AE-ILD incidence increased from 9.5% to 25.0% and 50.0% with increase in GPS of 0, 1, and 2, respectively. Univariate and multivariate analyses revealed remarkable associations between GPS 2 and both AE-ILD (odds ratio for GPS 2, 18.69; p = 0.046) and prognosis (hazard ratio of GPS 2, 13.52; p = 0.002). Furthermore, median OS in the GPS 0, 1, and 2 groups was 16.2, 9.8, and 7.1 months, respectively (p < 0.001). CONCLUSIONS: Our results suggest that GPS 2 is both a predictor of risk of chemotherapy-triggered AE-ILD and a prognostic indicator in patients with ILD associated with SCLC. We propose that GPS may be used as a guide to distinguish chemotherapy-tolerant patients from those at high risk of AE-ILD.

Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) Is Elevated in Patients with Asthma and Airway Obstruction.

Neutrophilic airway inflammation is one of the features of severe asthma. Neutrophil gelatinase-associated lipocalin (NGAL), or lipocalin-2, is a glycoprotein associated with neutrophilic inflammation and can be detected in blood. Recently, blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease. However, the clinical significance of serum NGAL levels in patients with asthma has not been elucidated. The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma. Sixty-one non-smoking people with stable asthma were enrolled in this study. All patients underwent blood collection and pulmonary function tests. The associations between serum NGAL levels and clinical parameters were analyzed retrospectively. Serum NGAL levels in patients with asthma and obstructive ventilatory defect were higher than those in patients with asthma without obstructive ventilatory defect (76.4±51.4 ng/mL vs. 39.3±27.4 ng/mL, P=0.0019). Serum NGAL levels were correlated with forced expired flow at 50% of vital capacity %predicted and forced expired flow at 75% of vital capacity %predicted (r=-0.3373, P=0.0078 and r=-0.2900, P=0.0234, respectively). Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory defect. Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory defect. NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.

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.

Glasgow Prognostic Score predicts chemotherapy-triggered acute exacerbation-interstitial lung disease in patients with non-small cell lung cancer.

BACKGROUND: Interstitial lung disease (ILD) in patients with non-small cell lung cancer (NSCLC) worsens the prognosis for overall survival (OS) due to chemotherapy-triggered acute exacerbation (AE)-ILD. The Glasgow Prognostic Score (GPS), which is based on serum C-reactive protein and albumin levels, has been suggested as a reliable prognostic tool for mortality in cancer patients, including NSCLC. In this study, we investigated whether GPS is a predictor for chemotherapy-triggered AE-ILD and the prognosis in patients with NSCLC and pre-existing ILD. METHODS: We conducted a retrospective review on 56 NSCLC and ILD patients at our hospital who received platinum agent-based treatment as first-line chemotherapy between June 2010 and May 2019. We categorized these patients according to their GPS (0-2) and compared the incidence of chemotherapy-triggered AE-ILD and OS. RESULTS: The GPS 0, 1, and 2 groups included 31, 16, and nine patients, respectively, out of 56. A total of 12 (21.4%) patients showed chemotherapy-triggered AE-ILD. The median OS was at 11.5 months (95% confidence interval: 8.0-15.1). The incidence of chemotherapy-triggered AE-ILD within the first year of chemotherapy in the GPS 0, 1, and 2 groups was three (9.6%), four (25.0%), and five (55.5%), and the median OS time was 16.9, 9.8 and 7.6 months, respectively. Univariate and multivariate analyses indicated that only GPS 2 could predict both chemotherapy-triggered AE-ILD and OS (P < 0.05). CONCLUSIONS: GPS assessment of patients with NSCLC and pre-existing ILD is a valuable prognostic tool for predicting chemotherapy-triggered AE-ILD and OS. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We found that GPS 2 was an independent risk factor for chemotherapy-triggered AE-ILD and prognosis in patients with ILD associated with NSCLC. WHAT THIS STUDY ADDS: GPS may potentially enable the discrimination of patients tolerant of chemotherapy from those at an increased risk of AE-ILD and predict the prognosis in patients with NSCLC and ILD receiving chemotherapy.

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.

Polymyxin B haemoperfusion treatment for respiratory failure and hyperferritinaemia due to COVID-19.

A 69-year-old man with a history of type 2 diabetes and high blood pressure was diagnosed with coronavirus disease 2019 (COVID-19). He had hyperferritinaemia and respiratory failure. Despite the initiation of favipiravir and high-dose corticosteroid and ceftriaxone, his respiratory failure progressed and serum ferritin levels increased. After polymyxin B-immobilized fibre column direct haemoperfusion (PMX-DHP) therapy, there was improvement of the respiratory failure and hyperferritinaemia. We report the first case of COVID-19-induced hyperferritinaemia and severe respiratory failure successfully treated by PMX-DHP.

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.

Bicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary disease.

Bicaudal D1 (BICD1), an adaptor for the dynein-dynactin motor complex, has been identified as a susceptibility gene in chronic obstructive pulmonary disease (COPD). Autophagy, an essential cellular homeostasis process, is defective in COPD, in which oxidative stress-induced misfolded proteins accumulate into toxic aggregates dependent on the accumulation of the autophagic cargo receptor p62. Defective autophagy can be caused by mutations in the dynein and dynactin motor complex suggesting a possible link between BICD1 and defective autophagy in COPD. BICD1 levels were measured in peripheral lung tissue from COPD patients together with markers of autophagy and found to be increased in COPD together with autophagosomes, p62 and p62 oligomers. In vitro exposure of bronchial epithelial cells to cigarette smoke extracts (CSEs) revealed that high concentrations of CSE induced defective autophagosome maturation with accumulation of BICD1, p62 and ubiquitin-associated p62 oligomers. This was confirmed in vivo using CS-exposed mice. Furthermore, we identified that formation of CS-induced p62 oligomers required an interaction with Keap1. Overexpression and ablation of BICD1 confirmed that increased BICD1 negatively regulates autophagosome maturation inducing accumulation of p62 and p62 oligomers and that it can be reversed by cardiac glycosides. We conclude that defective autophagosome maturation in COPD is caused by oxidative stress-mediated BICD1 accumulation.