Kinetics of pro- and anti-inflammatory spike-specific cellular immune responses in long-term care facility residents after COVID-19 mRNA primary and booster vaccination: a prospective longitudinal study in Japan.

BACKGROUND: The magnitude and durability of cell-mediated immunity in older and severely frail individuals following coronavirus disease 2019 (COVID-19) vaccination remain unclear. A controlled immune response could be the key to preventing severe COVID-19; however, it is uncertain whether vaccination induces an anti-inflammatory cellular immune response. To address these issues, a 48-week-long prospective longitudinal study was conducted. A total of 106 infection-naive participants (57 long-term care facility [LTCF] residents [median age; 89.0 years], 28 outpatients [median age; 72.0 years], and 21 healthcare workers [median age; 51.0 years]) provided peripheral blood mononuclear cell (PBMC) samples for the assessment of spike-specific PBMC responses before primary vaccination, 24 weeks after primary vaccination, and three months after booster vaccination. Cellular immune responses to severe acute respiratory syndrome coronavirus 2 spike protein were examined by measuring interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-4, IL-6, and IL-10 levels secreted from the spike protein peptide-stimulated PBMCs of participants. RESULTS: LTCF residents exhibited significantly lower IFN-γ, TNF, IL-2, and IL-6 levels than healthcare workers after the primary vaccination. Booster vaccination increased IL-2 and IL-6 levels in LTCF residents comparable to those in healthcare workers, whereas IFN-γ and TNF levels in LTCF residents remained significantly lower than those in healthcare workers. IL-10 levels were not significantly different from the initial values after primary vaccination but increased significantly after booster vaccination in all subgroups. Multivariate analysis showed that age was negatively associated with IFN-γ, TNF, IL-2, and IL-6 levels but not with IL-10 levels. The levels of pro-inflammatory cytokines, including IFN-γ, TNF, IL-2, and IL-6, were positively correlated with humoral immune responses, whereas IL-10 levels were not. CONCLUSIONS: Older and severely frail individuals may exhibit diminished spike-specific PBMC responses following COVID-19 vaccination compared to the general population. A single booster vaccination may not adequately enhance cell-mediated immunity in older and severely frail individuals to a level comparable to that in the general population. Furthermore, booster vaccination may induce not only a pro-inflammatory cellular immune response but also an anti-inflammatory cellular immune response, potentially mitigating detrimental hyperinflammation.

Kinetics of COVID-19 mRNA primary and booster vaccine-associated neutralizing activity against SARS-CoV-2 variants of concern in long-term care facility residents: a prospective longitudinal study in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) remains a threat to vulnerable populations such as long-term care facility (LTCF) residents, who are often older, severely frail, and have multiple comorbidities. Although associations have been investigated between COVID-19 mRNA vaccine immunogenicity, durability, and response to booster vaccination and chronological age, data on the association of clinical factors such as performance status, nutritional status, and underlying comorbidities other than chronological age are limited. Here, we evaluated the anti-spike IgG level and neutralizing activity against the wild-type virus and Delta and Omicron variants in the sera of LTCF residents, outpatients, and healthcare workers before the primary vaccination; at 8, 12, and 24 weeks after the primary vaccination; and approximately 3 months after the booster vaccination. This 48-week prospective longitudinal study was registered in the UMIN Clinical Trials Registry (Trial ID: UMIN000043558). RESULTS: Of 114 infection-naïve participants (64 LTCF residents, 29 outpatients, and 21 healthcare workers), LTCF residents had substantially lower anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant than outpatients and healthcare workers over 24 weeks after the primary vaccination. In LTCF residents, booster vaccination elicited neutralizing activity against the wild-type virus and Delta variant comparable to that in outpatients, whereas neutralizing activity against the Omicron variant was comparable to that in outpatients and healthcare workers. Multiple regression analyses showed that age was negatively correlated with anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant after the primary vaccination. However, multivariate regression analysis revealed that poor performance status and hypoalbuminemia were more strongly associated with a lower humoral immune response than age, number of comorbidities, or sex after primary vaccination. Booster vaccination counteracted the negative effects of poor performance status and hypoalbuminemia on the humoral immune response. CONCLUSIONS: LTCF residents exhibited suboptimal immune responses following primary vaccination. Although older age is significantly associated with a lower humoral immune response, poor performance status and hypoalbuminemia are more strongly associated with a lower humoral immune response after primary vaccination. Thus, booster vaccination is beneficial for older adults, especially those with a poor performance status and hypoalbuminemia.

Investigation of the combination of intratumoral and peritumoral radiomic signatures for predicting epidermal growth factor receptor mutation in lung adenocarcinoma.

PURPOSE: We investigated optimal peritumoral size and constructed predictive models for epidermal growth factor receptor (EGFR) mutation. METHODS: A total of 164 patients with lung adenocarcinoma were retrospectively analyzed. Radiomic signatures for the intratumoral region and combinations of intratumoral and peritumoral regions (3, 5, and 7 mm) from computed tomography images were extracted using analysis of variance and least absolute shrinkage. The optimal peritumoral region was determined by radiomics score (rad-score). Intratumoral radiomic signatures with clinical features (IRS) were used to construct predictive models for EGFR mutation. Combinations of intratumoral and 3, 5, or 7 mm-peritumoral signatures with clinical features (IPRS3, IPRS5, and IPRS7, respectively) were also used to construct predictive models. Support vector machine (SVM), logistic regression (LR), and LightGBM models with five-fold cross-validation were constructed, and the receiver operating characteristics were evaluated. Area under the curve (AUC) of the training and test cohorts values were calculated. Brier scores (BS) and decision curve analysis (DCA) were used to evaluate the predictive models. RESULTS: The AUC values of the SVM, LR, and LightGBM models derived from IRS were 0.783 (95% confidence interval: 0.602-0.956), 0.789 (0.654-0.927), and 0.735 (0.613-0.958) for training, and 0.791 (0.641-0.920), 0.781 (0.538-0.930), and 0.734 (0.538-0.930) for test cohort, respectively. Rad-score confirmed that the 3 mm-peritumoral size was optimal (IPRS3), and AUCs values of SVM, LR, and lightGBM models derived from IPRS3 were 0.831 (0.666-0.984), 0.804 (0.622-0.908), and 0.769 (0.628-0.921) for training and 0.765 (0.644-0.921), 0.783 (0.583-0.921), and 0.796 (0.583-0.949) for test cohort, respectively. The BS and DCA of the LR and LightGBM models derived from IPRS3 were better than those from IRS. CONCLUSION: Accordingly, the combination of intratumoral and 3 mm-peritumoral radiomic signatures may be helpful for predicting EGFR mutations.

Significance of alveolar nitric oxide concentration in the airway of patients with organizing pneumonia after allogeneic hematopoietic stem cell transplantation.

Organizing pneumonia (OP) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a manifestation of peripheral airway/alveolar inflammation. Recently, alveolar nitric oxide concentration (Calv) has been revealed as a noninvasive marker of peripheral airway inflammation; however, whether Calv levels are associated with OP and peripheral airway in patients after allo-HSCT remains unclear. Herein, we evaluated whether Calv levels could reflect the presence of OP and structural airway changes in patients after allo-HSCT. We measured the eNO levels of 38 patients (6 with OP and 32 without OP) who underwent allo-HSCT. Three-dimensional computed tomography (CT) analysis of the airway was performed in 19 patients. We found that in patients with OP, Calv levels were significantly higher than in those without OP (10.6 vs. 5.5 ppb, p < 0.01). Receiver-operating characteristic analyses revealed a Calv cut-off value for OP detection of 10.2 ppb. No significant differences in the patient characteristics, except for the presence of OP (p < 0.01), were noted between the two groups stratified by the Calv cut-off value. Three-dimensional CT images of the airway revealed gradually increasing positive correlations between Calv levels and airway wall area of the third-, fourth-, and fifth-generation bronchi (r = 0.20, 0.31, 0.38; p = 0.42, 0.19, 0.038, respectively), indicating that Calv levels are strongly correlated with the wall thickness of the distal bronchi. Our results suggest that the Calv level may be a useful noninvasive detectable marker for OP after an allo-HSCT.

Improved Prognostic Prediction by Combination of Early Initiation of Polymyxin B Hemoperfusion with Modified Gender-Age-Physiology Index in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Respiratory failure from acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) has been reported to have beneficial effects on patients with AE-IPF. Whether patient characteristics influence the extent of this benefit remains unclear. METHODS: We retrospectively examined the records of 30 patients with AE-IPF who underwent PMX-DHP. The favorable factors of survival were determined using Cox proportional hazards analyses. RESULTS: The 1- and 12-month survival rates after PMX-DHP were 70.0% and 50.0%, respectively. The multivariate analysis revealed that low modified Gender-Age-Physiology (GAP) index (≤8 points) (hazard ratio [HR] 0.317, p = 0.015) and PMX-DHP received within 48 h of steroid pulse (HR 0.289, p = 0.012) were favorable factors. Notably, even in the patients with high modified GAP index (>8 points), that is, more advanced IPF, those who received PMX-DHP within 48 h of steroid pulse had a better prognosis than those who did after 48 h of the steroid pulse (p = 0.032). CONCLUSIONS: Early PMX-DHP initiation in patients with AE-IPF, specifically within 48 h after the steroid pulse therapy, may improve prognosis regardless of the severity of chronic phase of IPF before AE-IPF.

Impact of sinus surgery on type 2 airway and systemic inflammation in asthma.

Objective: Asthma is frequently associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Although endoscopic sinus surgery (ESS) improves asthma control in CRSwNP patients with asthma, the mechanism that underlies the response to surgical treatment is still unclear. We evaluated the relevance of changes in asthma control and changes in airway/systemic inflammation in eosinophilic CRSwNP patients with not well controlled asthma who underwent ESS.Methods: We prospectively assessed changes in the asthma control questionnaire (ACQ) score, blood eosinophil counts (B-Eos), forced expiratory volume in 1 s (FEV1), and fraction of exhaled nitric oxide (FeNO) levels at 1-week before and 8 and 52 weeks after ESS.Results: Twenty-five subjects were analyzed. The ACQ score, B-Eos, and FeNO decreased, and FEV1 increased significantly after ESS. In the period from baseline to 52 weeks after ESS, changes in ACQ were significantly correlated with the changes in blood eosinophil counts (r = 0.58, p<.01) and FeNO (r = 0.45, p<.05). Ten subjects (40%) showed consistently improved asthma control at 52-weeks after ESS. In the remaining subjects, although the ACQ score temporarily improved at 8-weeks after ESS, but eventually deteriorated at 52-weeks. Higher levels of total immunoglobulin E were associated with long-term improved asthma control after ESS.Conclusions: In eosinophilic CRSwNP patients with asthma, sinus surgery impacts asthma control through the suppression of airway/systemic type 2 inflammation. The present study reinforced the common pathophysiology of type 2 inflammation between the upper and lower airways.

Orthogonality-Constrained CNMF-Based Noise Reduction with Reduced Degradation of Biological Sound.

The number of deaths due to cardiovascular and respiratory diseases is increasing annually. Cardiovascular diseases with high mortality rates, such as strokes, are frequently caused by atrial fibrillation without subjective symptoms. Chronic obstructive pulmonary disease is another condition in which early detection is difficult owing to the slow progression of the disease. Hence, a device that enables the early diagnosis of both diseases is necessary. In our previous study, a sensor for monitoring biological sounds such as vascular and respiratory sounds was developed and a noise reduction method based on semi-supervised convolutive non-negative matrix factorization (SCNMF) was proposed for the noisy environments of users. However, SCNMF attenuated part of the biological sound in addition to the noise. Therefore, this paper proposes a novel noise reduction method that achieves less distortion by imposing orthogonality constraints on the SCNMF. The effectiveness of the proposed method was verified experimentally using the biological sounds of 21 subjects. The experimental results showed an average improvement of 1.4 dB in the signal-to-noise ratio and 2.1 dB in the signal-to-distortion ratio over the conventional method. These results demonstrate the capability of the proposed approach to measure biological sounds even in noisy environments.

TLR3 activation augments matrix metalloproteinase production through reactive nitrogen species generation in human lung fibroblasts.

Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-κB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-κB and IRF-3 into the nucleus in fibroblasts and inhibition of NF-κB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF-κB- and IRF-3-dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways.

Persistently high exhaled nitric oxide and loss of lung function in controlled asthma.

BACKGROUNDS: It remains unclear whether a persistently high exhaled nitric oxide fraction (FeNO) in patients with controlled asthma is associated with the progressive loss of lung function. METHODS: This was a 3-year prospective study. We examined the changes in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) and FeNO in 140 patients with controlled asthma. We initially determined the FeNO cut-off point for identifying patients with a rapid decline in FEV1 (>40 mL/yr). Next, a total of 122 patients who maintained high or non-high FeNO were selected, and the associations between the FeNO trend and changes in FEV1 and bronchodilator response (BDR) were investigated. RESULTS: A FeNO level >40.3 ppb yielded 43% sensitivity and 86% specificity for identifying patients with a rapid decline in FEV1. Patients with persistently high FeNO had higher rates of decline in FEV1 (42.7 ± 37.5 mL/yr) than patients with non-high FeNO (16.7 ± 31.5 mL/yr) (p < 0.0005). The changes in BDR from baseline to the end of the study, in patients who had high or non-high levels of FeNO were -0.8% and 0.1%, respectively (p < 0.01). In a multivariate analysis adjusted by age, body mass index, asthma control, blood eosinophil numbers, and FEV1% of predicted, a FeNO level of ≥40 ppb was independently associated with an accelerated decline in FEV1 (p < 0.05). CONCLUSIONS: This study suggests that FeNO is potentially valuable tool for identifying individuals who are at risk of a progressive loss of lung function among patients with controlled asthma.

25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway.

Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblasts (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-ß1 production (P<0.01) and a neutralizing anti-TGF-ß antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-ß1 release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-ß dependent pathway.

Multi-scale simulations of pulmonary airflow based on a coupled 3D-1D-0D model.

Pulmonary airflow simulation is a valuable tool for studying respiratory function and disease. However, the respiratory system is a complex multiscale system that involves various physical and biological processes across different spatial and temporal scales. In this study, we propose a 3D-1D-0D multiscale method for simulating pulmonary airflow, which integrates different levels of detail and complexity of the respiratory system. The method consists of three components: a 3D computational fluid dynamics model for the airflow in the trachea and bronchus, a 1D pipe model for the airflow in the terminal bronchioles, and a 0D biphasic mixture model for the airflow in the respiratory bronchioles and alveoli coupled with the lung deformation. The coupling between the different components is achieved by satisfying the mass and momentum conservation law and the pressure continuity condition at the interfaces. We demonstrate the validity and applicability of our method by comparing the results with data of previous models. We also investigate the reduction in inhaled air volume due to the pulmonary fibrosis using the developed multiscale model. Our method provides a comprehensive and realistic framework for simulating pulmonary airflow and can potentially facilitate the diagnosis and treatment of respiratory diseases.

Management Reality of Female Patients with COPD: A Multicenter Cross-Sectional CAP Study in Japan.

Background: Reports from Europe and North America suggest that female chronic obstructive pulmonary disease (COPD) patients have a higher symptom burden and mortality than male patients. However, little is known about the management reality of female patients with COPD in Japan. Patients and Methods: We compared the clinical characteristics of female COPD patients with those of male using the cohort of the COPD Assessment in Practice study, which is a cross-sectional multicenter observational study. Results: Of the 1168 patients, 133 (11.4%) were female. A history of never smoking was higher in females than males (p<0.01). Although there was no difference in age or forced expiratory volume in one second (FEV1) % predicted between the groups, modified medical research council dyspnea scale (mMRC) and number of frequent exacerbators were higher in females (mMRC≥2: p<0.01; number of exacerbations≥2: p=0.011). The mean forced vital capacity and FEV1 values in females were lower than those in males (p<0.0001 and p<0.0001, respectively). Females were more likely to use long-term oxygen therapy and inhaled corticosteroids than males (p=0.016 and p<0.01, respectively). The prevalence of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, D (ABCD GOLD 2017 classification), and E (ABE GOLD 2023 classification) was higher in females than in males. Conclusion: The disease burden of female patients with COPD is higher than that of male patients in Japan, suggesting the importance of interventions considering female-dominant features such as lower absolute FVC and FEV1, respiratory failure, and asthma-like conditions.

Diagnostic Utility of Specific Frailty Questionnaire: The Kihon Checklist for Hippocampal Atrophy in COPD.

Background/Objectives: COPD patients who are frail have been reported to develop brain atrophy, but no non-invasive diagnostic tool has been developed to detect this condition. Our study aimed to explore the diagnostic utility of the Kihon Checklist (KCL), a frailty questionnaire, in assessing hippocampal volume loss in patients with COPD. Methods: We recruited 40 COPD patients and 20 healthy individuals using the KCL to assess frailty across seven structural domains. Hippocampal volumes were obtained from T1-weighted MRI images, and ROC analysis was performed to detect hippocampal atrophy. Results: Our results showed that patients with COPD had significantly greater atrophic left hippocampal volumes than healthy subjects (p < 0.05). The univariate correlation coefficient between the left hippocampal volume and KCL (1-20), which pertains to instrumental and social activities of daily living, was the largest (ρ = -0.54, p < 0.0005) among the KCL subdomains. Additionally, both KCL (1-25) and KCL (1-20) demonstrated useful diagnostic potential (93% specificity and 90% sensitivity, respectively) for identifying individuals in the lowest 25% of the left hippocampal volume (AUC = 0.82). Conclusions: Our study suggests that frailty questionnaires focusing on daily vulnerability, such as the KCL, can effectively detect hippocampal atrophy in COPD patients.

Correlation between frailty and reduction in cortical thickness in patients with chronic obstructive pulmonary disease.

Physical inactivity and cognitive impairment in patients with chronic obstructive pulmonary disease (COPD) can lead to frailty and poor prognoses. However, little is known regarding the association between frailty and the human brain. We hypothesized that the brain structure could change according to frailty in patients with COPD and focused on cortical thickness. Cortical thickness measured by magnetic resonance imaging and frailty scores using the Kihon Checklist (KCL) were assessed in 40 patients with stable COPD and 20 healthy controls. Among the 34 regions assessed, multiple regions were thinner in patients with COPD than in healthy individuals (p < 0.05). We found significant negative correlations between the eight regions and the KCL scores only in patients with COPD. After adjusting for age and cognitive impairment, the association between the left and six right regions remained statistically significant. The correlation coefficient was the strongest in the bilateral superior frontal gyrus (left: ρ = - 0.5319, p = 0.0006) (right: ρ = - 0.5361, p = 0.0005). Interestingly, among the KCL scores, the daily activity domain showed the strongest correlation (sensitivity, 90%; specificity, 73%) with the bottom quartile of the reduction in the superior frontal gyrus. Frailty in patients with COPD is associated with a thickness reduction in the cortical regions, reflecting social vulnerability.

Gender Difference in the Relationship between Extrapulmonary Factors and Reduced Lung Function in Early Adulthood.

(1) Background: Reduced lung function in early adulthood is associated with future risks to health outcomes that have not been fully explored by gender. We investigated gender-specific relationships between lung function and extrapulmonary variables, assessing their potential as screening markers for respiratory dysfunction in young adults. (2) Methods: The participants were 151 medical students. Clinical data, handgrip strength (HS); body composition parameters such as skeletal muscle mass index (SMI), whole-body phase angle (WBPhA), and bone mineral content (BMC); and pulmonary function variables, vital capacity (VC), forced VC (FVC), and forced expiratory volume in one second (FEV1), were measured. (3) Results: FEV1 was significantly correlated with BMI, SMI, WBPhA, BMC, and both left and right HS (p < 0.0001, respectively) across all participants. According to gender, FEV1 had the strongest positive association with left HS in males (p < 0.0001) and BMC in females (p < 0.0001). The area under the curve for detecting the bottom quartile of FEV1 was 0.705 (cut-off 41.0 kg, sensitivity 91%) for left HS in males and 0.742 (cut-off 2.11 kg, sensitivity 81%) for BMC in females. (4) Conclusions: Gender-specific relationships between intrapulmonary and extrapulmonary factors such as left HS and BMC could be useful for screening suspected respiratory dysfunction in early adulthood.

Relief of Airflow Limitation and Airway Inflammation by Endoscopic Sinus Surgery in a Patient with Severe Asthma with Eosinophilic Chronic Rhinosinusitis.

Although endoscopic sinus surgery (ESS) is beneficial in improving asthma symptoms, its impact on the lung function in patients with asthma and chronic rhinosinusitis remains unclear. We herein report a case of severe asthma with eosinophilic chronic rhinosinusitis, in which ESS substantially improved airflow limitation and concomitantly reduced fractional exhaled nitric oxide and blood eosinophil counts. ESS likely relieved airflow limitation by suppressing type 2 inflammatory pathways. This case highlights ESS as a promising strategy for achieving clinical remission in patients with severe asthma and chronic rhinosinusitis.

Difference in time-course of improvement in asthma control measures between budesonide and budesonide/formoterol.

Combinations of inhaled corticosteroids (ICS) and inhaled long-acting beta(2)-agonists (LABA) have become widely used for the initiation of maintenance treatment for asthma. However, it has not been fully elucidated whether ICS/LABA alters the time-course of different control outcome measures in steroid-naive patients with asthma compared to the treatment with ICS alone. We compared the time-response in Asthma Control Questionnaire (ACQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide fraction (FE(NO)), and airway responsiveness to methacholine (PD(200)) between budesonide (BUD) and budesonide/formoterol (BUD/FM). BUD/FM therapy significantly improved the ACQ score at week 2 and week 4 (p < 0.01 and p < 0.05), and increased FEV1 and the methacholine threshold at week 8 and week 24 (all p < 0.05) compared to BUD alone. A logistic function model showed that the BUD/FM combination significantly improved ACQ, FEV1, FE(NO) and PD(200) at a faster rate than BUD over 24 weeks (p < 0.001 for ACQ, FEV1, PD(200), and p < 0.05 for FE(NO), z-test). A significant variance in the time-response was also found in the outcomes of the two treatment groups (FE(NO) and ACQ > FEV1 and PD(200), p < 0.001, z-test). The present study provides evidence that ICS/LABA combination therapy results in a more rapid improvement in asthma symptoms, lung function, and airway inflammation compared to ICS monotherapy in steroid-naive patients with asthma.

Predictors for identifying the efficacy of systemic steroids on sustained exhaled nitric oxide elevation in severe asthma.

BACKGROUND: Some patients with asthma have high levels of exhaled nitric oxide fraction (FENO) despite inhaled corticosteroids (ICS) therapy. Early studies suggested that this might be explained by the presence of heterogeneous airway inflammation. We aimed to assess the predictors for identifying the efficacy of systemic corticosteroids on residual FENO elevations in severe asthma. METHODS: Twenty severe asthmatics with persistent FENO elevation (≥40ppb) despite maintenance therapy including high-daily-dose ICS were enrolled. Asthma Control Questionnaire (ACQ), lung function, blood eosinophils, and FENO were assessed before and after 14 days treatment with 0.5mg/kg oral prednisolone/day. RESULTS: ACQ, blood eosinophils, FENO level, FVC, FEV1, FEV1/FVC ratio and the slope of the single nitrogen washout curve (ΔN2) were significantly improved by treatment with prednisolone. 70% of the subjects showed ≥20% reductions in the FENO levels. The reduction in FENO levels was significantly correlated with the improvements in ACQ (p < 0.0001), FVC (p < 0.01), FEV1 (p < 0.0001), and ΔN2 (p < 0.05). Among the measurements at baseline, the FENO levels and blood eosinophil numbers were identified as significant predictors of ≥20% reductions in the FENO levels by systemic steroid therapy. CONCLUSIONS: Systemic corticosteroids could suppress the residual FENO elevations in more than half of the patients with severe asthma and the reduction in FENO levels was associated with improvements in asthma control and airflow limitation. The FENO levels and blood eosinophil numbers were the predictors of improved residual airway inflammation by systemic steroid therapy in severe asthma.