Artificial intelligence-based analysis of the spatial distribution of abnormal computed tomography patterns in SARS-CoV-2 pneumonia: association with disease severity.

BACKGROUND: The substantial heterogeneity of clinical presentations in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia still requires robust chest computed tomography analysis to identify high-risk patients. While extension of ground-glass opacity and consolidation from peripheral to central lung fields on chest computed tomography (CT) might be associated with severely ill conditions, quantification of the central-peripheral distribution of ground glass opacity and consolidation in assessments of SARS-CoV-2 pneumonia remains unestablished. This study aimed to examine whether the central-peripheral distributions of ground glass opacity and consolidation were associated with severe outcomes in patients with SARS-CoV-2 pneumonia independent of the whole-lung extents of these abnormal shadows. METHODS: This multicenter retrospective cohort included hospitalized patients with SARS-CoV-2 pneumonia between January 2020 and August 2021. An artificial intelligence-based image analysis technology was used to segment abnormal shadows, including ground glass opacity and consolidation. The area ratio of ground glass opacity and consolidation to the whole lung (GGO%, CON%) and the ratio of ground glass opacity and consolidation areas in the central lungs to those in the peripheral lungs (GGO(C/P)) and (CON(C/P)) were automatically calculated. Severe outcome was defined as in-hospital death or requirement for endotracheal intubation. RESULTS: Of 512 enrolled patients, the severe outcome was observed in 77 patients. GGO% and CON% were higher in patients with severe outcomes than in those without. Multivariable logistic models showed that GGO(C/P), but not CON(C/P), was associated with the severe outcome independent of age, sex, comorbidities, GGO%, and CON%. CONCLUSION: In addition to GGO% and CON% in the whole lung, the higher the ratio of ground glass opacity in the central regions to that in the peripheral regions was, the more severe the outcomes in patients with SARS-CoV-2 pneumonia were. The proposed method might be useful to reproducibly quantify the extension of ground glass opacity from peripheral to central lungs and to estimate prognosis.

Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma.

BACKGROUND: Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. METHODS: In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. RESULTS: Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = -0.33, p = 0.004). CONCLUSIONS: Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma.

Pneumonia Caused by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza Virus: A Multicenter Comparative Study.

BACKGROUND: Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. METHODS: A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. RESULTS: Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. CONCLUSIONS: Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings.

Induction of airway remodeling and persistent cough by repeated citric acid exposure in a guinea pig cough model.

BACKGROUND: A previous study involving guinea pigs showed that repeated cough could increase peripheral airway smooth muscle area, which can also aggravate cough. The airway pathologic changes produced by prolonged cough are still unknown. OBJECTIVE: To study the airway pathologic changes in prolonged cough models of guinea pigs. METHODS: Guinea pigs were assigned to three treatment groups: citric acid inhalation (CA) alone, citric acid inhalation with codeine pretreatment (COD), or saline solution inhalation (SA). Animals were challenged with citric acid or saline solution three times weekly. The intervention period was 22 or 43 days. Animals were challenged with citric acid on the first and last days of exposure. Lung specimens were obtained for pathologic analysis 72 h after the last exposure. RESULTS: Compared with the other two groups, the CA group had increased frequency of cough on both 22 and 43 days of exposure. Tracheal basement membrane (BM) thickness was increased after 43 days of exposure, correlating with the frequency of cough. The area of airway smooth muscles (ASM index) in small airways increased in the CA group after both 22 and 43 days of exposure, compared with the SA group. Compared with the COD group, the ASM index in small airways increased in the CA group after 22 days of exposure instead of 43 days of exposure. CONCLUSIONS: An increase in peripheral smooth muscle area by repeated cough was confirmed. Moreover, this is the first study to show that tracheal BM thickness increased after prolonged exposure (43 days). Repeated cough may lead to airway remodeling, which was also associated with an increased frequency of cough.

Pseudoprogression in Previously Treated Patients with Non-Small Cell Lung Cancer Who Received Nivolumab Monotherapy.

INTRODUCTION: Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression. METHODS: We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death. RESULTS: Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p < 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001). CONCLUSIONS: Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.

INTRODUCTION: Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS: We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. RESULTS: Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). CONCLUSIONS: Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Neuroendocrine carcinoma of the lung expressing anaplastic lymphoma kinase on high-sensitivity immunohistochemistry: A case report.

It has been reported that anaplastic lymphoma kinase (ALK) protein is expressed in a proportion of non-small-cell carcinomas (mainly adenocarcinomas). By contrast, high-sensitivity immunohistochemistry (IHC) rarely detects ALK protein expression in neuroendocrine carcinomas (NECs) of the lung, which include small-cell carcinomas and large-cell neuroendocrine carcinomas (LCNECs). We herein present a case of NEC that was identified as ALK-positive via high-sensitivity IHC. A 51-year-old man was diagnosed with small-cell carcinoma in the upper lobe of the right lung. Although high-sensitivity IHC revealed that the tumor weakly expressed the ALK protein, no fusion gene with ALK was found using fluorescence in situ hybridization (FISH). Standard chemotherapy was administered to the patient. Six months after the first visit to the hospital for the tumor, another tumor was identified in the upper lobe of the left lung. The tumor was resected and diagnosed as NEC displaying LCNEC-like characteristics. This NEC also moderately expressed ALK protein by high-sensitivity IHC, without exhibiting fusion genes with ALK on FISH. These data suggest that the presence of ALK fusion genes should be confirmed by FISH or reverse transcription polymerase chain reaction, even if high-sensitivity IHC for ALK protein is positive in lung cancer.

A 12-week, randomized, parallel-group, proof-of-concept study of tulobuterol patch and salmeterol inhaler as add-on therapy in adult-onset mild-to-moderate asthma.

Patch formulation of tulobuterol has been used in asthma treatment as a long-acting ß2 -agonist (LABA) through sustained skin absorption. Its treatment efficacy, especially in small airways, remains poorly understood. The study aim was to investigate LABA add-on effects of tulobuterol patch (TP) and salmeterol inhaler (SA) on pulmonary function, asthma control and health status. Patients who had adult-onset under-control asthma, despite taking inhaled corticosteroids, were enrolled in a randomized, open-label, parallel-group, proof-of-concept study of 12-week add-on treatment with TP (n=16) or SA (n=17). Spirometry, impulse oscillometry (IOS), exhaled nitric oxide levels, and clinical questionnaires of asthma control, health status (St. George's Respiratory Questionnaire: SGRQ), and symptoms were evaluated every 4 weeks. Add-on treatment of SA significantly improved the spirometric indices of small airway obstruction (forced expiratory flow between 25% and 75% of FVC: FEF25-75 , and maximum expiratory flow at 25% of FVC: MEF25 ) and IOS indices of whole respiratory resistance (resistance at 5 Hz) as compared to TP. In intra-group comparisons, add-on treatment of TP improved the scores of the asthma control test and the total SGRQ, as well as the symptom and impact components of the SGRQ. SA add-on treatment improved FEV1 and IOS parameters of resistance at 20 Hz and reactance at 5 Hz. Neither of the treatments improved exhaled nitric oxide levels. In conclusion, add-on treatment of TP improved asthma control and health status, whereas SA improved pulmonary function measures associated with large and small airway involvement among patients with adult-onset mild-to-moderate asthma.

Airway remodeling associated with cough hypersensitivity as a consequence of persistent cough: An experimental study.

BACKGROUND: Chronic cough involves airway remodeling associated with cough reflex hypersensitivity. Whether cough itself induces these features remains unknown. METHODS: Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or CA+dextromethorphan (DEX). All animals were exposed to 0.5M CA on days 1 and 22. On days 4-20, the CA and CA+DEX groups were exposed to CA, and the SA group to saline thrice weekly, during which the CA+DEX group was administered DEX pretreatment to inhibit cough. The number of coughs was counted during each 10-min CA or SA exposure. Terbutaline premedication was started to prevent bronchoconstriction. Bronchoalveolar lavage and pathology were examined on day 25. Average cough number for 10 CA exposures was examined as "cough index" in the CA group, which was divided into frequent (cough index>5) and infrequent (<5) cough subgroups for lavage and pathology analysis. RESULTS: The number of coughs significantly increased in the CA group from day 13 onwards. In the CA+DEX and SA groups, the number of coughs did not differ between days 1 and 22, while average number of coughs during days 4-20 was significantly lower than at days 1 and 22. Bronchoalveolar cell profiles were similar among the four groups. The smooth muscle area of small airways was significantly greater in the frequent-cough subgroup than in the other groups (in which it was similar), and highly correlated with cough index in CA group. CONCLUSION: Repeated cough induces airway smooth muscle remodeling associated with cough reflex hypersensitivity.

Severe fever with thrombocytopenia syndrome presenting as hemophagocytic syndrome: two case reports.

INTRODUCTION: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was first reported in China in 2011. However, it is now endemic in Japan, and the SFTS viruses in Japan and China have evolved independently. Its fatality rate is 26.5 % in Japan, and the viral load is related to morbidity. CASE DESCRIPTION: We encountered two patients with SFTS. Case 1 is a 72-year-old woman who visited our hospital owing to severe fatigue, diarrhea, and nausea. Her consciousness level score on the Glasgow Coma Scale was 14 points, and her serum lactate dehydrogenase level was 646 IU/L. Case 2 is an 82-year-old woman who visited our hospital owing to diarrhea and general fatigue. Her consciousness level score on the Glasgow Coma Scale was 11 points, and her serum lactate dehydrogenase level was 935 IU/L. DISCUSSION AND EVALUATION: Both patients had hemophagocytic syndrome and presented with similar symptoms. Although both were treated with similar drug regimens, their clinical courses were different: after treatment, the 72-year-old woman survived whereas the 82-year-old woman died. In addition to age, the two patients differed in terms of time between symptom onset and treatment initiation, consciousness level, viral load, and extent of elevation of liver enzyme levels. CONCLUSIONS: The viral load, which is a predictor of morbidity, was associated with the level of consciousness and the serum lactate dehydrogenase level, both of which might be useful for predicting death in patients with SFTS.

CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling.

OBJECTIVES: Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. METHODS: We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). RESULTS: The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. CONCLUSIONS: The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma.

Mechanical Stimulation by Postnasal Drip Evokes Cough.

Cough affects all individuals at different times, and its economic burden is substantial. Despite these widespread adverse effects, cough research relies on animal models, which hampers our understanding of the fundamental cause of cough. Postnasal drip is speculated to be one of the most frequent causes of chronic cough; however, this is a matter of debate. Here we show that mechanical stimuli by postnasal drip cause chronic cough. We distinguished human cough from sneezes and expiration reflexes by airflow patterns. Cough and sneeze exhibited one-peak and two-peak patterns, respectively, in expiratory airflow, which were also confirmed by animal models of cough and sneeze. Transgenic mice with ciliary dyskinesia coughed substantially and showed postnasal drip in the pharynx; furthermore, their cough was completely inhibited by nasal airway blockade of postnasal drip. We successfully reproduced cough observed in these mice by injecting artificial postnasal drip in wild-type mice. These results demonstrated that mechanical stimulation by postnasal drip evoked cough. The findings of our study can therefore be used to develop new antitussive drugs that prevent the root cause of cough.

Assessment of Small Airways with Computed Tomography: Mosaic Attenuation or Lung Density?

BACKGROUND: Computed tomography (CT) assessment of air trapping has been considered useful as a measure of small airway disease. Mean lung density (MLD) and the percentage of the lung field occupied by low attenuation area (LAA%) can be evaluated automatically, and their expiratory/inspiratory (E/I) ratios correlate with asthma severity and spirometry parameters. However, mosaic attenuation, another indicator of air trapping, has been assessed visually, and its functional relevance remains controversial. OBJECTIVES: This retrospective study was conducted to correlate mosaic attenuation, which was assessed visually and automatically, and the E/I ratios of MLD and LAA% (defined as areas <-960 Hounsfield units) with clinical and physiological variables, including impulse oscillometry (IOS) indices. MATERIAL AND METHODS: In 36 nonsmoking patients with stable asthma, the lungs were scanned at full inspiration and full expiration. Mosaic attenuation was measured visually and automatically, by counting areas with CT values higher than the surrounding areas. MLD and LAA% were measured using our validated method. Spirometry, IOS, exhaled NO and the sputum eosinophil count were evaluated. RESULTS: The automatic results and visual scores of mosaic attenuation correlated well on expiratory scans (r = 0.894) and to a lesser degree on inspiratory scans (r = 0.629; p < 0.0001 for both). However, only the E/I ratios of MLD and LAA% correlated with forced expiratory volume in 1 s/forced vital capacity of spirometry and the IOS indices of resistance from 5 to 20 Hz and the integrated area of low-frequency reactance. CONCLUSIONS: Our automatic method for analysis of mosaic attenuation is likely useful, but the results themselves may not be reflecting small airway involvement of asthma, unlike the E/I ratios of MLD and LAA%.

Pathophysiological characteristics of asthma in the elderly: a comprehensive study.

BACKGROUND: Comprehensive studies of the pathophysiologic characteristics of elderly asthma, including predominant site of disease, airway inflammation profiles, and airway hyperresponsiveness, are scarce despite their clinical importance. OBJECTIVE: To clarify the pathophysiologic characteristics of elderly patients with asthma. METHODS: Patients older than 65 years (elderly; n = 45) vs those no older than 65 years (nonelderly; n = 67) were retrospectively analyzed by spirometry, computed tomographic indices of large airway wall thickness and small airway involvement (air trapping), impulse oscillation measurements, exhaled nitric oxide levels, blood and induced sputum cell differentials, methacholine airway responsiveness, and total and specific serum IgE levels. RESULTS: Elderly patients with asthma had significantly lower values for forced expiration volume in 1 second, mid-forced expiratory flow (percentage predicted), and ratio of forced expiration volume in 1 second to forced vital capacity than nonelderly patients with asthma (median 81.2% vs 88.8%, P = .02; 50.9% vs 78.6%, P = .03; 0.72 vs 0.78, P = .001, respectively). In computed tomographic measurements, elderly patients with asthma had significantly greater airway wall thickening and air trapping than nonelderly patients. Impulse oscillation measurements indicated that elderly patients with asthma showed significantly greater resistance at 5 Hz (used as an index of total airway resistance), greater decrease in resistance from 5 to 20 Hz, a higher ratio of decrease in resistance from 5 to 20 Hz to resistance at 5 Hz, higher integrated area between 5 Hz and frequency of resonance, greater frequency of resonance, and lower reactance at a frequency of 5 Hz (potential markers of small airway disease) than nonelderly patients. There were no significant differences in blood or sputum cell differentials, exhaled nitric oxide, or methacholine airway responsiveness between the 2 groups. Total serum IgE levels and positive rates of specific IgE antibodies against several allergens were significantly lower in elderly than in nonelderly patients with asthma. CONCLUSION: Based on spirometric, computed tomographic, and impulse oscillation analyses, elderly patients with asthma have greater involvement of small and large airways than nonelderly patients with asthma.

Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, is reportedly an effective treatment for severe allergic asthma. However, there have been few comprehensive analyses of its efficacy, including assessments of small airways or airway remodeling. OBJECTIVE: To comprehensively evaluate the efficacy of omalizumab, including its effects on small airways and airway remodeling, in adult patients with severe refractory asthma. METHODS: In this prospective, time-series, single-arm observational study, 31 adult patients with severe refractory asthma despite the use of multiple controller medications, including high-dose inhaled corticosteroids (1,432 ± 581 µg/d of fluticasone propionate equivalent), were enrolled. Clinical variables, including Asthma Quality of Life Questionnaire, asthma exacerbations, exhaled nitric oxide, pulmonary function, methacholine airway responsiveness, induced sputum, and chest computed tomogram, were assessed at baseline and after 16 and 48 weeks of treatment with omalizumab. RESULTS: Twenty-six of the 31 patients completed 48 weeks of treatment. For these patients, Asthma Quality of Life Questionnaire scores and peak expiratory flow values significantly and continuously improved throughout the 48 weeks (P < .001 for all comparisons). Unscheduled physician visits, asthma exacerbations requiring systemic corticosteroids, fractional exhaled nitric oxide at 50 mL/s and alveolar nitric oxide levels, sputum eosinophil proportions, and airway-wall thickness as assessed by computed tomography significantly decreased at 48 weeks (P < .05 for all comparisons). CONCLUSION: Omalizumab was effective for adult patients with severe refractory asthma. Omalizumab may have anti-inflammatory effects on small airways and reverse airway remodeling. TRIAL REGISTRATION: UMIN000002389.

Prevalence and clinical relevance of allergic rhinitis in patients with classic asthma and cough variant asthma.

BACKGROUND: A clinically relevant relationship between classic asthma and allergic rhinitis has been reported. However, the possible link between cough variant asthma (CVA) and allergic rhinitis remains unknown. OBJECTIVES: To clarify the prevalence and clinical relevance of perennial allergic rhinitis or seasonal allergic rhinitis in CVA patients compared to classic asthma patients. METHODS: We retrospectively studied adult patients with classic asthma (n = 190) and those with CVA (n = 83). The prevalence of perennial allergic rhinitis or seasonal allergic rhinitis and associations of concomitant perennial or seasonal allergic rhinitis with asthma severity, forced expiratory volume in 1 s (% predicted), fractional exhaled nitric oxide (FeNO) levels, and eosinophil proportions in sputum and blood were analyzed in the two groups. RESULTS: The prevalence of perennial allergic rhinitis and/or seasonal allergic rhinitis was significantly higher in classic asthma patients than in CVA patients (all p < 0.05). Concomitant perennial allergic rhinitis was associated with higher FeNO levels and eosinophil proportions in sputum and blood in classic asthma patients (p = 0.035, p = 0.036, and p = 0.008, respectively) and with higher asthma severity, FeNO levels, and sputum eosinophil proportions in CVA patients (p = 0.031, p = 0.007, and p = 0.010, respectively). Concomitant seasonal allergic rhinitis was only associated with higher sputum eosinophil proportions in CVA patients with active rhinitis symptoms during the sensitized pollen season (p = 0.025). CONCLUSIONS: Perennial allergic rhinitis may be relevant for CVA patients as well as classic asthma patients by consistently augmenting eosinophilic lower airway inflammation.

Association of eosinophilic inflammation with FKBP51 expression in sputum cells in asthma.

BACKGROUND: Airway eosinophilia is a predictor of steroid responsiveness in steroid-naïve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor co-chaperone that plays a role in steroid insensitivity in asthma, remains unknown. OBJECTIVE: To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma. METHODS: The FKBP51 mRNA levels in sputum cells from steroid-naïve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed. RESULTS: In steroid-naïve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r = -0.52) and sputum (r = -0.57), and exhaled nitric oxide levels (r = -0.42) (all p<0.05). No such associations were observed in patients on ICS. In steroid-naïve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r = -0.73) (all p<0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naïve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p<0.0001). CONCLUSIONS: Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naïve asthmatic patients.

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma.

BACKGROUND: Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown. OBJECTIVE: To examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation. METHODS: Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed. RESULTS: A total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control. CONCLUSION: Ciclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000001083.