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.

Sensitization to Staphylococcus aureus enterotoxins in smokers with asthma.

BACKGROUND: Sensitization to Staphylococcus aureus enterotoxins (SEs) augments eosinophilic inflammation in asthma. Recent epidemiologic studies demonstrate that sensitization to SEs is increased in healthy smokers; however, there is no evidence on the association between sensitization to SEs and eosinophilic inflammation in smokers with asthma. OBJECTIVE: To clarify the role of SEs on clinical indexes, including eosinophilic inflammation and lung function in smokers with asthma. METHODS: The frequency of atopic sensitization to SEs was examined in adult patients with asthma. In current or ex-smokers with asthma, the association of sensitization to SEs with eosinophilic inflammation, airflow limitation, or treatment steps was determined. Clinical indexes were examined at the first visit, and treatment steps were assessed 6 months after enrollment. RESULTS: Overall, 23 current smokers, 40 ex-smokers, and 118 never smokers with asthma were enrolled. The frequency of sensitization to SEs, but not to other aeroallergens, was significantly higher in current, ex-, and never smokers, in decreasing order. In current or ex-smokers with asthma, patients with sensitization to SEs exhibited higher serum levels of total and specific IgE to aeroallergens, higher blood eosinophil counts, greater airflow limitation, and more severe disease 6 months later than those without sensitization to SE. A longer smoking abstinence period was associated with serum specific IgE levels to SEs, and 3 years was the best cutoff of abstinence period to predict the absence of sensitization to SEs. CONCLUSION: Sensitization to SEs is increased in smokers with asthma, and it may be a marker of eosinophilic inflammation and severe asthma in smokers with asthma. TRIAL REGISTRATION: umin.ac.jp Identifier: UMIN000007818.

Staphylococcus aureus enterotoxin sensitization involvement and its association with the CysLTR1 variant in different asthma phenotypes.

BACKGROUND: Sensitization to Staphylococcus aureus enterotoxin (SE) is a known risk factor for asthma susceptibility and severity. However, how SE sensitization is involved in asthma, particularly nonatopic asthma and/or late-onset asthma, remains uncertain. OBJECTIVE: To clarify the involvement of SE sensitization in nonatopic and/or late-onset asthma and its association with a polymorphism of the cysteinyl leukotriene receptor 1 gene (CysLTR1), which was examined because CysLT signaling is closely associated with late-onset eosinophilic asthma. METHODS: We assessed associations between sensitization to SE (A and/or B) and clinical indexes in 224 patients with asthma (mean age, 62.3 years; 171 women) from a cohort of the Kinki Hokuriku Airway Disease Conference, particularly those with nonatopic asthma (not sensitized to common aeroallergens) and/or late-onset asthma. Associations between SE sensitization and CysLTR1 polymorphism (rs2806489), a potential regulatory variant for atopic predisposition in women, were also assessed in a sex-stratified manner. RESULTS: A total of 105 patients (47%) with asthma were sensitized to SE. Among patients with nonatopic asthma (n = 67) or with late-onset asthma (n = 124), those sensitized to SE had significantly higher serum total IgE and periostin levels than those not sensitized. In nonatopic patients, a rapid decrease in forced expiratory volume in 1 second was associated with SE sensitization. In women with asthma, rs2806489 was associated with sensitization to SEB and age at asthma onset. CONCLUSION: SE sensitization contributes to TH2 inflammation in nonatopic and/or late-onset asthma. In women with asthma, the CysLTR1 variant might be associated with sensitization to SEB and age at asthma onset.

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.

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.

Gastroesophageal dysmotility is associated with the impairment of cough-specific quality of life in patients with cough variant asthma.

BACKGROUND: Gastroesophageal reflux disease (GERD) is known as a common comorbidity of asthma and chronic cough. The impact of GERD symptoms on cough-specific quality of life (QoL) in patients with asthmatic cough is poorly understood. The aim of this study is to determine the association of GERD symptoms with cough-specific quality of life in patients with cough variant asthma (CVA) using the Leicester Cough Questionnaire (LCQ). METHODS: A total of 172 consecutive patients (121 females) with mean cough duration of 45.1 months (range 2-480 months) completed the Japanese version of the LCQ. The Frequency Scale for the Symptoms of Gastroesophageal reflux was administered to assess symptoms of acid-reflux and dysmotility. A range of clinical variables that may determine cough-specific QoL (LCQ) were estimated. RESULTS: The mean LCQ scores was 12.9 (SD 3.5), consistent with severe impairment in QoL. Female gender, symptoms of gastroesophageal dysmotility, sensitization to allergens (house dust and Japanese cedar pollen) and the number of sensitized allergens were associated with lower LCQ scores (i.e. impaired cough-specific QoL) in univariate regression analysis. Acid-reflux symptoms, airway hyperresponsiveness, fractional exhaled nitric oxide, and sensitization to molds were unrelated to the LCQ score. After adjustment for gender, symptoms of gastroesophageal dysmotility was the only significant determinant of impaired cough-specific QoL accounting for 23% of the variance. CONCLUSIONS: Cough-specific QoL is severely impaired in patients with CVA. Symptoms of gastroesophageal dysmotility are an independent predictor of cough-specific QoL of patients with CVA.

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.

Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.

BACKGROUND: Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE: We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS: Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS: High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS: Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.

Clinical features of pneumothorax associated with COVID-19: A retrospective analysis of two centres.

BACKGROUND: Pneumothorax is a known sequela of coronavirus disease 2019 (COVID-19). However, the clinical features of pneumothorax associated with COVID-19 have not been fully elucidated. METHODS: Patients who developed pneumothorax within 6 months of being diagnosed with COVID-19 were retrospectively analysed at two institutions. We investigated the background factors, COVID-19 severity and treatment, timing of pneumothorax onset, treatment modalities, treatment duration, and prognosis of these patients. RESULTS: A total of 21 patients were diagnosed with pneumothorax within 6 months of COVID-19 diagnosis. The combined incidence rate of pneumothorax at two institutions was 0.89 %. The mean age of these patients was 72.5 years, and they were predominantly male (90.5 %), with a history of smoking (76.1 %). The most frequent comorbidity was hypertension, followed by type 2 diabetes mellitus, COPD, and malignancy. Approximately 76 % of the patients had moderate or severe disease requiring oxygenation. Moreover, 90.5 % of these patients were taking antiviral drugs; 52.4 %, immunosuppressant agents (baricitinib/tocilizumab); and 66.7 % were on dexamethasone. The median time to the onset of pneumothorax was 15.0 days, and 86 % of cases occurred within 1 month of COVID-19 diagnosis. Bilateral pneumothorax and pneumomediastinum were noted in one patient each. Chest drainage was performed in 71.4 % of the patients. The mean treatment duration for pneumothorax was 14.1 days, and the 30-day mortality rate was 28.6 %. CONCLUSION: Pneumothorax associated with COVID-19 was more common in patients with moderate or severe disease requiring oxygenation, and occurred within 1 month of COVID-19 diagnosis. Pneumothorax associated with COVID-19 is a serious complication with a high mortality rate and clinicians should pay attention to it.

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.

Phase II study of pemetrexed and erlotinib in pretreated nonsquamous, non-small-cell lung cancer patients without an EGFR mutation.

BACKGROUND: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed. PATIENTS AND METHODS: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m(2)) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred. RESULTS: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively. CONCLUSIONS: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531).

Transient asymptomatic pulmonary opacities in a patient with MET exon 14 skipping non-small cell lung cancer: A case report.

Mesenchymal epithelial transition factor receptor (MET) tyrosine kinase inhibitors (MET-TKIs) have been approved for the treatment of non-small cell lung cancers with MET exon 14 skipping mutations. Transient asymptomatic pulmonary opacities (TAPOs) associated with epidermal growth factor receptor (EGFR)-TKIs have been reported. Here, we report a case wherein ground-glass opacities (GGOs) appeared during the course of treatment with tepotinib, a MET-TKI, but spontaneously resolved with drug withdrawal, after which treatment was resumed with a reduced dose. Although there have been no reports of TAPOs with MET-TKIs, the clinical and imaging findings of this case were consistent with TAPOs. For TAPOs occurring because of MET-TKI, the drug can be continued under careful observation even if GGOs appear.

Physiologic 18F-FDG muscle uptake in severe COPD: Implications for accurate lung cancer staging.

Recognizing physiologic 18F-fluorodeoxyglucose (FDG) uptake in severe COPD is crucial to avoid mistaking it for lung cancer metastasis. Correlating 18F-FDG avid lesions with co-registered computed tomography is essential for accurate lung cancer staging and preventing unnecessary interventions.

Concurrent trastuzumab deruxtecan-induced interstitial lung disease and COVID-19 in the treatment of advanced breast cancer.

Patients with cancer are at an increased risk of developing coronavirus disease 2019 (COVID-19) infection. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) against epidermal growth factor receptor 2 (HER2)-positive cancer, known to cause drug-induced interstitial lung disease (DILD), including drug-induced pneumonitis. A 60-year-old woman with breast cancer developed a fever during treatment with T-DXd and was diagnosed with COVID-19. The fever persisted for approximately 3 weeks, and chest computed tomography showed multiple consolidations with bilateral peripheral predominance. Since the clinical course was atypical for COVID-19 due to the long duration of the fever and the CT pattern was frequently seen in T-DXd-induced ILD, the patient was diagnosed with T-DXd-induced ILD, following which, prednisolone was started, leading to improvement in the symptoms and fading of shadows. Even in patients suspected of COVID-19 pneumonia, physicians should consider the possibility of DILD, particularly in patients undergoing cancer treatment.

Interleukin-13 enhanced Ca2+ oscillations in airway smooth muscle cells.

Physiological mechanisms associated with interleukin-13 (IL-13), a key cytokine in asthma, in intracellular Ca(2+) signaling in airway smooth muscle cells (ASMCs) remain unclear. The aim of this study was to assess effects of IL-13 on Ca(2+) oscillations in response to leukotriene D4 (LTD4) in human cultured ASMCs. LTD4-induced Ca(2+) oscillations in ASMCs pretreated with IL-13 were imaged by confocal microscopy. mRNA expressions of cysteinyl leukotriene 1 receptors (CysLT1R), CD38, involved with the ryanodine receptors (RyR) system, and transient receptor potential canonical (TRPC), involved with store-operated Ca(2+) entry (SOCE), were determined by real-time PCR. In IL-13-pretreated ASMCs, frequency of LTD4-induced Ca(2+) oscillations and number of oscillating cells were significantly increased compared with untreated ASMCs. Both xestospongin C, a specific inhibitor of inositol 1,4,5-triphosphate receptors (IP(3)R), and ryanodine or ruthenium red, inhibitors of RyR, partially blocked LTD4-induced Ca(2+) oscillations. Ca(2+) oscillations were almost completely inhibited by 50 µM of 2-aminoethoxydiphenyl borate (2-APB), which dominantly blocks SOCE but not IP(3)R at this concentration. Pretreatment with IL-13 increased the mRNA expressions of CysLT1R and CD38, but not of TRPC1 and TRPC3. We conclude that IL-13 enhances frequency of LTD4-induced Ca(2+) oscillations in human ASMCs, which may be cooperatively modulated by IP(3)R, RyR systems and possibly by SOCE.

Sputum YKL-40 levels and pathophysiology of asthma and chronic obstructive pulmonary disease.

BACKGROUND: Recent evidence suggests that YKL-40, also called chitinase-3-like-1 protein, is involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Details of sputum YKL-40 in asthma and COPD, however, remain unknown. OBJECTIVES: To clarify associations of sputum YKL-40 levels with clinical indices in asthma and COPD. METHODS: Thirty-nine patients with asthma, 14 age-matched never-smokers as controls, 45 patients with COPD, and 7 age-matched smokers as controls were recuited for this study. Sputum YKL-40 levels were measured and YKL-40 expression in sputum cells was evaluated by immunocytochemistry. RESULTS: Sputum YKL-40 levels were higher in patients with COPD (346 ± 325 ng/ml) than in their smoker controls (125 ± 122 ng/ml; p < 0.05), but were not significantly different between patients with asthma (117 ± 170 ng/ml) and their controls (94 ± 44 ng/ml; p = 0.15). In patients with asthma only, sputum YKL-40 levels were positively correlated with disease severity (r = 0.34, p = 0.034) and negatively correlated with pre- and postbronchodilator %FEV(1) (r = -0.47 and -0.42, respectively; p < 0.01) and forced mid-expiratory flow (r = -0.48 and -0.46, respectively, p < 0.01). Sputum YKL-40 levels were positively correlated with sputum neutrophil counts in asthma (r = 0.55, p < 0.001) and with neutrophil and macrophage counts in COPD (r = 0.45 and 0.65, respectively, p < 0.01). YKL-40 was expressed in the cytoplasm of sputum neutrophils and macrophages in all groups. CONCLUSIONS: Elevated sputum YKL-40 reflects airflow obstruction in asthma whereas the roles of YKL-40 in the proximal airways in COPD remain to be elucidated.

Cough triggers and their pathophysiology in patients with prolonged or chronic cough.

BACKGROUND: The character or timing of chronic cough is considered to be unpredictable for diagnosing its cause. However, the associations of cough triggers with cough pathophysiology remains unknown. METHODS: We developed a closed questionnaire listing 18 triggers that were reported by ≥1% of 213 patients in a retrospective survey. Using this questionnaire, patients with cough-predominant or cough-variant asthma (n = 140) and those with non-asthmatic cough (54) were asked whether their cough was induced by the listed triggers. Associations of triggers with causes of cough, airway sensitivity to inhaled methacholine, exhaled nitric oxide (NO) levels, number of sensitizing allergens, and scores from gastroesophageal reflux (GER) questionnaires were examined. Factor analysis was used to categorize variables, including the 12 most common cough triggers, diagnosis of asthmatic cough, airway sensitivity, and exhaled NO levels. RESULTS: "Cold air" and "fatigue/stress" induced cough more often in asthmatic coughers than in non-asthmatic coughers. "Spices" and "meals" induced cough more frequently in GER-coughers (n = 19). Patients who marked "cold air" as the trigger were more sensitive to inhaled methacholine and showed higher exhaled NO levels than those who did not mark this trigger. The "post-nasal drip" trigger was associated with elevated exhaled NO levels, and this association was mainly exhibited by patients with cough-predominant asthma. The triggers "pollen" and "mold smell" were associated with a number of sensitizing allergens. The number of triggers was weakly associated with GER scores. By factor analysis, "cold air," "fatigue/stress," asthmatic cough, airway hypersensitivity, and elevated NO levels were categorized into the same factor. CONCLUSIONS: Several cough triggers may reflect the pathophysiology of prolonged or chronic cough.

Negative pressure pulmonary edema in a patient with COVID-19.

Negative pressure pulmonary edema (NPPE) should be considered in the differential diagnosis from an episode of asphyxia, and even if NPPE is diagnosed, the possibility of COVID-19 should be kept in mind under coronavirus pandemic conditions.