Endobronchial Ultrasound is Useful in the Assessment of Bronchial Wall Changes Related to Bronchial Thermoplasty.

Background: Bronchial thermoplasty (BT) is an interventional endoscopic treatment for severe asthma leading to the clinical improvement, but morphologic changes of bronchial wall related to the procedure and predictors of a favorable response to BT remain uncertain. The aim of the study was to validate an endobronchial ultrasound (EBUS) in assessing the effectiveness of BT treatment. Methods: Patients with severe asthma who met the clinical criteria for BT were included. In all patients clinical data, ACT and AQLQ questionnaires, laboratory tests, pulmonary function tests and bronchoscopy with radial probe EBUS and bronchial biopsies were collected. BT was performed in patients with the thickest bronchial wall L2 layer representing ASM. These patients were evaluated before and after 12 months of follow-up. The relationship between baseline parameters and clinical response was explored. Results: Forty patients with severe asthma were enrolled to the study. All 11 patients qualified to BT successfully completed the 3 sessions of bronchoscopy. BT improved asthma control (P=0.006), quality of life (P=0.028) and decreased exacerbation rate (P=0.005). Eight of the 11 patients (72.7%) showed a clinically meaningful improvement. BT also led to a significant decrease in the thicknesses of bronchial wall layers in EBUS (L1 decreased from 0.183 to 0.173 mm, P=0.003; L2 from 0.207 to 0.185 mm, P = 0.003; and L3-5 from 0.969 to 0.886 mm, P=0.003). Median ASM mass decreased by 61.8% (P=0.002). However, there was no association between baseline patient characteristics and the magnitude of clinical improvement after BT. Conclusion: BT was associated with a significant decrease in the thickness of the bronchial wall layers measured by EBUS including L2 layer representing ASM and ASM mass reduction in bronchial biopsy. EBUS can assess bronchial structural changes related to BT; however, it did not predict the favorable clinical response to therapy.

Bronchial epithelial cell transcriptome shows endotype heterogeneity of asthma in patients with NSAID-exacerbated respiratory disease.

BACKGROUND: Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) is currently classified as a type-2 (T2) immune-mediated disease characterized by asthma, chronic rhinosinusitis, and hypersensitivity to cyclooxygenase-1 inhibitors. OBJECTIVES: The aim of this study was to characterize immunological endotypes of N-ERD based on the gene expression profile in the bronchial epithelium. METHODS: mRNA transcriptome (mRNA-sequencing) was analyzed in bronchial brushings from patients with N-ERD (n = 22), those with nonsteroidal anti-inflammatory drug-tolerant asthma (NTA, n = 21), and control subjects (n = 11). Additionally, lipid and protein mediators were measured in bronchoalveolar lavage fluid (BALF). RESULTS: Initial analysis of the entire asthma group revealed 2 distinct gene expression signatures: "T2-high" with increased expression of T2-related genes (eg, CLCA1, CST1), and "proinflammatory" characterized by the expression of innate immunity (eg, FOSB, EGR3) and IL-17A response genes. These endotypes showed similar prevalence in N-ERD and NTA (eg, T2-high: 33% and 32%, respectively). T2-high asthma was characterized by increased expression of mast cell and eosinophil markers, goblet cell hyperplasia, and elevated LTE4 and PGD2 in BALF. Patients with a proinflammatory endotype showed mainly neutrophilic inflammation and increased innate immunity mediators in BALF. Furthermore, the proinflammatory signature was associated with a more severe course of asthma and marked airway obstruction. These signatures could be recreated in vitro by exposure of bronchial epithelial cells to IL-13 (T2-high) and IL-17A (proinflammatory). CONCLUSIONS: T2-high signature was found only in one-third of patients with N-ERD, which was similar to what was found in patients with NTA. The proinflammatory endotype, which also occurred in N-ERD, suggests a novel mechanism of severe disease developing on a non-T2 background.

Predictors of excessive short-acting ß2-agonist use and asthma exacerbations: a retrospective analysis of a Polish prescription database.

Introduction: Despite being linked to unfavourable outcomes, short-acting ß2-agonists (SABAs) are still overused by a substantial proportion of patients with asthma. Aim: To analyse the prevalence and predictors of SABA overuse and exacerbations in patients with asthma in a nationwide database of prescription purchase records. Material and methods: The prevalence of excessive SABA use (≥ 12 canisters) and overuse (≥ 3 canisters) was analysed among patients aged 18-64 years who purchased asthma medications in 2018. Predictors of excessive SABA use and SABA overuse were examined by quasi-Poisson regression. Negative binomial regression was used to study the association of excessive SABA use or overuse to the risk of asthma exacerbation defined as a prescription for oral corticosteroids. Results: Of 91,763 patients with asthma, 42,189 (46%) were SABA users (mean age, 47 years; 58% female). Among them, 34% purchased ≥ 3 SABA canisters, and 6% purchased ≥ 12 canisters. The risk (risk ratio, 95% CI) of excessive SABA use was lower in patients with concomitant prescriptions for inhaled corticosteroids (0.41, 0.34-0.48) or inhaled corticosteroids and long-acting ß2-agonists (0.52, 0.47-0.56), women (0.63, 0.58-0.68), and those in secondary care (0.60, 0.44-0.66); older age was associated with a higher risk of excessive SABA use (1.06, 1.03-1.10). Excessive SABA use was the strongest predictor of asthma exacerbations among all patients (3.24, 2.84-3.70) and in those with ≥ 1 exacerbation (1.60, 1.50-1.71). Conclusions: Excessive SABA use is highly prevalent in asthma management, is associated with lack of prescriptions for inhaled corticosteroids, and substantially increases the exacerbation risk.

Clinical and Polysomnographic Features Associated with Poor Sleep Quality in Patients with Obstructive Sleep Apnea.

Background and Objectives: Poor sleep quality in patients with obstructive sleep apnea (OSA) may be associated with different clinical and polysomnographic features. The aim of this study was to identify features associated with poor sleep quality in OSA patients. Materials and Methods: This was a cross-sectional study enrolling patients with OSA confirmed by polysomnography (PSG). In addition to gathering clinical data, patients were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Clinical Global Impression Scale. Univariate and multivariable analyses were performed to identify factors associated with an increased risk of poor sleep quality in this population. Results: Among 505 enrolled patients (mean age of 57.1 years, 69.7% male) poor quality of sleep (PSQI score ≥ 5) was confirmed in 68.9% of them. Multivariable analysis revealed the following factors associated with poor sleep quality: chronic heart failure (OR 3.111; 95% CI, 1.083−8.941, p = 0.035), male sex (OR 0.396; 95% CI, 0.199−0.787, p = 0.008), total ESS score (OR 1.193; 95% CI, 1.124−1.266, p < 0.001), minimal saturation during sleep (OR 1.034; 95% CI, 1.002−1.066, p = 0.036), and N3 percentage of total sleep time (OR 1.110; 95% CI, 1.027−1.200, p = 0.009). Conclusions: Our study suggests that both the female sex and coexistence of heart failure are independent risk factors for poor sleep quality. Moreover, we hypothesize that nocturnal hypoxia may lead to a misperception of sleep quality and may explain the counterintuitive association between a higher proportion of deep sleep and poor sleep quality.

The impact of clinical and psychological factors on asthma control: the experience of a single asthma center in Poland.

OBJECTIVE: The asthma control test (ACT) is commonly used to identify patients with uncontrolled asthma. The goal of this study was to determine whether clinical parameters such as asthma history and medications, exacerbation rate, comorbidities, lung function, and socioeconomic status are risk factors for uncontrolled asthma assessed with the ACT, and to evaluate the psychological status of controlled and uncontrolled asthmatics. METHODS: Adult asthmatics (n = 104) were recruited from a single asthma center, Poland. Asthma control was assessed with the ACT, using <20 as the cutoff point for uncontrolled asthma. Data on clinical factors were collected and spirometry was performed. Patients completed the Asthma Quality of Life Questionnaire, General Health Questionnaire, Acceptance of Illness Scale, Life Orientation Test-Revised, and Eysenck's Personality Inventory. RESULTS: Asthma was uncontrolled in 42.3% of patients. Asthma exacerbations in the preceding 12 months and high inhaled corticosteroid (ICS) doses were identified as independent risk factors for uncontrolled asthma. Uncontrolled asthmatics had a significantly worse psychological status than controlled asthmatics. The groups did not differ in terms of personality traits, but in the controlled asthma group numerous significant correlations between psychological factors and personality traits were observed. In the uncontrolled asthma group, however, the occurrence of correlations between personality traits and other psychological variables was rarer. CONCLUSIONS: The study identified independent risk factors for uncontrolled asthma, namely, exacerbations in the recent 12 months and treatment with high-dose ICS. Uncontrolled asthmatics have a significantly worse psychological status than controlled asthmatics, irrespective of personality traits.

Dual role of the miR-146 family in rhinovirus-induced airway inflammation and allergic asthma exacerbation.

Rhinovirus (RV) infections are associated with asthma exacerbations. MicroRNA-146a and microRNA-146b (miR-146a/b) are anti-inflammatory miRNAs that suppress signaling through the nuclear factor kappa B (NF-κB) pathway and inhibit pro-inflammatory chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR-146a/b could regulate cellular responses to RVs in HBECs and airways during RV-induced asthma exacerbation. We demonstrated that expression of miR-146a/b and pro-inflammatory chemokines was increased in HBECs and mouse airways during RV infection. However, transfection with cell-penetrating peptide (CPP)-miR-146a nanocomplexes before infection with RV significantly reduced the expression of the pro-inflammatory chemokines CCL5, IL-8 and CXCL1, increased interferon-λ production, and attenuated infection with the green fluorescent protein (GFP)-expressing RV-A16 in HBECs. Concordantly, compared to wild-type (wt) mice, Mir146a/b-/- mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV-A1b infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)-induced allergic airway inflammation and RV-induced exacerbation models. Interestingly, intranasal administration of CPP-miR-146a nanocomplexes reduced HDM-induced allergic airway inflammation without a significant effect on the Th2/Th1/Th17 balance in wild-type mice. In conclusion, the overexpression of miR-146a has a strong anti-inflammatory effect on RV infection in HBECs and a mouse model of allergic airway inflammation, while a lack of miR-146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway inflammation and RV-induced exacerbation of allergic airway inflammation. Furthermore, our data indicate that the application of CPP-miR-146a nanocomplexes has therapeutic potential for targeting airway inflammation.

Remodeling of bronchial epithelium caused by asthmatic inflammation affects its response to rhinovirus infection.

Human rhinoviruses (HRV) are frequent cause of asthma exacerbations, however the influence of airway inflammation on the severity of viral infection is poorly understood. Here, we investigated how cytokine-induced remodeling of airway epithelium modulates antiviral response. We analyzed gene expression response in in vitro differentiated bronchial epithelium exposed to cytokines and next infected with HRV16. IL-13-induced mucous cell metaplasia (MCM) was associated with impaired ciliogenesis and induction of antiviral genes, resulting in lower susceptibility to HRV. Epithelial-mesenchymal transition caused by TGF-ß was associated with increased virus replication and boosted innate response. Moreover, HRV infection per se caused transient upregulation of MCM markers and growth factors, followed by low-level virus replication and shedding. Our data suggest that the outcome of HRV infection depends on the type of lower airway inflammation and the extent of epithelial damage. Type-2 inflammation (eosinophilic asthma) may induce antiviral state of epithelium and decrease virus sensitivity, while growth factor exposure during epithelial repair may facilitate virus replication and inflammatory response. Additionally, responses to HRV were similar in cells obtained from asthma patients and control subjects, which implicates that antiviral mechanisms are not intrinsically impaired in asthma, but may develop in the presence of uncontrolled airway inflammation.

Responsiveness of human bronchial fibroblasts and epithelial cells from asthmatic and non-asthmatic donors to the transforming growth factor-ß1 in epithelial-mesenchymal trophic unit model.

BACKGROUND: The asthma-related airway wall remodeling is associated i.a. with a damage of bronchial epithelium and subepithelial fibrosis. Functional interactions between human bronchial epithelial cells and human bronchial fibroblasts are known as the epithelial-mesenchymal trophic unit (EMTU) and are necessary for a proper functioning of lung tissue. However, a high concentration of the transforming growth factor-ß1 (TGF-ß1) in the asthmatic bronchi drives the structural disintegrity of epithelium with the epithelial-to-mesenchymal transition (EMT) of the bronchial epithelial cells, and of subepithelial fibrosis with the fibroblast-to-myofibroblast transition (FMT) of the bronchial fibroblasts. Since previous reports indicate different intrinsic properties of the human bronchial epithelial cells and human bronchial fibroblasts which affect their EMT/FMT potential beetween cells derived from asthmatic and non-asthmatic patients, cultured separatelly in vitro, we were interested to see whether corresponding effects could be obtained in a co-culture of the bronchial epithelial cells and bronchial fibroblasts. In this study, we investigate the effects of the TGF-ß1 on the EMT markers of the bronchial epithelial cells cultured in the air-liquid-interface and effectiveness of FMT in the bronchial fibroblast populations in the EMTU models. RESULTS: Our results show that the asthmatic co-cultures are more sensitive to the TGF-ß1 than the non-asthmatic ones, which is associated with a higher potential of the asthmatic bronchial cells for a profibrotic response, analogously to be observed in '2D' cultures. They also indicate a noticeable impact of human bronchial epithelial cells on the TGF-ß1-induced FMT, stronger in the asthmatic bronchial fibroblast populations in comparison to the non-asthmatic ones. Moreover, our results suggest the protective effects of fibroblasts on the structure of the TGF-ß1-exposed mucociliary differentiated bronchial epithelial cells and their EMT potential. CONCLUSIONS: Our data are the first to demonstrate a protective effect of the human bronchial fibroblasts on the properties of the human bronchial epithelial cells, which suggests that intrinsic properties of not only epithelium but also subepithelial fibroblasts affect a proper condition and function of the EMTU in both normal and asthmatic individuals.

The influence of self-assessment of asthma control on the Asthma Control Test outcome.

OBJECTIVE: The Asthma Control Test (ACT) consists of five items, one of which is self-assessment of asthma control. The goal of this study was to compare the responses to the first four ACT items with the response to the fifth item and determine whether this response affects the final ACT score. METHODS: Adult asthmatics (n = 417) were recruited from a specialty asthma center in Poland. Clinical data were collected by questionnaire. Spirometry and skin prick tests were performed for clinical evaluation. Asthma control was assessed through the ACT. The cutoff point for uncontrolled asthma was <20 points. RESULTS: Asthma was uncontrolled in 42.5% of patients. Based upon scores of the first four ACT items, three clusters of patients were identified. Cluster 1 comprised very well-controlled asthmatics [mean (sd) ACT total score 24.7 (0.7)]. Cluster 2 included both controlled and uncontrolled asthmatics [ACT total score 20.1 (2.5)]. Cluster 3 comprised poorly controlled asthmatics [ACT total score 12.1 (2.9)]. Misjudgment of asthma control in the fifth ACT item had no impact on the ACT total score in clusters 1 and 3. In cluster 2, the response to this item caused misclassification in 10.2% of patients. CONCLUSIONS: In patients with either very well or very poorly controlled asthma, the response to the fifth ACT item did not alter the assignment into the appropriate asthma control group. Only in a small group of patients with a total ACT score of approximately 20 points did the asthma group classification result in either controlled or uncontrolled.

The comparison between pulmonary rehabilitation with music therapy and pulmonary rehabilitation alone on respiratory drive, cortisol level and asthma control in patients hospitalized with asthma exacerbation.

INTRODUCTION: Much emphasis is being placed on the role of music therapy as an easy-to-use, noninvasive and relatively cheap method of asthma treatment. The objective of this interventional double-blinded randomized controlled trial was to assess whether music therapy, as a complementary modality to pulmonary rehabilitation, can help to improve respiratory drive, asthma control and quality of life in patients with asthma exacerbation. METHODS: Hospitalized patients with asthma exacerbation enrolled in the study were randomly assigned to experimental (music therapy) or control (popular science program) group. Both groups during hospitalization received standard pharmacotherapy accompanied by respiratory physiotherapy. Respiratory drive, asthma control, quality of life and serum cortisol in all participants were assessed at the beginning and at the end of their hospitalizations. RESULTS: The experimental group consisted of 39 asthmatics and 34 subjects with asthma were assigned to the control group. During the hospitalization, the levels of the inspiratory occlusion pressure for the first 0.1 s of inspiration (P0.1) decreased (p = 0.004) and the maximum P0.1 increased (p = 0.041) only in the experimental group. The serum cortisol level decreased in both groups (p = 0.001). The changes in asthma control and quality of life did not reach significant levels in either subject group. CONCLUSION: Passive music therapy and its effects on the mental state of patients seem to improve the efficiency of the respiratory system. The results of this experimental study demonstrate that a complementary music therapy has beneficial effects on the treatment of asthma exacerbations in adults.

Heterogeneity of lower airway inflammation in patients with NSAID-exacerbated respiratory disease.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) asthma is characterized by chronic rhinosinusitis and intolerance of aspirin and other COX1 inhibitors. Clinical data point to a heterogeneity within the N-ERD phenotype. OBJECTIVE: Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD. METHODS: Levels of cytokines (determined by using Luminex assay) and eicosanoids (determined by using mass spectrometry) were measured in bronchoalveolar lavage fluid (BALF) from patients with N-ERD (n = 22), patients with NSAID-tolerant asthma (n = 21), and control subjects (n = 11). mRNA expression in BALF cells was quantified by using TaqMan low-density arrays. RESULTS: Lower airway eosinophilia was more frequent in N-ERD (54.5%) than in NSAID-tolerant asthma (9.5% [P = .009]). The type-2 (T2) immune signature of BALF cells was more pronounced in the eosinophilic subphenotype of N-ERD. Similarly, BALF concentrations of periostin and CCL26 were significantly increased in eosinophilic N-ERD and correlated with T2 signature in BALF cells. Multiparameter analysis of BALF mediators of all patients with asthma revealed the presence of 2 immune endotypes: T2-like (with an elevated level of periostin in BALF) and non-T2/proinflammatory (with higher levels of matrix metalloproteinases and inflammatory cytokines). Patients with N-ERD were classified mostly as having the T2 endotype (68%). Changes in eicosanoid profile (eg, increased leukotriene E4 level) were limited to patients with N-ERD with airway eosinophilia. Blood eosinophilia appeared to be a useful predictor of airway T2 signature (area under the curve [AUC] = 0.83); however, surrogate biomarkers had moderate performance in distinguishing eosinophilic N-ERD (for blood eosinophils, AUC = 0.72; for periostin, AUC = 0.75). CONCLUSIONS: Lower airway immune profiles show considerable heterogeneity of N-ERD, with skewing toward T2 response and eosinophilic inflammation. Increased production of leukotriene E4 was restricted to a subgroup of patients with eosinophilia in the lower airway.

Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-ß/Smad2/3 pathway intensification and antifibrotic TGF-ß/Smad1/5/(8)9 pathway impairment.

Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-ß1-induced fibroblast-to-myofibroblast transition (FMT), a key event in subepithelial fibrosis. As commonly used anti-asthmatic drugs do not reverse the structural changes of the airways, and the molecular mechanism of enhanced asthma-related TGF-ß1-induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-ß/Smad2/3 and the antifibrotic TGF-ß/Smad1/5/9 signalling pathways and its role in the myofibroblast formation of HBF populations derived from asthmatic and non-asthmatic donors. Our findings showed for the first time that TGF-ß-induced activation of the profibrotic Smad2/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1/5/(8)9 pathway by TGF-ß1 was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-ß/Smad1/5/(8)9 pathway in HBFs derived from asthmatic donors was correlated with enhanced FMT. Furthermore, we showed that Smad1 silencing in HBFs from non-asthmatic donors increased the FMT potential in these cells. Additionally, we demonstrated that activation of antifibrotic Smad signalling via BMP7 or isoliquiritigenin [a small-molecule activator of the TGF-ß/Smad1/5/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., α-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-ß/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma.

Spirometry during the SARS-CoV-2 pandemic. Guidelines and practical advice from the expert panel of Respiratory Physiopathology Assembly of Polish Respiratory Society.

At the end of 2019, in Wuhan, the Hubei Province's capital city in China, the first cases of COVID-19 disease caused by the novel coronavirus, SARS-CoV-2, were described. The rapid spread of the infection through the world resulted in the World Health Organization announcing the COVID-19 a global pandemic in March 2020. The main routes of transmission of the novel coronavirus SARS-CoV-2, according to current evidence, are via droplets inhalation, direct contact with contaminated surfaces, and transmission via the mucous membranes of the mouth, nose, and eyes, and probably through airborne particles from the respiratory tract, generated during coughing and sneezing of infected individuals. During the pulmonary function testing (PFTs), which require strenuous breathing maneuvers and generate high-intensity airflow, aerosols, and micro-aerosols are formed from respiratory secretions and may contain viral and bacterial particles. Therefore, such forced respiratory maneuvers pose a significant risk of spreading the infection to patients and laboratory staff. According to current knowledge, the source of infection may also be an asymptomatic and a pre-symptomatic individual. Coronavirus SARS-CoV-2 has been increasingly prevalent in the community, and this increases a potential risk to all patients tested lung function and staff working there. As the patients' and staff's safety is of unprecedented importance, the additional precautions when performing pulmonary function tests are necessary and unquestionable. In consequence, the greater availability of consumables and personal protective equipment is indispensable. The reorganization of daily practice will prolong test time, reduce the number of tests performed, and slow down patients' flow. The guidance provides practical advice to health care professionals on performing pulmonary function tests during the COVID-19 pandemic. It has been developed basing on currently available information and recommendations from relevant health care institutions. As the COVID-19 pandemic is a rapidly evolving situation and the new scientific data has been becoming are available, the guidance will be updated over time.

Reduced expression of miR-146a in human bronchial epithelial cells alters neutrophil migration.

BACKGROUND: The role of miRNAs in the pathogenesis and determining the phenotypes of asthma is not fully elucidated. miR-146a has been previously shown to suppress inflammatory responses in different cells. In this study, we investigated the functions of miR-146a in human bronchial epithelial cells (HBECs) in association with neutrophilic, eosinophilic, and paucigranulocytic phenotypes of asthma. METHODS: Bronchial brushing specimens and brochial mucosal biopsy samples were collected from adult patients with asthma and from age- and gender-matched non-asthmatic individuals. The expression of miR-146a in bronchial brushing specimens, bronchial biopsy tissue sections or cultured primary bronchial epithelial cells was analyzed by RT-qPCR or by in situ hybridization. The expression of direct and indirect miR-146a target genes was determined by RT-qPCR or ELISA. The migration of neutrophils was studied by neutrophil chemotaxis assay and flow cytometry. For statistical analysis, unpaired two-way Student's t test, one-way ANOVA or linear regression analysis were used. RESULTS: Reduced expression of miR-146a was found in bronchial brushing specimens from asthma patients as compared to non-asthmatics and irrespective of the phenotype of asthma. In the same samples, the neutrophil attracting chemokines IL-8 and CXCL1 showed increased expression in patients with neutrophilic asthma and increased IL-33 expression was found in patients with eosinophilic asthma. Linear regression analysis revealed a significant negative association between the expression of miR-146a in bronchial brushings and neutrophil cell counts in bronchoalveolar lavage fluid of patients with asthma. In bronchial biopsy specimens, the level of miR-146a was highest in the epithelium as determined with in situ hybridization. In primary conventional HBEC culture, the expression of miR-146a was induced in response to the stimulation with IL-17A, TNF-α, and IL-4. The mRNA expression and secretion of IL-8 and CXCL1 was inhibited in both stimulated and unstimulated HBECs transfected with miR-146a mimics. Supernatants from HBECs transfected with miR-146a had reduced capability of supporting neutrophil migration in neutrophil chemotaxis assay. CONCLUSION: Our results suggest that decreased level of miR-146a in HBECs from patients with asthma may contribute to the development of neutrophilic phenotype of asthma.

The Comorbidity of Chronic Obstructive Pulmonary Disease and Peripheral Artery Disease - A Systematic Review.

The comorbidity of peripheral arterial disease (PAD) and chronic obstructive pulmonary disease (COPD) is obvious from a clinical point of view, especially as smoking is an important risk factor for both. Another factor connecting these two clinical conditions is chronic inflammation, which plays a crucial role in their pathophysiology. The aim of this study was to present the prevalence of COPD in patients with PAD, as well as the prevalence of PAD in COPD patients confirmed in all patients by two reliable methods: spirometry and ankle-brachial index (ABI), respectively. The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible publications from the previous 10 years. The published characteristics of different PAD and COPD populations were analyzed. A database search identified 894 records. Reliable criteria of both COPD and PAD diagnosis were used only in seven publications. The prevalence of PAD among patients with COPD ranged from 8.5 to 81.4%. The severity of the disease and the exclusion of nonsmokers or symptomatic patients from the analyses were important factors affecting this parameter. The prevalence of COPD in patients with PAD was measured reliably only in one study and assessed as 27.2%. The comorbidity of COPD and PAD is a relatively common occurrence. There are very few publications addressing this issue based on reliable diagnostic criteria, especially in the field of PAD. In the case of COPD and PAD patients, spirometry and ABI measurements are worth considering as noninvasive screening tests for COPD and PAD, respectively.

Heart Rate Variability in the Diagnostics and CPAP Treatment of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is the most common manifestation of sleep-related breathing disorders that are often accompanied by dysfunction of the autonomic nervous system. The main objective of the study was to assess the usefulness of heart rate variability (HRV) analysis in the diagnosis of patients with severe OSA and in the assessment of the effects of 3-month treatment with continuous positive airway pressure (CPAP). There were 54 patients enrolled in the study. The OSA group consisted of 39 patients suffering from severe OSA (apnea/hypopnea index >30/h), and the control group included 15 non-OSA patients with matched demographic characteristics and comorbidities. All patients underwent 24-h Holter electrocardiographic monitoring. HRV was analyzed using the time- and frequency-domains. We found that OSA patients had decreases in time-domains and increases in frequency-domains of HRV, compared to non-OSA controls, which strongly suggested a clinically disadvantageous shift in the balance of parasympathetic/sympathetic activity toward the latter. Further, CPAP treatment, partly, albeit significantly, reversed the OSA-induced changes in HRV. We conclude that HRV analysis may be of help in the diagnosis of OSA and in the monitoring of the effectiveness of treatment.

Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper.

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.

The utility of biomarkers in diagnosis of aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E4 (uLTE4) levels and blood eosinophilia can improve the prediction of AERD diagnosis. METHODS: Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE4 levels were measured in urine by HPLC and ELISA, respectively. RESULTS: Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE4 levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE4 and blood eosinophils were already taken into account (p = 0.57). CONCLUSION: UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.

Diagnostic Accuracy of Urinary LTE4 Measurement to Predict Aspirin-Exacerbated Respiratory Disease in Patients with Asthma.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are distinguished from patients with aspirin-tolerant asthma (ATA) by significantly higher baseline concentrations of urinary leukotriene E4 (uLTE4). However, an overlap between the individual values of the groups exists. OBJECTIVE: The objective of this study was to estimate the discriminative value of uLTE4 concentration in differentiating between patients with AERD and patients with ATA and evaluate the diagnostic accuracy of uLTE4 measurement alone and added to clinical parameters to predict AERD diagnosis in patients with asthma. METHODS: Clinical data were collected from questionnaires. Spirometry, skin prick tests, total IgE, and blood eosinophilia were evaluated. ULTE4 concentrations were measured in morning urine samples by enzyme-linked immune assay (ELISA). RESULTS: Patients with AERD (n = 247) had significantly higher uLTE4 concentrations than those with ATA (n = 239). The uLTE4 concentration of 800.0 pg/mg creatinine as measured by ELISA on a spot sample best discriminated the 2 groups (area under the curve 0.7; 95% confidence interval 0.66-0.74, sensitivity 49%, specificity 81%). The positive predictive value and negative predictive value (NPV), after considering the prevalence of AERD in the population of asthmatics, were 16% and 96%, respectively. Nasal polyps, upper airway symptoms, nasal corticosteroid treatment, asthma exacerbations, forced expiratory volume in the 1 second predicted, and age of asthma onset were independent predictors of AERD diagnosis. The addition of elevated uLTE4 concentration to the set of clinical parameters enhanced slightly the prediction of AERD diagnosis beyond the level predicted by clinical parameters (P = .036). CONCLUSIONS: A set of typical clinical parameters has a superior accuracy in prediction of AERD diagnosis than the measurement of uLTE4 concentration alone. The addition of uLTE4 concentration to clinical parameters slightly enhances the prediction of AERD diagnosis, especially due to a high NPV.