Modeling of Inhalation Profiles Through Dry Powder Inhaler in Healthy Adults and Asthma Patients As a Prerequisite for Further In Vitro and In Silico Studies.

Background: The severity of airway obstruction may affect patient's ability to perform an effective drug inhalation from a dry powder inhaler (DPI). Also, an incorrect inhalation technique may negatively affect the efficacy of asthma treatment. The aims of the study were (1) to analyze and compare inhalation profiles recorded with the use of different inhalation techniques, and thus, (2) to establish model inhalation profiles representative for healthy subjects and subjects with mild and moderate-to-severe asthma. Methods: This study was performed in healthy volunteers, patients with mild and moderate-to-severe asthma. A modified flow-volume test to define two different expiratory levels (to residual volume and half-way to residual volume) was performed. Inspiratory flow parameters were extracted: peak inspiratory flow rate (PIFinh), time at which peak inspiratory flow rate occurs (tPIFinh), total inhalation time (T), and inhaled volume (V). Test of frequency for tPIFinh100% and tPIFinh50% by asthma severity was performed, to provide information about initial flow accelerations. The impact of two different expiratory levels preceding inhalation (with severity of asthma as a categorical factor) on inspiratory flow parameters was examined. Results: PIFinh was dependent upon asthma severity (p = 0.046). Type of exhalation before inhalation had no effect on PIFinh values. V value was significantly affected both by asthma severity (p = 0.024) and type of exhalation before inhalation (p < 0.0001). Mean T value was influenced by type of exhalation before inhalation (p = 0.0003), but not by asthma severity. Mean tPIFinh value was affected by the type of exhalation before inhalation only in healthy subjects (p = 0.01). Conclusions: Both asthma severity and type of exhalation before inhalation have little impact on the dynamics of inhalation through a DPI. An alternative form of equation describing inhalation profiles demonstrating a relationship between lung mechanics and dynamics of inspiratory profile has been proposed.

Blood eosinophils, FeNO and small airways dysfunction in predicting airway hyperresponsiveness in patients with asthma-like symptoms.

PURPOSE: In patients with suspected asthma and no airflow limitation in spirometry, methacholine challenge testing (MCT) for airway hyperresponsiveness (AHR) is an option of documenting variable airflow limitation. The goal of the study was to assess the ability of blood eosinophils, fractional concentration of exhaled nitric oxide (FeNO) and distal airways function to discriminate patients with AHR from those with normal airway responsiveness (AR). METHODS: We analyzed baseline data from 42 participants who underwent MCT because of asthma-like symptoms and no airflow limitation in spirometry. RESULTS: Eosinophil count was higher among participants with borderline AHR comparing to those with normal AR (340 cells/µL, IQR 285-995 vs. 125 cells/µL, IQR 75-180, post-hoc p = 0.041). FeNO and percent predicted of functional residual volume (FRC%pred) were higher in participants with moderate-marked AHR compared to those with normal AR (40 ppb, IQR 30.5-100.5 vs. 18 ppb, IQR 13-50, post-hoc p = 0.008; 140.1%±17.0% vs. 107.3%±20.7%, post-hoc p < 0.001, respectively). Percentage predicted of the maximal expiratory flow at 25% of the forced vital capacity (MEF25%pred) was lower in participants with mild AHR and borderline AHR compared to those with normal AR (72.9%±16.9% vs. 113.0%±36.8%, post-hoc p = 0.017; 73.3%±15.9% vs. 113.0%±36.8%, post-hoc p = 0.045; respectively). Level of AHR correlated with eosinophil count, FeNO, MEF25%pred, forced expiratory flow between 25% and 75% of vital capacity (FEF25-75%pred), FRC%pred and specific airway resistance (sRaw). CONCLUSIONS: Blood eosinophils, FeNO and small airways dysfunction markers are related to the level of AR to methacholine in patients with asthma-like symptoms and no airflow limitation in spirometry.

The improved clinical course of persistent tachypnea of infancy with inhaled bronchodilators and corticosteroids.

BACKGROUND: Persistent tachypnea of infancy (PTI) is the most common interstitial lung disease in young children. As no standardized therapeutic guidelines exist, different pharmaceuticals are used to treat PTI; inhaled corticosteroids (ICS) and bronchodilators being mostly used. This observation assessed the effectiveness of bronchodilators and ICS in children with PTI enrolled in the children's interstitial lung diseases (chILD)-EU Register. METHODS: Symptomatic children with PTI were observed according to a predetermined stepwise protocol including bronchodilators as the first choice treatment (6 weeks). In patients with incomplete response, additionally, ICS was given (12 weeks). Signs, symptoms, and pulmonary function were evaluated at three time points: at baseline, 6 (±1) weeks after initiation of bronchodilators, and 12 (±1) weeks after bronchodilators/ICS. RESULTS: Thirty-one children (median age: 44 months, interquartile range [IQR]: 15-67) were included. The therapy was associated with a significant reduction of tachypnea (53.3% of patients, p = 0.02), exercise intolerance (52.2% of patients, p < 0.001), chest retractions (43.8% of patients, p = 0.04), and crackles (29.2% of patients, p = 0.02). Also, a significant improvement in forced expiratory volume in 1 s (FEV1 ) (median z score: -2.21 vs. -0.47, p = 0.03), residual volume (RV) (median z score 5.28 vs. 1.07, p = 0.007), RV% total lung capacity (TLC) (median z score: 6.05 vs. 1.48, p = 0.01), sRaw (median z score: 6.6 vs. 4.64, p = 0.01), R5 (median z score: 1.27 vs. 0.31, p = 0.009), and R5-R20 (median: 0.58 vs. 0.26 kPa/(l/s), p = 0.002) was demonstrated. CONCLUSIONS: Inhaled bronchodilators and ICS may exert a positive effect on the severity of symptoms and pulmonary function test (PFT) in symptomatic children with PTI. However, a randomized control trial should be conducted to confirm their effectiveness.

Inhalation Profiles Through a Dry Powder Inhaler: Relation Between Inhalation Technique and Spirometric Measures.

Background: The understanding of the real flow profiles through a dry powder inhaler (DPI), generated by asthma patients, is a prerequisite for satisfactory drug delivery to the lungs. The aims of the study were to assess the relationship between spirometric measures and inhalation profiles through a low-resistance DPI, and to compare parameters of those profiles between optimal and suboptimal inhalation technique type. Methods: Both healthy adult volunteers and patients with asthma were included in the study. Spirometry was conducted along with modified flow-volume test to detect expiratory levels (maximum "100%" exhalation to residual volume [RV] and halfway "50%" to RV). These were the reference levels of the depth of exhalation for each patient to simulate the effect of incomplete exhalation. Individual inhalation profiles were recorded using spirometry in-house software as the volumetric airflow through the inhaler versus time. Inspiratory flow parameters were extracted: time to peak inspiratory flow through inhaler (PIFinh), time at which peak inspiratory flow occurs (tPIFinh), total inhalation time (T), and inhaled volume during maneuver (V). Results and Conclusions: There are significant relationships between spirometric indices and parameters of inhalation through a low-resistance, cyclohaler-type DPI (assessed by single-factor analysis of Spearman's rank correlation coefficient). Multiple regression models were constructed, predicting inspiratory flow parameters (including spirometric indices, demographic parameters, and inhaler's usage history as determinants). The exhalation halfway to RV before inhalation did not affect significantly PIFinh and tPIFinh (and, thus, initial flow dynamics) in asthma patients. T and V parameters were then significantly decreased, but seemed sufficient for successful DPI performance. Both exhalation to RV and incomplete exhalation halfway to RV preceding inhalation allow for effective usage of low-resistance DPI.

Methacholine Challenge Testing: Comparison of FEV1 and Airway Resistance Parameters.

BACKGROUND: A 20% reduction in the FEV1 is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV1 is effort dependent, and some patients are not able to perform acceptable and repeatable forced expiration maneuvers. The goal of the present study was to investigate the diagnostic value of airway resistance measurement by forced oscillation technique (FOT), body plethysmography, and interrupter technique compared with the traditionally accepted standard FEV1 measurement in evaluating the responsiveness to methacholine during MCT. METHODS: We included in the study adult subjects referred for MCT because of asthma-like symptoms and with normal baseline spirometry. We modified routine MCT protocol by adding the assessment of airway resistance to the measurement of FEV1 at each step of MCT. RESULTS: We observed, in the subjects with airway hyper-responsiveness versus those with normal airway responsiveness, a significantly greater percentage change in median (interquartile range) FOT resistance at 10 Hz (25.9% [13.7%-35.4%] vs 16% [15.7%-27.2%]), plethysmographic resistance (70.2% [39.5%-116.3%] vs 37.1% [23.9%-81.9%]), and mean ± SD conductance (-41.3 ± 15.4% vs -29.6 ± 15.9%); and a significantly greater change in mean ± SD FOT reactance at 10 Hz (-0.41 ± 0.48 cm H2O/L/s vs -0.09 ± 0.32 cm H2O/L/s) and at 15 Hz (-0.29 ± 0.2 cm H2O/L/s vs -0.1 ± 0.19 cm H2O/L/s). We also recorded significant differences in airway resistance parameters (FOT resistance at 10 Hz, FOT reactance at 15 Hz, plethysmographic airway resistance, and conductance indices as well as interrupter resistance) in FEV1 non-responders at the onset of respiratory symptoms during MCT compared with baseline. CONCLUSIONS: Measurements of airway resistance could possibly be used as an alternative method to spirometry in airway challenge. Significant changes in airway mechanics during MCT are detectable by airway resistance measurement in FEV1 non-responders with methacholine-induced asthma-like symptoms. (ClinicalTrials.gov registration NCT02343419.).

Lung ultrasound-a new diagnostic modality in persistent tachypnea of infancy.

Lung ultrasound (LUS) has been increasingly used in diagnosing and monitoring of various pulmonary diseases in children. The aim of the current study was to evaluate its usefulness in children with persistent tachypnea of infancy (PTI). This was a controlled, prospective, cross-sectional study that included children with PTI and healthy subjects. In patients with PTI, LUS was performed at baseline and then after 6 and 12 months of follow-up. Baseline results of LUS were compared to (a) baseline high-resolution computed tomography (HRCT) images, (b) LUS examinations in control group, and (c) follow-up LUS examinations. Twenty children with PTI were enrolled. B-lines were found in all children with PTI and in 11 (55%) control subjects (P < .001). The total number of B-lines, the maximal number of B lines in any intercostal space, the distance between B-lines, and pleural thickness were significantly increased in children with PTI compared to controls. An irregularity of the pleural line was found in all patients with PTI and in none of the healthy children. There were no significant changes in LUS findings in patients with PTI during the study period. The comparison of HRCT indices and LUS findings revealed significant correlations between the mean lung attenuation, skewness, kurtosis and fraction of interstitial pulmonary involvement, and the number of B-lines as well as the pleural line thickness. LUS seems to be a promising diagnostic tool in children with PTI. Its inclusion in the diagnostic work-up may enable to reduce the number of costly, hazardous, and ionizing radiation-based imaging procedures.

Methods of airway resistance assessment.

Airway resistance is the ratio of driving pressure to the rate of the airflow in the airways. The most frequent methods used to measure airway resistance are whole-body plethysmography, the interrupter technique and the forced oscillation technique. All these methods allow to measure resistance during respiration at the level close to tidal volume, they do not require forced breathing manoeuvres or deep breathing during measurement. The most popular method for measuring airway resistance is whole-body plethysmography. The results of plethysmography include among others the following parameters: airway resistance (Raw), airway conductance (Gaw), specific airway resistance (sRaw) and specific airway conductance (sGaw). The interrupter technique is based on the assumption that at the moment of airway occlusion, air pressure in the mouth is equal to the alveolar pressure . In the forced oscillation technique (FOT), airway resistance is calculated basing on the changes in pressure and flow caused by air vibration. The methods for measurement of airway resistance that are described in the present paper seem to be a useful alternative to the most common lung function test - spirometry. The target group in which these methods may be widely used are particularly the patients who are unable to perform spirometry.

Clinical characteristics of 323 children with parapneumonic pleural effusion and pleural empyema due to community acquired pneumonia.

BACKGROUND: An increasing incidence of parapneumonic effusion and pleural empyema (PPE/PE) in children has been found in several studies published in the last decades. The aim of the study was to evaluate the incidence, etiology, clinical features, treatment strategies and outcomes of PPE/PE in children treated in a referral pulmonary center in central Poland. MATERIAL AND METHODS: We performed a retrospective analysis of clinical, radiological and laboratory data of all children aged between 1 month and 18 years with PPE/PE due to community acquired pneumonia (CAP) between January 2002 and December 2013. RESULTS: One thousand nine hundred and thirty three children with CAP were hospitalized between 2002 and 2013. Parapneumonic effusion or PE was diagnosed in 323 children (16.7%). The proportion of children with CAP related PPE/PE increased from 5.4% in 2002 to 18.8% in 2013. Streptococcus pneumoniae was the most common causative microorganism, responsible for 66.7% cases of known etiology. All children were treated with antibiotics and in 22.6%, and 74.3% of the patients therapeutic thoracentesis, pleural drainage with or without intrapleural fibrinolysis was performed, respectively. Approximately 3% of patients required surgical intervention. CONCLUSIONS: A significant increase in the incidence of PPE/PE in children with CAP treated in our institution in the last twelve years was found. S. pneumoniae was the most common causative microorganism. Antibiotic therapy with chest drain insertion ± intrapleural fibrinolysis is an effective treatment of PPE/PE and surgical intervention is seldom necessary. With proper management, the overall prognosis in children with CAP related PPE/PE is good.

Lung ultrasound in the diagnosis and monitoring of community acquired pneumonia in children.

Lung ultrasound (LUS) is as an easily accessible, radiation-free imaging technique that might be used as a diagnostic tool in community-acquired pneumonia (CAP). The aim of the study was to evaluate the usefulness and accuracy of LUS in the diagnosis and monitoring of childhood CAP. One hundred six consecutive children aged between 1 and 213 (median 52.5) months referred to the hospital with suspicion of CAP were enrolled. All patients underwent LUS on the day of admission, followed by chest radiograph (CXR). Lung ultrasound was also performed in 25 children between 5th-7th and 31 children between 10th-14th day after admission. Radiographic signs of pneumonia were demonstrated in 76 children, while lung ultrasound revealed pulmonary abnormalities consistent with pneumonia in 71 children. LUS gave false negative results in 5 patients with parahilar pulmonary infiltrates demonstrated by CXR. Almost perfect overall agreement between LUS and CXR was found in terms of pneumonia diagnosis (Cohen kappa coefficient of 0.89). The diagnostic performance of LUS in demonstration of lung involvement was as follows: sensitivity of 93.4%, specificity of 100%, positive predictive value of 100%, negative predictive value of 85.7% and accuracy of 95.3%. Our study showed that LUS is a sensitive and highly specific diagnostic method in children with CAP. Therefore, LUS may be considered as the first imaging test in children with suspicion of CAP. A diagnostic algorithm of CAP which includes LUS should be validated in prospective studies. Lung ultrasound can also be used to follow-up resolution of pneumonic lesions.

Necrotizing Pneumonia and Its Complications in Children.

Necrotizing pneumonia (NP) is an emerging complication of community acquired pneumonia (CAP) in children. This study aimed at the evaluation of etiology, clinical features, treatment, and prognosis of NP. The institutional database of children with CAP treated between April 2008 and July 2013 was searched to identify children with NP. Then, data on the NP characteristics were retrospectively reviewed and analyzed. We found that NP constituted 32/882 (3.7%) of all CAPs. The median age of children with NP was 4 (range 1-10) years. The causative pathogens were identified in 12/32 children (37.5%) with Streptococcus pneumoniae being the most common (6/32). All but one patient developed complications: parapneumonic effusion (PPE), pleural empyema or bronchopleural fistula (BPF), which required prompt local treatment. The median duration of hospital stay and antibiotic treatment was 26 (IQR 21-30) and 28 (IQR 22.5-32.5) days, respectively. Despite severe course of the disease no deaths occurred. A follow-up visit after 6 months revealed that none of the patients presented with any signs and symptoms which could be related to earlier pneumonia. Chest radiographs showed complete or almost complete resolution of pulmonary and pleural lesions in all patients. We conclude that necrotizing pneumonia is a relatively rare but severe form of CAP that is almost always complicated by PPE/empyema and/or BPF. It can be successfully treated with antibiotics and pleural drainage without major surgical intervention.

Anxiety, its relation to symptoms severity and anxiety sensitivity in sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic systemic granulomatous disease of unknown etiology. Previous studies demonstrated that patients with sarcoidosis had high rates of depression and anxiety, and high magnitude of stressful life events. To date, however, studies have not examined the anxiety sensitivity in sarcoid patients and the relationship between psychopathology and symptom severity of sarcoidosis.The aims of this study were to evaluate prevalence of depression and anxiety in sarcoid patients, to assess their relationship with the disease symptom severity, and to investigate the relationship between sarcoidosis and anxiety sensitivity. METHODS: Thirty three sarcoid patients and thirty three control subjects completed the following:Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index-3. RESULTS: The prevalence of depression (29%) and anxiety (31%) was high among patients and comparable to results from other research groups. Anxiety was significantly correlated with symptom severity and was the main covariate of physical symptoms reported by sarcoid patients. Patients exhibited an increase of their total anxiety sensitivity index and had an increased number of physical concerns. CONCLUSIONS: These data confirmed earlier reports that anxiety and depression are common in patients with sarcoidosis and expanded on the previous results by showing that patients exhibited increased anxiety sensitivity and a fear of physical sensations. These results, together with the findings that anxiety was associated with sarcoidosis symptom severity, suggest that targeting anxiety and the physical health concerns may be important in the diagnosis and management of this disease.

S Fas in bronchoalveolar lavage fluid of patients with sarcoidosis in relation to cigarette smoking.

Sarcoidosis is a multiorgan granulomatous disease with frequent spontaneous remission. Apoptosis is postulated to participate in the granuloma resolution. Soluble Fas (sFas) is known to inhibit Fas-induced apoptosis. The aim of this study was to determine the sFas concentration in the BALf of ever smoking (S) and never smoking (NS) patients with sarcoidosis. We investigated 57 patients with confirmed SA: 36 NS and 21 S. The sFas concentration was measured by ELISA method. The sFas concentration was lower in the BALf of patients S group compared with NS (median values 68.3 vs. 96.1 pg/mL, p=0.07) and it was significantly lower in active smokers when compared with NS (62.9 vs. 96.1 pg/mL, p=0.03). There was a significant correlation between sFas concentration and proportion of lymphocytes and negative relation with macrophage proportion. Lower concentration of sFas in smoking SA patients may result in higher apoptosis rate of inflammatory cells and hereby promote resolution of granulomas.

Th1/Th2/Th17­related cytokines in the bronchoalveolar lavage fluid of patients with sarcoidosis: association with smoking.

INTRODUCTION: Sarcoidosis is a multiorgan granulomatous disease of unknown etiology. The predominance of Th1­related cytokines is observed in the bronchoalveolar fluid (BALF) in pulmonary sarcoidosis. Recently, Th17 cells have been postulated to be involved in the pathogenesis of sarcoidosis. Sarcoidosis is more prevalent in nonsmokers than in smokers. The exact effect of smoking on granulomatous inflammation in this disease remains unclear. OBJECTIVES: The aim of the study was to evaluate the Th1/Th2/Th17­related cytokine concentration in the BALF of patients with pulmonary sarcoidosis in relation to smoking status. PATIENTS AND METHODS: The study included 74 patients with confirmed pulmonary sarcoidosis. Data on smoking status were available for 61 patients (26 ever­smokers, 35 never­smokers; mean 11 ±9.1 pack-years in smokers). The concentrations of interleukin (IL) 17A (IL­17A), IL­10, IL­6, IL­4, and IL­2 as well as interferon γ (IFN­Î³) and tumor necrosis factor α (TNF­α) were measured in BALF supernatants using a flow cytometry method--the Cytometric Bead Array. RESULTS: The median concentration of IL­6, IFN­Î³, and IL­17A (2.19 pg/ml, 1.28 pg/ml, and 6.08 pg/ml, respectively) did not differ significantly between smokers and nonsmokers. TNF­α, IL­10, IL­4 and IL­2 levels were below the detection limit in most patients. We observed a significant correlation between IFN­Î³ concentration and the number of macrophages in BALF (r = 0.66, P <0.05) and between IL­17A and IL­6 levels (r = 0.94, P <0.05). CONCLUSIONS: We confirmed a significant role of IL­6, IFN­Î³, and IL-17A in the local inflammatory response in sarcoidosis. However, the interpretation of the limited number of cytokine measurements should be made with caution. Further studies are needed to explain the effect of smoking on the pathomechanism of inflammation in sarcoidosis.

[Sarcoidosis and tobacco smoking--clinical picture, diagnostic tests results and bronchoalveolar lavage fluid composition]. / Sarkoidoza a palenie tytoniu: obraz kliniczny, wyniki badan dodatkowych i sklad plynu z plukania oskrzelowo-pecherzykowego.

UNLABELLED: Sarcoidosis is a multiorgan granulomatous disease of unknown aetiology. Bronchoalveolar lavage (BAL) is approved in diagnostics of sarcoidosis. The aim of the study was to assess epidemiological data, demographic status, clinical picture of sarcoidosis patients and to correlate above-mentioned findings with smoking status. MATERIAL AND METHODS: The study included 101 patients hospitalized due to suspicion of pulmonary sarcoidosis. The results of clinical assessment and smoking status data were obtained by retrospective analysis of 78 confirmed sarcoidosis case records. RESULTS: Investigated group comprised 54 non-smokers (NS) and 24 smokers (S), including 9 (11.5%) active smokers (AS). Smokers were significantly younger than nonsmokers. Most of the smokers were males. The mean number of pack-years was 8.2. Respiratory symptoms occurred with similar frequency among non-smokers and smokers. The incidence of the Loefgren's syndrome was similar in S and NS . The pulmonary function tests results were comparable in both groups, however, the obstruction was more frequent among smokers. Composition of BAL fluid (BALf) differed significantly between S and NS. The total cell count was significantly higher among active smokers than among nonsmokers (29.3 +/- 19.2 x 10(6) vs 13.7 +/- 6.3 x 10(6)). Compared to non-smokers, smokers had higher number of macrophages and lower percentage of lymphocytes (11.3 +/- 11 x 10(6) vs 6.5 +/- 3.9 x 10(6), 29 +/- 19 vs 41 +/- 17%, respectively). CONCLUSIONS: A significantly lower proportion of smokers is observed among sarcoidosis patients than in general population. The influence of smoking on clinical picture and results of pulmonary function tests is not evident in sarcoidosis. However, tobacco smoking causes significant alteration in the composition of BALf, which should be taken into account in diagnostics of sarcoidosis.