Water Sorption and Structural Properties of Human Airway Mucus in Health and Muco-Obstructive Diseases.

Muco-obstructive diseases change airway mucus properties, impairing mucociliary transport and increasing the likelihood of infections. To investigate the sorption properties and nanostructures of mucus in health and disease, we investigated mucus samples from patients and cell cultures (cc) from healthy, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) airways. Atomic force microscopy (AFM) revealed mucin monomers with typical barbell structures, where the globule to spacer volume ratio was the highest for CF mucin. Accordingly, synchrotron small-angle X-ray scattering (SAXS) revealed more pronounced scattering from CF mucin globules and suggested shorter carbohydrate side chains in CF mucin and longer side chains in COPD mucin. Quartz crystal microbalance with dissipation (QCM-D) analysis presented water sorption isotherms of the three types of human airway mucus, where, at high relative humidity, COPD mucus had the highest water content compared to cc-CF and healthy airway mucus (HAM). The higher hydration of the COPD mucus is consistent with the observation of longer side chains of the COPD mucins. At low humidity, no dehydration-induced glass transition was observed in healthy and diseased mucus, suggesting mucus remained in a rubbery state. However, in dialyzed cc-HAM, a sorption-desorption hysteresis (typically observed in the glassy state) appeared, suggesting that small molecules present in mucus suppress the glass transition.

Reliability of respiratory event detection with continuous positive airway pressure in moderate to severe obstructive sleep apnea - comparison of polysomnography with a device-based analysis.

PURPOSE: Monitored polysomnography (PSG) is considered the gold standard technique to diagnose obstructive sleep apnea (OSA) and titrate continuous positive airway pressure (CPAP), the accepted primary treatment method. Currently, the American Academy of Sleep Medicine (AASM) considers automatic PAP therapy initiation at home comparable to laboratory titration and recommends telemonitoring-guided interventions. Advanced CPAP devices evaluate and report the residual apnea-hypopnea index (AHI). However, in order to control the effectiveness of the prescribed therapy outside of a PSG setting, the automatic event detection must provide reliable data. METHODS: A CPAP titration was performed in the sleep laboratory by PSG in patients with OSA. The residual event indices detected by the tested device (prismaLine, Loewenstein Medical Technology) were compared to the manually scored PSG indices. Results of the device (AHIFLOW) were compared according to the AASM scoring criteria 1A (AHI1A, hypopneas with a flow signal reduction of ≥ 30% with ≥ 3% oxygen reduction and/or an arousal) and 1B (AHI1B, hypopneas with a flow signal decrease by ≥ 30% with a ≥ 4% oxygen desaturation). RESULTS: In 50 patients with OSA, the mean PSG AHI1A was 10.5 ± 13.8/h and the PSG AHI1B was 7.4 ± 12.6/h compared to a mean device AHIFlow of 8.4 ± 10.0/h. The correlation coefficient regarding PSG AHI1A and AHIFlow was 0.968. The correlation regarding central hypopneas on the other hand was 0.153. There were few central events to be compared in this patient group. CONCLUSION: The device-based analysis showed a high correlation in the determination of residual obstructive AHI under therapy. The recorded residual respiratory event indices in combination with the data about leakage and adherence of the studied device provide reliable information for the implementation and follow-up of CPAP therapy in a typical group of patients with OSA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04407949, May 29, 2020, retrospectively registered.

Effects of endobronchial coils for endoscopic lung volume reduction on sleep in COPD patients with advanced pulmonary emphysema.

PURPOSE: Treatment of advanced pulmonary emphysema with endobronchial coils can improve clinical outcomes like quality of life (QOL). Yet, patients with chronic obstructive pulmonary disease (COPD) are also known to suffer from reduced sleep quality. The effect of coil therapy on sleep has not yet been investigated. The primary aim of this study was to investigate sleep efficiency before and after coil treatment. Secondly, we investigated the effects on nocturnal breathing pattern, QOL, and physical activity. METHODS: Polysomnography (PSG) testing was performed before (T0), 6 month after (T3), and 12 months after (T4) treatment with endobronchial coils. Further examinations included QOL by St George's Respiratory Questionnaire (SGRQ) and COPD assessment test (CAT), and physical activity using an accelerometer for 1 week after each visit. RESULTS: Of 21 patients, 14 completed the study: 6 women; mean age 58.0 ± 4.9 years; BMI 22.6 ± 4.6 kg/m2; FEV1 28.6 ± 7.1% predicted; residual volume (RV) 278.2 ± 49.4% predicted. Sleep efficiency did not vary between baseline and follow-up examinations (T0 69.0 ± 15.8%; T3 70.9 ± 16.0%; T4 66.8 ± 18.9%). Non-REM respiratory rate decreased compared to baseline (T0 19.4 ± 3.9/min; T3 17.8 ± 3.5/min; T4 17.1 ± 3.1/min (p = 0.041; p = 0.030) and QOL improved meeting the minimal clinically important difference (MCID) (SGRQ, T3 -12.8 units; T4 -7.1 units; CAT: T3 -5.6 units; T4 -3.4 units). No increase in physical activity was recorded (light activity T0 31.9 ± 9.9; T3 30.8 ± 16.9; T4 26.3 ± 10.6 h/week). CONCLUSIONS: Treatment with endobronchial coils did not influence objectively measured sleep quality or physical activity, but reduced nocturnal breathing frequency and improved QOL in severe emphysema patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02399514, First Posted: March 26, 2015.

[Digital Health in Respiratory Medicine - Current Status]. / Stand der digitalen Medizin in der Pneumologie.

Everyday life is increasingly influenced by digitization. Digitization creates large, often unstructured amounts of data ("big data"), which have been used in consumer industry for years, but yet not widely in medicine. For pulmonology, digitization offers opportunities and risks in different areas like obstructive lung diseases, thoracic oncology, pulmonary rehabilitation, sleep medicine, home mechanical ventilation, and in intensive care medicine. One of the opportunities is that the use of new technologies such as telemedicine and medical apps and the analysis of this new support make it possible to better understand and manage diseases. One of the key advantages is the use of "big data" for displaying dynamic behavior ("trajectories" = movement paths), to better understand disease processes, and to optimize patient management by using analytic techniques such as machine learning. Risks to be considered are data privacy and security as well as the use of artificial intelligence. The vision is to enable precision medicine in pulmonology.

A New Tool for Transbronchial Cryobiopsies in the Lung: An Experimental Feasibility ex vivo Study.

BACKGROUND: Transbronchial cryobiopsy (TBCB) is a minimally invasive procedure to establish a diagnosis of interstitial lung disease though with the disadvantage that samples have to be extracted together with the bronchoscope. OBJECTIVES: The aim of the present study was to evaluate the feasibility of a new cryoprobe with which biopsy samples can be obtained through the working channel of the flexible bronchoscope. METHODS: The feasibility of obtaining transbronchial specimens with TBCB was tested and the technique was compared to transbronchial forceps biopsy (TBFB) in a prospectively randomized ex vivo animal study using a standard flexible bronchoscopy technique. The rate of successful biopsies and the duration of the sampling procedure were recorded for both methods. Size and quality of the biopsies were histologically evaluated and measured. RESULTS: Biopsy samples could be obtained in 93.3% of TBCB and in 79.0% of TBFB procedures (p = 0.182). Sampling procedure time did not differ in any clinically relevant manner between the two methods. The mean specimen area of TBCB samples was significantly higher compared to that of TBFB samples (8.08 ± 5.80 vs. 2.61 ± 2.14 mm2; p < 0.0001). TBCB specimens showed less artifacts and a significantly higher percentage of alveolar tissue (53.57 vs. 25.42%; p = 0.0285) than TBFB specimens. CONCLUSIONS: It is feasible to retrieve TBCB samples of good quality and size with the new mini cryoprobe through the working channel of the bronchoscope, while the bronchoscope remains within the central airways throughout the whole procedure. Further studies are necessary to evaluate the safety and efficacy in an in vivo setting.

Transbronchial Catheter Aspiration and Transbronchial Needle Aspiration in the Diagnostic Workup of Peripheral Lung Lesions.

PURPOSE: Increasingly frequent, it is clinically indicated to obtain tissue from a peripheral lung lesion (PLL) to yield a pathological diagnosis. The aim of the present study was to evaluate the diagnostic sensitivity of transbronchial needle aspiration (TBNA) and transbronchial catheter aspiration (TBCA) in addition to transbronchial forceps biopsy (TBB) at conventional bronchoscopy. METHODS: Eligible patients showing a PLL on computed tomography scans were included in the study. In all patients, following TBB, TBNA and TBCA were employed in randomised order under fluoroscopy. RESULTS: Fourty-eight patients were enrolled, of whom 46 patients with 46 PLLs were included in the analysis. The mean ± SD diameter of the PLL was 27.0 ± 13.3 mm. The overall sensitivity for all modalities was 69.6%; PLL ≤20 or >20 and ≤30 mm in diameter showed a sensitivity of 60.0 and 72.2%, respectively. For malignant PLL (n = 33), the combined sensitivity of TBNA + TBCA versus TBB was significantly higher (63.6 vs. 33.3%, p ≤ 0.05), and could not further be improved by TBB. For benign PLL, TBB was superior to TBNA + TBCA (76.9 vs. 38.5%). CONCLUSIONS: TBB, TBNA and TBCA are complementary to one another. Combining the three techniques, even allows transbronchial specimen collection of PLL <3 cm in diameter at conventional bronchoscopy.

The cryo-needle: a new tool for histological biopsies. A feasibility study.

PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure for intrathoracic lymph node biopsies. The newly developed cryo-needle operates in a similar way to the EBUS-TBNA but is able to obtain specimens for histological evaluation. The purpose of this animal study was to evaluate the feasibility, effect, and safety of the cryo-needle biopsies. METHODS: Four EBUS-guided cryo-needle biopsies were obtained from a mediastinal lymph node of a healthy pig. In an open surgery approach, cryo-needle biopsies using activation times of 1, 2, and 3 s (A1/A2/A3) and needle biopsies using a 21-gauge EBUS-TBNA needle were obtained from mesenteric lymph nodes. Cryo-needle biopsies A2 were performed with (A2+) and without (A2-) an oversheath. The size, weight, percentage of lymphatic tissue and artefact-free area of each cryobiopsy were evaluated. Smears were made with the TBNA-needle aspirates to determine the number of lymphocytes per high-power field (HPF). The bleeding duration was measured. RESULTS: We successfully obtained EBUS-guided cryo-needle biopsies. The area and weight of the biopsies A3 and A2+ were significantly larger compared with A1 (1.7 ± 0.8 and 1.4 ± 0.3 vs. 0.9 ± 0.4 mm(2); 5.2 ± 2.4 and 3.4 ± 1.8 vs. 1.5 ± 0.7 mg). The percentage of lymphatic tissue of the cryobiopsies was 90 ± 25 and 98 % of samples were artefact-free. The number of lymphocytes/HPF of TBNA-needle smears was 128 ± 54.3. There was no difference in bleeding duration between the techniques. CONCLUSIONS: The cryo-needle yields large histological specimens of high quality.

Effects of nasal insufflation on arterial gas exchange and breathing pattern in patients with chronic obstructive pulmonary disease and hypercapnic respiratory failure.

High flow nasal insufflations (NI) can improve gas exchange and alleviate dyspnea in patients with acute respiratory failure. In the present study we investigated the effects of high flow nasal insufflations in COPD patients with chronic hypercapnic respiratory failure (HRF). Seventeen patients with severe COPD and HRF were recruited. We delivered a mixture of 20 L/min room air and 2 L/min O(2) through a nasal cannula either into both nostrils (NI) or into one nostril (Partial NI). Respiratory pattern and PaCO(2) responses under NI were compared with low flow oxygen of 2 L/min. High flow nasal insufflations led to a systematic reduction in respiratory rate from 19.8 ± 4.2 at baseline to 18.0 ± 4.7 during NI (p < 0.008) and 18.1 ± 5.2 breaths/min during Partial NI (P < 0.03). The mean group inspiratory duty cycle (T(I)/T(T)) and mean group PaCO(2) remained constant between all experimental conditions. Individual responses to NI were heterogeneous: six patients demonstrated marked reductions in respiratory rate (>20% fall from baseline), another group (n = 6) demonstrated no change in respiratory rate but marked reductions in arterial carbon dioxide of more than 8 mmHg. In conclusion, high flow (20 L/min) nasal insufflations of warm and humidified air during wakefulness for 45 min reduced respiratory rate without deterioration of hypercapnia. Our data indicate that high flow NI improved efficiency of breathing and may be used as an adjunct to low flow oxygen for preventing hypercapnic respiratory failure in severely ill COPD patients.

The contribution of endobronchial ultrasound-guided forceps biopsy in the diagnostic workup of unexplained mediastinal and hilar lymphadenopathy.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) provides material for the cytological diagnostic workup. To improve the evaluation of unexplained intrathoracic lymphadenopathy, the availability of material for histological evaluation would be desirable. For this purpose, the technique of endobronchial ultrasound-guided mediastinal forceps biopsy (EBUS-guided forceps biopsy) is a potentially good candidate. The aim of the present study was, using simple methodology, to establish the additional diagnostic yield provided by supplemental EBUS-guided forceps biopsy in comparison with EBUS-TBNA alone. METHODS: The data of 50 consecutive patients with mediastinal, lobar, and hilar space-consuming lesions were analyzed. In all patients, immediately following EBUS-TBNA with a 22-gauge needle, a 21-gauge forceps was introduced through the opening created in the bronchial wall and an EBUS-guided forceps biopsy performed. The improvement in the diagnostic yield was determined. The diagnostic yield of the EBUS-guided forceps biopsy in relation to the size of the biopsy specimen and that of the EBUS-TBNA in relation to the cell-block technique were determined. RESULTS: Combining the techniques increased the diagnostic sensitivity of the EBUS-TBNA from 50.0 to 82.0%. EBUS-guided forceps biopsies measuring ≥ 3 mm enabled a specific diagnosis to be established more often than did forceps biopsies <3 mm (90.9% vs. 57.1%). A cell block was prepared in 29 patients. In this case, EBUS-TBNA provided a higher diagnostic yield (65.5% vs. 28.6%) compared to cytology alone. CONCLUSION: EBUS-guided forceps biopsy should be employed for the bronchoscopic diagnosis of intrathoracic lymphadenopathy of unknown etiology.

Removal of the tracheal tube after prolonged mechanical ventilation: assessment of risk by oscillatory impedance.

BACKGROUND: Decannulation failure is usually due to tracheal obstruction. Prior to decannulation, inspection by the invasive procedure of bronchoscopy that permits morphological evaluation of a tracheal stenosis is standard practice. A non-invasive method enabling the quantification of the airway obstruction that requires little cooperation is measurement of the airway resistance by the forced oscillation technique. OBJECTIVES: The aim of the present study was to define oscillatory impedance thresholds which predict successful decannulation. METHODS: A total of 131 patients were investigated prospectively. Step 1: Following probatory decannulation, measurement of the oscillatory impedance. Step 2: Blinded to the results of the impedance measurement, bronchoscopy-assisted decannulation attempt. The criteria for renewed cannulation were high-grade laryngeal or tracheal obstruction, dyspnea or stridor, or a drop in SaO(2) <90% under O(2) insufflation. STATISTICS: Determination of the ratio tracheal tube remains/tracheal tube removed (TT+/TT-) for every measured value of the oscillatory resistance at 5 Hz (Ros 5 Hz). Determination of specificity and positive predictive value for determined threshold values with respect to TT-. RESULTS: The data of 126 patients were evaluated. TT+ n = 26, TT- n = 100. Decannulation on the basis of bronchoscopy criteria: Specificity and positive predictive value found out for Ros 5 Hz <0.35 kPa/l/s (n = 44) were 1.00 and 1.00, respectively, and for Ros 5 Hz <0.47 kPa/l/s (n = 71) 0.88 and 0.96, respectively. CONCLUSIONS: Measurement of the oscillatory airway resistance represents a practicable method prior to decannulation. Below a value of Ros 5 Hz <0.35 kPa/l/s, bronchoscopy would appear not to be necessary.

Prospective controlled animal study on biopsy sampling with new flexible cryoprobes versus forceps: evaluation of biopsy size, histological quality and bleeding risk.

BACKGROUND: Cryoextraction is a procedure used for the recanalization of obstructed airways caused by visible exophytic endobronchial tumor. Biopsy samples obtained by this technique have been shown to be useful for histological assessment. OBJECTIVES: The aim of the present animal study was to systematically evaluate biopsy size, histological quality and bleeding risk after cryobiopsy with new, flexible cryoprobes in comparison with forceps biopsy, serving as the gold standard. METHODS: Biopsies were obtained from anesthetized pigs with the flexible bronchoscopy technique, and evaluated histologically with respect to their size and quality. Bleeding frequency, bleeding duration and histological changes in the biopsy bed were also recorded. RESULTS: Cryobiopsies were significantly larger than forceps biopsies. The size of cryobiopsies was dependent on the freezing time. The histological quality of the cryobiopsy specimenswas not impaired by the freezing process, whereas forceps biopsies showed typical crush artifacts. Despite the larger defects left in the tracheobronchial system after cryobiopsy, bleeding frequency and duration were not higher compared to forceps biopsy. CONCLUSIONS: Since cryobiopsy sampling is not associated with a higher bleeding risk compared with forceps biopsy, this new biopsy technique offers--in addition to a good specimen quality--a safe and valuable tool with the potential of improving the outcome of diagnostic endoscopy.

Experimental study on biopsy sampling using new flexible cryoprobes: influence of activation time, probe size, tissue consistency, and contact pressure of the probe on the size of the biopsy specimen.

Cryoextraction is a procedure for recanalization of obstructed airways caused by exophytic growing tumors. Biopsy samples obtained with this method can be used for histological diagnosis. The objective of this study was to evaluate the parameters influencing the size of cryobiopsies in an in vitro animal model. New flexible cryoprobes with different diameters were used to extract biopsies from lung tissue. These biopsies were compared with forceps biopsy (gold standard) in terms of the biopsy size. Tissue dependency of the biopsy size was analyzed by comparing biopsies taken from the lung, the liver, and gastric mucosa. The effect of contact pressure exerted by the tip of the cryoprobe on the tissue was analyzed on liver tissue separately. Biopsy size was estimated by measuring the weight and the diameter. Weight and diameter of cryobiopsies correlated positively with longer activation times and larger diameters of the cryoprobe. The weight of the biopsies was tissue dependent: lung < liver < stomach. Only little tissue dependency was found for the biopsy diameter. The biopsy size increased when the probe was pressed on the tissue during cooling. Cryobiopsies can be taken from different tissue types with flexible cryoprobes. The size of the samples depends on tissue type, probe diameter, application time, and pressure exerted by the probe on the tissue. Even the cryoprobe with the smallest diameter can provide larger biopsies than a forceps biopsy in lung. It can be expected that the same parameters influence the sample size of biopsies in vivo.

Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (Removab) (anti-EpCAM x Anti-CD3): results of a phase 1/2 study.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.