Bronchial Thermoplasty Global Registry (BTGR): 2-year results.

OBJECTIVES: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. DESIGN: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. SETTING: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. RESULTS: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). CONCLUSIONS: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. TRIAL REGISTRATION NUMBER: NCT02104856.

Hyperimmune plasma infusion in an immunocompromised Covid-19 patient previously treated for follicular lymphoma.

Covid-19 in immunocompromised patients shows a prolonged course and may lead to a poor prognosis. Although data on hyperimmune plasma for treatment of Covid-19 suggest an improved outcome in immunocompetent patients, limited data are currently available in immunocompromised patients. We present the case of a 62-year-old Caucasian woman, who was previously treated with obinutuzumab and bendamustine for follicular lymphoma and showed a prolonged positive test for Covid-19. Since no improvement was observed with standard of care (including remdesivir), the possibility of hyperimmune plasma infusion was discussed. A first dose of hyperimmune plasma was administered, with subsequent onset of fever, increasing inflammatory indexes and worsening radiological findings. Three days later a second dose of plasma was administered. Within twelve hours cough and fever disappeared, and oxygen at rest was discontinued. The patient was discharged 5 days later, and nasopharyngeal swabs resulted negative 16 days after discharge.

Competence in bronchoscopic treatments in emphysema.

Bronchoscopic lung volume reduction (BLVR) has been proven to be effective in patients with severe emphysema. These techniques are divided into two groups: non-blocking devices that are independent of collateral ventilation and blocking devices that are dependent on collateral ventilation so the choice of the target lobe with inadequate scissors is crucial for the success of the treatment. Current evidences suggest that not all classes and phenotypes of emphysema will benefit from BLVR, and that each technique appears to provide a greater benefit to specific sub-groups of patients. Careful patient selection is imperative to prevent insertion in patients unlikely to gain clinical benefits as well as wasteful expenditure. The Chartis system represents the gold standard for measuring fissure integrity and is a direct measurement method. Indirect method is instead the TC study which, thanks to the development of software for quantitative analysis, allows us to obtain reliable measurements of regional density of parenchyma, airway thickness and scissor integrity. BLVR is a highly complex procedure: a first-level competence is a pre-requisite for admission to training. The practical training must be based on discussion of clinical cases and the insertion techniques of the different devices on plastic or animal models, or on cadavers. A specific course, offering final certification, has been developed on the use of Zephyr valves.

Complications related to endoscopic lung volume reduction for emphysema with endobronchial valves: results of a multicenter study.

BACKGROUND: Despite bronchoscopic lung volume reduction (BLVR) with valves is a minimally invasive treatment for emphysema, it can associate with some complications. We aimed at evaluating the rate and type of complications related to valve treatment and their impact on clinical outcomes. METHODS: It is a retrospective multicenter study including all consecutive patients with severe heterogeneous emphysema undergoing BLVR with endobronchial valve treatment and developed any complications related to this procedure. The type of complication, the time of onset, the treatment required and the out-come were evaluated. Response to treatment was assessed according to the minimal clinically important difference (MCID) as follows: an improvement of ≥15% in forced expiratory volume in one second (FEV1); of -8% in residual volume (RV); of ≥26 m in 6-minnute walking distance (6MWD); and of ≥4 points on the St. George's Respiratory Questionnaire (SGRQ). Target lobe volume reduction (TLVR) ≥350 mL was considered significant. RESULTS: One hundred and seven out of 423 (25.3%) treated patients had complications related to valve treatment including pneumothorax (17.3%); pneumonia (1.7%), chronic obstructive pulmonary disease (COPD) exacerbation (0.9%), respiratory failure (1.4%), valve migration (2.1%), and hemoptysis (1.9%). In all cases complications resolved with appropriate treatment including removal of valves in 21/107 cases (19.6%). Patients with TLVR ≥350 mL (n=64) vs. those <350 mL (n=43) had a statistically significant higher improvement in FEV1 (19.0%±3.9% vs. 3.0%±0.9%; P=0.0003); in RV (-10.0%±4.8% vs. -4.0%±2.9%; P=0.002); in 6MWD (33.0±19.0 vs. 12.0±6.3 metres; P=0.001); and in SGRQ (-15.0±2.9 vs. -8.0±3.5 points; P=0.01). Only patients with TLVR ≥350 mL met or exceeded the MCID cut-off criteria for FEV1 (19.0%±3.9%), RV (-10.0%±4.8%), 6MWT (33.0±19.0 metres), and SGQR (-15.0±2.9 points). Five patients (1.2%) died during follow-up for causes not related to valves treatment neither to any of the complications described. CONCLUSIONS: Valve treatment is a safe and reversible procedure. The presence of complications seems not to have a significant impact on clinical outcome in patients with lobar atelectasis. Due to poor clinical conditions and possible complications, BLVR should be performed in high volume centers with a multidisciplinary approach.

Additive effect on pulmonary function and disability of intensive pulmonary rehabilitation following bronchoscopy lung volume reduction (BLVR) for severe emphysema.

BACKGROUND: Pulmonary rehabilitation (PR) is mandatory before bronchoscopy lung volume reduction (BLVR); there is scant information about its efficacy post-BLVR. We retrospectively evaluated pulmonary function (PF) and disability in patients pre/post-BLVR and its additive effect on an intensive PR program post-BLVR vs matched non-BLVR controls. We analyzed changes within BLVR patients according to presence or not of atelectasis. METHODS: We compared PF and exercise tolerance (6-min walk test, 6MWT) in 39 BLVR patients (FEV1% pred. 28.9 ±â€¯1.5; RV% pred. 236.1 ±â€¯7.7) pre-/post-BLVR, and vs. 32 controls (FEV1% pred. 32.7 ±â€¯1.5; RV % pred. 217.8 ±â€¯8.3) before and after PR. RESULTS: BLVR patients showed a greater improvement than controls in PF (difference between groups: 3.8 for FEV1% pred., p = 0.043; -20.5 for RV % pred., p = 0.02) and 6MWT response rate (12/39 vs. 1/39 subjects, p = 0.003). Both groups further improved significantly 6MWT after PR without a significant difference between groups. Atelectasis after BLVR mainly accounted for the improvement in FEV1% pred, RV% pred. and 6MWT compared to both BLVR without atelectasis and controls. CONCLUSION: BLVR improves PF (particularly RV) and exercise tolerance, patients with lobar exclusion being the best improvers. PR following BLVR yields a further improvement in exercise tolerance in both (atelectasis and non-atelectasis) subgroups.

Mechanical consequences of allergic induced remodeling on mice airway resistance and compressibility.

The effect of remodeling on airway function is uncertain. It may affect airway compressibility during forced expirations differently than airflow resistance, providing a tool for its assessment. The aim of the current study was to compare the effects of acute and chronic antigen challenge on methacholine-induced bronchoconstriction assessed from resistance and maximal tidal expiratory flow. Balb/C mice were sensitized with ovalbumin (OVA) and challenged either daily for three days with intra-nasal OVA or daily for 5 days and three times a week for 5 subsequent weeks. Acute and chronic allergen challenge induced airway hyperresponsiveness (AHR) to methacholine. However the relationship between maximal tidal expiratory flow and resistance during methacholine challenge was different between the two conditions, suggesting that the determinants of AHR are not identical following acute and chronic allergen exposure. We conclude that the contrast of changes in maximal tidal expiratory flow and respiratory resistance during methacholine-induced bronchoconstriction may allow the detection of the mechanical consequences of airway remodeling.

Nanotubes connect CD4+ T cells to airway smooth muscle cells: novel mechanism of T cell survival.

Contact between airway smooth muscle (ASM) cells and activated CD4(+) T cells, a key interaction in diseases such as asthma, triggers ASM cell proliferation and enhances T cell survival. We hypothesized that direct contact between ASM and CD4(+) T cells facilitated the transfer of anti-apoptotic proteins via nanotubes, resulting in increased survival of activated CD4(+) T cells. CD4(+) T cells, isolated from PBMCs of healthy subjects, when activated and cocultured with ASM cells for 24 h, formed nanotubes that were visualized by immunofluorescence and atomic force microscopy. Cell-to-cell transfer of the fluorescent dye calcein-AM confirmed cytoplasmic communication via nanotubes. Immunoreactive B cell lymphoma 2 (Bcl-2) and induced myeloid leukemia cell differentiation protein (Mcl-1), two major anti-apoptotic proteins, were present within the nanotubes. Downregulation of Mcl-1 by small interfering RNA in ASM cells significantly increased T cell apoptosis, whereas downregulation of Bcl-2 had no effect. Transfer of GFP-tagged Mcl-1 from ASM cells to CD4(+) T cells via the nanotubes confirmed directionality of transfer. In conclusion, activated T cells communicate with ASM cells via nanotube formation. Direct transfer of Mcl-1 from ASM to CD(+) T cells via nanotubes is involved in T cell survival. This study provides a novel mechanism of survival of CD4(+) T cells that is dependent on interaction with a structural cell.

Effects of CPAP on systemic hypertension in OSAH: a monocentric, observational, cohort study.

BACKGROUND: Obstructive sleep apnea-hypopnea (OSAH) is a risk factor for development of systemic arterial hypertension (SAH) and can worse the control of established SAH. We investigated the effects of long-term continuous positive airway pressure (CPAP) treatment in controlling and preventing SAH in a large cohort of subjects referred for sleep study for suspected OSAH. METHODS: In 495 subjects of whom 422 with OSAH and 73 without OSAH, the clinical history was obtained, arterial blood pressure was measured and the current anti-hypertensive drugs was recorded at diagnosis and/or at CPAP start. Subjects were interviewed after a follow-up period of (mean ± SD) 3.4 ± 2.2 yr (range 1-8 yr) and divided in patients with moderate-to-severe OSAH (n = 125) who referred to use CPAP regularly for at least 4 h every night (group 1), with moderate-to-severe OSAH (n = 70) who refused or abandoned the CPAP treatment after few weeks (group 2), with mild OSAH (n = 227) with no CPAP indication (group 3) and simple snorers or normals (n = 73) (group 4). For each group clinical status, BMI, and changes in SAH therapy and occurrence of SAH were assessed at the follow-up. RESULTS: At the follow-up, a higher risk of increasing treatment for SAH was found for group 2 and group 3 versus group 1 (OR = 5, 95%CI 1-20, p < 0.01 and OR = 3, 95%CI 1-10, p < 0.05), respectively. The occurrence of SAH was lower (p < 0.001) in the group 1 (1.9%), vs group 2 (35.9%), 3 (21.1%) and 4 (18.6%). CONCLUSIONS: In moderate-to-severe OSAH patients, long-term CPAP treatment significantly reduces the development of SAH and, in those with SAH at baseline, the need of anti-hypertensive drugs.

Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells.

Asthma is a chronic inflammatory disease that is associated with airway remodeling, including hyperplasia of airway epithelial cells and airway smooth muscle cells, and goblet cell differentiation. We wished to address the potential role of histamine, a key biogenic amine involved in allergic reactions, in airway remodeling through the epidermal growth factor receptor (EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands, amphiregulin and heparin-binding epidermal growth factor-like growth factor (HB-EGF), from airway epithelial cells. Amphiregulin and HB-EGF were expressed in airway epithelium of patients with asthma. Histamine up-regulated their mRNA expression (amphiregulin 3.2-fold, P<0.001; HB-EGF 2.3-fold, P<0.05) and triggered their release (amphiregulin EC(50) 0.50 µM, 31.2 ± 2.7 pg/ml with 10 µM histamine, P<0.01; HB-EGF EC(50) 0.54 µM, 78.5 ± 1.8 pg/ml with 10 µM histamine, P<0.001) compared to vehicle control (amphiregulin 19.3 ± 0.9 pg/ml; HB-EGF 60.2 ± 1.0 pg/ml), in airway epithelial cells. Histamine increased EGFR phosphorylation (2.1-fold by Western blot analysis) and induced goblet cell differentiation (CLCA1 up-regulation by real-time qPCR) in normal human bronchial epithelial (NHBE) cells. Moreover, amphiregulin and HB-EGF caused proliferation and migration of both NHBE cells and human airway smooth muscle cells. These results suggest that histamine may induce airway remodeling via the epithelial-derived EGFR ligands amphiregulin and HB-EGF.

Influence of upper airway size on volume exhaled under negative pressure during evaluation of upper airway collapsibility.

STUDY OBJECTIVES: It has been shown that volume exhaled in the first 0.5 s after application at the mouth of 5 cmH(2)O negative pressure (V,NEP(0.5)) during wakefulness strongly reflects critical pressure (Pcrit) during sleep but only in males with neck circumference (NC) >37 cm. The aim of this study was to establish the relationship between upper airway (UA) size and V,NEP(0.5), to obtain V,NEP(0.5) values as percent predicted and then correlate them with Pcrit obtained in the same subjects. PATIENTS AND MEASUREMENTS: In 20 (8 women) normal subjects (age, 39 ± 16 years; BMI, 22.5 ± 3.0 kg/m(2); AHI, 0.8 ± 1.0), NC, mean pharyngeal cross-sectional area (APmean) by acoustic pharyngometry and V,NEP(0.5) in the supine position were measured. Correlations between APmean, NC and V,NEP(0.5) were performed. A strong relationship was found between APmean and NC, and the predicted V,NEP(0.5) values were obtained using the equation derived from the relationship between V,NEP0.5 and NC. Subsequently, nine normal subjects (age, 26.3 ± 2.5 yrs, BMI 23.9 ± 3.2 kg/m(2), AHI 2.3 ± 0.5), ten snorers (age, 68 ± 11 years; BMI, 26.6 ± 4.6 kg/m(2); AHI, 3.5 ± 0.8) and ten OSAH patients (age, 64 ± 9 years; BMI, 32 ± 4.9 kg/m(2); AHI, 43.8 ± 24.4) underwent measurement of V,NEP(0.5) in the supine position while awake and Pcrit during sleep. Correlations between Pcrit and both V,NEP(0.5) and V,NEP(0.5) expressed as percent predicted were performed in all subjects. RESULTS: Controls had V,NEP(0.5) of 387 ± 103 mL (100.1 ± 13% predicted) and Pcrit of -3.7 ± 2.0 cmH(2)O, snorers had V,NEP(0.5) of 320 ± 33 mL (62 ± 12% predicted) and Pcrit of -0.6 ± 0.3 cmH(2)O while OSAH patients had V,NEP(0.5) of 295 ± 67 mL (48 ± 12% predicted) and Pcrit of 1.0 ± 1.0 cmH(2)O. The linear regression analysis showed a close and highly significant correlation between V,NEP(0.5) percent predicted and Pcrit (r (2) = 0.79, p < 0.001). CONCLUSIONS: V,NEP(0.5) expressed as percent predicted according to NC strongly reflects Pcrit in a wide range of values and can be used as a surrogate of Pcrit to assess UA collapsibility independently from UA size and sex.

Effect of training on airways inflammatory response and remodeling in a rat model.

Training has many beneficial effects, however few studies report its effects on the lungs. The aim of this study was to assess the effects of acute exercise and exercise training on inflammatory responses and remodeling in central and peripheral airways. Sixteen Sprague-Dawley rats trained for 10 weeks, while 14 rats served as controls. Before sacrifice, 8 trained (TR(AC)) and 8 untrained control (CON(AC)) rats underwent a single acute exercise bout, while 8 trained (TR) and 6 untrained control (CON) rats were sacrificed without acute exercise. The central and peripheral airways were morphologically examined for inflammatory cells and immunostained for decorin, collagen I, α-smooth muscle actin. No significant differences were found for morphometric analysis in central and peripheral airways, however CON(AC) showed a significant increase in polymorphonuclear cells in the central airways compared to CON. In contrast, TR(AC) did not show an inflammatory response different from TR. A similar trend was present in peripheral airways. Training did not induce differences in airways inflammation and remodeling as compared to CON. However, training seemed to limit the inflammatory response induced by acute exercise in the central airways.

Predictors of nocturnal oxyhemoglobin desaturation in COPD.

It would be useful to detect predictors of marked nocturnal oxyhemoglobin desaturation (NOD) among COPD patients, who do not have respiratory failure when awake and sleep apnea (SA). Stable COPD patients with awake Pa(O2) ≥ 60 mmHg and Pa(CO2) ≤ 45 mmHg underwent cardio-respiratory polysomnography to exclude SA and to assess NOD. The patients that spent more than 30% of night time with Sp(O2) < 90%, were defined desaturators (D), and the others non desaturators (ND). Pulmonary function testing was performed to determine lung volumes, maximal flow rates, lung diffusion capacity for carbon monoxide and maximal inspiratory and expiratory pressure (P(Imax) and P(Emax)). Negative expiratory pressure test was performed to assess tidal expiratory flow limitation. Supine pharyngometry was performed to determine upper airway size, shuttle walking test to assess exercise desaturation. Twenty-one patients were included in the study (18 male, age 66.0±7.2 years, Body Mass Index 25.9±4.4 kg/m(2), FEV(1) 47.2±16.4% pred., Pa(O2) 74.7±6.9 mmHg, Pa(CO2) 40.3±3.4 mmHg): 10 were D and 11 ND. Significant differences between the two groups were found in diurnal Pa(CO2) (D: 42.4±3.0 vs. ND: 38.3±2.6mmHg; p<0.01), diurnal Sp(O2) (D: 94.0±1.5 vs. ND: 95.9±0.9%; p<0.01), inspiratory capacity (IC) (D: 69.6±11.9 vs. ND: 87.0±17.7% pred.; p<0.05), and oro-pharyngeal junction area (OPJ) (D: 0.8±0.2 vs. ND: 1.2±0.3 cm(2); p<0.01). Among parameters related to marked NOD at the univariate analysis, [Formula: see text] and OPJ remained as independent predictors after stepwise multiple regression analysis. These findings indicate that previously unrecognized factors such as smaller upper airway caliber and lung dynamic hyperinflation are associated with marked NOD in stable COPD patients without daytime respiratory failure and SA.

Small animals models for drug discovery.

There has been an explosion of studies of animal models of asthma in the past 20 years. The elucidation of fundamental immunological mechanisms underlying the development of allergy and the complex cytokine and chemokines networks underlying the responses have been substantially unraveled. Translation of findings to human asthma have been slow and hindered by the varied phenotypes that human asthma represents. New areas for expansion of modeling include virally mediated airway inflammation, oxidant stress, and the interactions of stimuli triggering innate immune and adaptive immune responses.

Effects on small airway obstruction of long-term treatments with beclomethasone/formoterol hydrofluoroalkane (metered-dose inhaler) versus fluticasone/salmeterol (dry-powder inhaler) in asthma: a preliminary study.

New formulations of extrafine particles of long-acting beta-2 agonists plus inhaled corticosteroids (LABA + ICS) have been shown to reach peripheral regions of the lung. The aim of the study was to assess the effect on small airway obstruction of long-term treatments with two different LABA + ICS formulations in asthma. Ten subjects with moderate persistent asthma were enrolled. After a 4-week washout period they were treated in a randomized crossover design for 24 weeks with formoterol, 12 micrograms, and beclomethasone, 200 micrograms, hydrofluoroalkane (HFA; by metered-dose inhaler) b.i.d. (FB) or salmeterol, 50 micrograms, and fluticasone, 250 micrograms (by dry-powder inhaler), b.i.d. (SF). At baseline and at the end of each period subjects underwent an Asthma Control Test (ACT) and Pulmonary Function Testing. The N(2) phase III slope and closing volume (CV) during single-breath washout test and difference between the maximal expiratory flow rates with air and heliox at isovolume corresponding to 50% [Delta(heliox-air)MEF(50%)] were measured to assess changes on peripheral airways function. Two subjects dropped out and eight completed the study. After SF and FB, forced expiratory volume at 1 second (FEV(1); p < 0.01) and FEV(1)/forced vital capacity (FVC; p < 0.01 for SF and p < 0.05 for FB) increased when compared with baseline. Although both FB and SF treatments slightly increased delta(heliox-air)MEF(50% isovolume) versus baseline, only after FB the N(2) phase III slope and CV decreased from 1.61 ± 0.61%/L to 1.35 ± 0.49 N(2)%/L (p = 0.054) and from 0.98 ± 0.56 L to 0.88 ± 0.58 L (p < 0.05), respectively. ACT score raised from 19 ± 5 (baseline) to 23 ± 1 after FB (p < 0.02) and 23 ± 2 after SF (p < 0.05). When compared with baseline and in contrast to SF (50/250 micrograms b.i.d.), FB HFA (12/200 micrograms b.i.d.) significantly improved functional parameters reflecting small airway obstruction in asthmatic patients. Registered in the public trial registry at www.ClinicalTrials.gov identifier: NCT01255579.