Organization, Clinical and Management Indicators on the First Year of Activity of an Outpatient Clinic Dedicated to the Diagnosis and Treatment of Severe Asthma in Italy.

PURPOSE: A Regional Technical Commission was set in 2017 by Veneto region (Italy) to provide opinions and recommendations on drug prescriptions and to implement treatment-pathway guidelines for severe asthma. In this observational study, we describe the first structured, integrated, multidisciplinary, patient-centered outpatient clinic for the care of severe-asthma patients in Italy, and characterize patients referring to the center for specialist visits. PATIENTS AND METHODS: To characterize patients that accessed the outpatient clinic in 2018, data on demographic characteristics, treatments, severity of asthma, phenotypes, and relevant comorbidities by phenotype were collected. Use of biologic agents and indicators of the performance of the outpatient clinic were described. RESULTS: A structured multidisciplinary outpatient pathway for taking charge of patients and for administration and monitoring of biological agents was developed. A total of 146 patients accessed the outpatient clinic in 2018: 62.3% had uncontrolled asthma upon admission and 27.4% were already being treated with biologic agents. Among patients with uncontrolled asthma, 66% had severe uncontrolled asthma, 22% had moderate-severe uncontrolled asthma, and 12% had mild-moderate uncontrolled asthma. Main asthma phenotypes in uncontrolled-asthma patients were allergic (58% of patients), eosinophilic (22%), allergic plus eosinophilic (10%) and non-atopic asthma (10%). Among patients affected by severe asthma, 47% had allergic asthma, 28% had eosinophilic asthma, 13% had allergic plus eosinophilic asthma, and 12% had non-atopic asthma. Nasal polyps were more frequent in eosinophilic and allergic plus eosinophilic asthma, while gastro-esophageal reflux disease was more frequent in non-atopic asthma. CONCLUSION: This structure of an outpatient clinic for the treatment of severe asthma, with its dedicated pathway and multidisciplinary approach, may allow a stricter control of asthma and optimization of therapies, as well as minimization of drug misuse.

Competence in bronchial thermoplasty.

Bronchial thermoplasty (BT) is an innovative non-pharmacological endoscopic treatment for patients with severe persistent asthma based on controlled heat release with a device called Alair™ Catheter (Boston Scientific, Natick, MA, USA). The Alair™ system is the first device that works by delivering radiofrequency or thermal energy to selectively reduce the amount of airway smooth muscle (ASM) in bronchi. Literature showed significant improvement in clinical outcomes such as symptom control, severe exacerbation rate, hospitalization, quality of life, and number of working or school days lost for asthma. Besides smooth muscle effects changes in inflammatory pattern after BT have been documented. Bronchial thermoplasty requires an experienced physician who had a proficiency training in bronchoscopy and had rigor, dexterity and a thorough knowledge of the airway anatomy. Furthermore, right selection of severe asthma patient is crucial in order to have best response after BT. This article reviews BT device description and how to perform the procedure. Criteria for right selection and management of patient before and after BT will be discussed.

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.

Chronic obstructive pulmonary disease with mild airflow limitation: current knowledge and proposal for future research - a consensus document from six scientific societies.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, with high and growing prevalence. Its underdiagnosis and hence under-treatment is a general feature across all countries. This is particularly true for the mild or early stages of the disease, when symptoms do not yet interfere with daily living activities and both patients and doctors are likely to underestimate the presence of the disease. A diagnosis of COPD requires spirometry in subjects with a history of exposure to known risk factors and symptoms. Postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7 or less than the lower limit of normal confirms the presence of airflow limitation, the severity of which can be measured by FEV1% predicted: stage 1 defines COPD with mild airflow limitation, which means postbronchodilator FEV1 ≥80% predicted. In recent years, an elegant series of studies has shown that "exclusive reliance on spirometry, in patients with mild airflow limitation, may result in underestimation of clinically important physiologic impairment". In fact, exercise tolerance, diffusing capacity, and gas exchange can be impaired in subjects at a mild stage of airflow limitation. Furthermore, growing evidence indicates that smokers without overt abnormal spirometry have respiratory symptoms and undergo therapy. This is an essential issue in COPD. In fact, on one hand, airflow limitation, even mild, can unduly limit the patient's physical activity, with deleterious consequences on quality of life and even survival; on the other hand, particularly in younger subjects, mild airflow limitation might coincide with the early stage of the disease. Therefore, we thought that it was worthwhile to analyze further and discuss this stage of "mild COPD". To this end, representatives of scientific societies from five European countries have met and developed this document to stimulate the attention of the scientific community on COPD with "mild" airflow limitation. The aim of this document is to highlight some key features of this important concept and help the practicing physician to understand better what is behind "mild" COPD. Future research should address two major issues: first, whether mild airflow limitation represents an early stage of COPD and what the mechanisms underlying the evolution to more severe stages of the disease are; and second, not far removed from the first, whether regular treatment should be considered for COPD patients with mild airflow limitation, either to prevent progression of the disease or to encourage and improve physical activity or both.

Noninvasive proportional assist ventilation and pressure support ventilation during arm elevation in patients with chronic respiratory failure. A preliminary, physiologic study.

BACKGROUND: It has been shown that upper limbs activity increases the respiratory workload in patients with chronic respiratory failure (CRF). The object of the present study was to investigate whether, in these patients: (i) noninvasive positive pressure ventilation (NPPV) could sustain the inspiratory muscles to meet the greater ventilatory demand during upper limbs activity with the arm elevation test (AE); (ii) proportional assist ventilation (PAV) might be superior to pressure support ventilation (PSV) during AE, because of its potential more adaptable response to sudden changes in the ventilatory pattern. METHODS: The study was performed in the pulmonary function laboratory of the Pulmonary Division in Verona General Hospital, Verona, Italy. We studied 8 male patients with CRF due to chronic obstructive pulmonary disease (COPD). Each patient received 2 treatment in random order with a crossover design: spontaneous breathing (SB), SB with AE, either PSV or PAV without and with AE, SB without and with AE, either PSV or PAV without and with AE. We measured: lung function tests, lung mechanics, ventilatory pattern and diaphragmatic effort (pressure time product, PTP(di)). RESULTS: (i) AE increases minute ventilation (+14%) and PTP(di) (+64%); (ii) ventilatory support, both with PSV and PAV unloads the diaphragm both at rest (PTP(di) -77% and -54%, respectively) and during arm elevation (PTP(di) -54% and -44%, respectively). CONCLUSIONS: PAV and PSV unloads the diaphragm in patients with CRF due to COPD both during SB and AE; PAV can be more efficient than PSV in assisting the diaphragm during AE in producing a greater level of minute ventilation for a similar rise in PTP(di) compared to PSV. Noninvasive ventilatory support should be considered in rehabilitation programs for training of upper limbs activity.

Chest physiotherapy with positive airway pressure: a pilot study of short-term effects on sputum clearance in patients with cystic fibrosis and severe airway obstruction.

BACKGROUND: The periodic administration of positive airway pressure combined with directed cough could aid mucus clearance in patients with cystic fibrosis (CF) and severe airway obstruction. OBJECTIVE: To compare the short-term effect of positive expiratory pressure (PEP) physiotherapy via mask (mask PEP), continuous positive airway pressure (CPAP), and noninvasive positive-pressure ventilation (NPPV) physiotherapies on amount of sputum collected. METHODS: Directed cough was standardized for each patient and used as the control treatment. We studied 17 patients with CF (mean +/- SD age 28 +/- 7 y) and severe airway obstruction (forced expiratory volume in the first second 25 +/- 6% of predicted) admitted for pulmonary exacerbation. Mask PEP, CPAP, NPPV, and the control treatment (directed cough) were administered in a random sequence. Each patient received each treatment twice a day (in 70-min sessions) for 2 consecutive days. We measured the wet and dry weight of sputum collected and the number of directed and spontaneous coughs during each session. Spirometry and pulse oximetry were conducted before and after each session. For mask PEP, CPAP, and NPPV, each patient gave a subjective score for the efficacy and tolerability of the treatment, compared to the control treatment. RESULTS: There was no statistically significant difference in the dry weight of sputum collected: mask PEP 0.9 +/- 0.6 g, CPAP 0.8 +/- 0.4 g, NPPV 0.9 +/- 0.6 g, control treatment 1.0 +/- 0.8 g. There was a statistically significant difference in the wet weight of sputum collected: mask PEP 15.8 +/- 5.5 g, CPAP 13.7 +/- 5.5 g, NPPV 13.2 +/- 5.0 g, control treatment 14.0 +/- 5.0 g (p < 0.05), but that difference became nonsignificant when we took into account the number of spontaneous coughs. There were no statistically significant changes in the spirometry and pulse-oximetry values. The patients' subjective efficacy scores were similar for mask PEP, CPAP, and NPPV. Less fatigue was reported after NPPV and CPAP than after mask PEP. CONCLUSIONS: There were no differences in sputum clearance or pulmonary-function measures between mask PEP and short-term administration of either CPAP or NPPV combined with directed cough. After mask PEP these patients felt more tired than after CPAP or NPPV secretion-clearance therapy.

Indacaterol: a comprehensive review.

At present there is no cure for chronic obstructive pulmonary disease (COPD). However, some nonpharmacologic treatments, such as rehabilitation and lung volume reduction surgery, as well as pharmacologic intervention, can relieve some of the patient's symptoms and improve quality of life, while also reducing the rate of exacerbations and hospitalizations. There needs to be a paradigm shift away from the unjustified nihilistic approach to COPD towards considering it a preventable and treatable disease. After patients quit smoking and start to lead healthier lifestyles, long-acting bronchodilators, such as long-acting beta-adrenergic agents (LABA) and long-acting antimuscarinic agents (LAMA), are recommended as the cornerstone of treatment for COPD, either as monotherapy or in combination. COPD is characterized by a reduced maximum expiratory flow and slow forced emptying of the lungs, which progress over time and are not completely reversible. In this condition, gas gets trapped in the lungs and pulmonary hyperinflation occurs. LABA and LAMA improve airway patency and deflate the lungs. Indacaterol is the first once-daily LABA approved for treatment of COPD, and is administered by inhalation through the Breezhaler® device. The speed of bronchodilation is similar to that with salbutamol (ie, about five minutes) and longer (ie, 24 hours) than that with traditional LABA, with the same 12-hour effect as salmeterol and formoterol, both of which require twice-daily administration. This is why indacaterol has been called the "ultra-LABA". On the one hand, the fast onset of action provides immediate relief of symptoms, and on the other, its constant 24-hour bronchodilation provides "pharmacologic stenting" which facilitates lung emptying, thereby decreasing trapped gas and pulmonary hyperinflation. Once-daily administration of a fast and long-acting bronchodilator can improve patient adherence with therapy, which is known to be a major problem for many medical treatments. Dose-finding trials have shown that 75 µg is the minimum dose needed to achieve clinically important improvement. However, indacaterol 150 µg and 300 µg achieve an even greater improvement in lung function and patient-oriented outcomes. Further, these two doses of indacaterol significantly reduce pulmonary hyperinflation, thereby improving exercise tolerance and ability to perform day-to-day activities. It is more effective on lung volumes at the 300 µg dose than formoterol, and better than salmeterol and tiotropium at the 150 µg dose, at least in the acute setting. It is noteworthy that few studies document these results in patients with COPD and moderate airflow obstruction. These are exactly the kind of patients our research should be concentrating on, in view of the accelerated decay in forced expiratory volume in one second at this stage of the disease. Finally, all the relevant studies show that indacaterol is consistently well tolerated by patients with COPD at every stage, and that it has a high safety profile.

Assessment of asthma control: the SERENA study.

BACKGROUND: Several studies suggest that many asthmatic subjects have uncontrolled asthma. The control of asthma is now considered the major goal of therapy. OBJECTIVES: to ascertain the level of asthma control, by Asthma Control Test (ACT), in "real-life" clinical practice and the potential risk factors for uncontrolled disease in patients treated with inhaled corticosteroids (ICS) and long-acting beta-adrenergic agonists (LABA). METHODS: SERENA is a multi-centre, cross-sectional, 6-month observational, non-interventional study carried out in 16 Pulmonary Units in Italy. Asthmatic outpatients aged over 18, undergoing treatment with ICS at medium-high daily doses associated with LABA, were enrolled. The patients were divided in 3 subgroups according to the level of asthma control by ACT score (25:controlled; 20-24:partly controlled; <20: uncontrolled). RESULTS: Out of a total of 548 patients, 396 met the inclusion criteria. Only 9.1% of patients had asthma controlled, while partly controlled and uncontrolled asthma accounted for 39.6% and 51.3% respectively. The mean age was 54.5 ± 15.8 and the mean duration of asthma was 16.1 ± 14.1 years. There were more females than males (63% vs 37%) and females had highest prevalence of uncontrolled asthma (63.1%). The mean values of FEV1% predicted were lower in the uncontrolled group (p < 0.001). The percentage of patients with at least 1 exacerbation, unscheduled visit and/or admissions was lower in controlled (22.2%, 8.3%, 8.3%) than in partly controlled (50%, 38.6%, 9.2%) and uncontrolled (83.2%, 66.2%, 27.8%) groups (p < 0.0001). The multivariate ordinal logistic regression analysis identified female sex, FEV1 and exacerbations as the strongest independent factors associated with the uncontrolled disease. CONCLUSION: This study highlights the importance in clinical practice of a periodic assessment by a validated asthma control instrument and exacerbations/health care contacts during previous year. Clinicians should be aware that a significant proportion of patients can have uncontrolled asthma, despite regular pharmacological treatment.

Neurally adjusted ventilatory assist: a new approach to mechanically ventilated infants.

Neurally adjusted ventilator assist (NAVA) is a new mode of partial ventilatory support, in which neural inspiratory activity is monitored through the continuous esophageal recording of the electrical activity of the diaphragm. Assistance is triggered and cycled off in according to this signal and is delivered in proportion to its intensity. NAVA can improve patient-ventilator synchrony while maintaining spontaneous breathing. Small preliminary studies have shown that NAVA can be successfully used also in term and preterm infants, being safe and well tolerated. However, much additional work is still needed before NAVA can be recommended in the everyday practice of the neonatologist.

On-line monitoring of lung mechanics during spontaneous breathing: a physiological study.

BACKGROUND: Monitoring the mechanics of breathing in patients with advanced chronic obstructive lung diseases prior to lung transplantation is useful to characterize changes in the mechanical properties of the lungs. On-line methods of monitoring immediately process the data for clinical decisions. However, the few available methods are so far limited to monitor respiratory mechanics in ventilator-dependent patients. We investigated whether on-line monitoring of the lung mechanics, including intrinsic PEEP, was feasible in spontaneously breathing patients. METHODS: In 9 stable patients with chronic obstructive pulmonary disease (COPD) and 11 with cystic fibrosis (CF) undergoing the procedure for the lung transplantation waiting list, we applied 2 methods of on-line monitoring (modified recursive least squares, RLS and modified multiple linear regression methods, SLS) of intrinsic PEEP (P(0)), dynamic lung elastance (E(Ldyn)) and inspiratory resistance (R(Linsp)), and compared them with an off-line graphical analysis (GA), our reference technique. RESULTS: In CF patients, there was no difference between methods, while in COPD, the median values of E(Ldyn) and R(Linsp) were significantly different between GA/SLS and GA/RLS, respectively (Dunn's, p<0.05). However, the correlation was very high for all comparisons, particularly for E(Ldyn) (R>0.98) and R(Linsp) (R>0.93). Moreover, Bland-Altman plots showed that the mean differences were consistently low and the intervals of agreement reasonable. CONCLUSIONS: Our study suggests that on-line methods are reliable for monitoring lung mechanics in spontaneous breathing patients with severe lung diseases and could help clinicians in their decision-making process.

A comparison between inhaled salmeterol and theophylline in the short-term treatment of stable chronic obstructive pulmonary disease.

BACKGROUND: International guidelines indicate that the long-acting bronchodilators play a key role in the treatment of patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the short term efficacy and safety of 50 and 100 microg bid inhaled salmeterol, compared with placebo and orally dose titrated slow-release theophylline in patients with stable COPD. METHODS: Thirteen patients (67+/-7 years, three females) with moderate-to-severe COPD (FEV1<70% predicted and >30% predicted) and with poor reversibility (post-bronchodilator FEV1<12% and <200 ml from pre-bronchodilator values) completed this single centre randomised, double-blind, double-dummy, four-phase cross-over clinical trial. Patients were randomised to treatment after a 2-week oral corticosteroid trial and a theophylline titration phase. Each treatment lasted 2 week with a 2-week washout period. Values at the end of treatments were compared. RESULTS: Inhaled salmeterol at both tested doses was better than placebo in improving lung function (FEV1, FVC, and morning PEF) of stable patients with moderate COPD over a period of 2 weeks. Although slight (about 170 ml, 150 ml, and 120 ml/min on average, for FEV1, FVC, and PEF, respectively) the improvement was significant. The effects seem to improve only slightly with the higher dose. Salmeterol appeared to be more effective than theophylline treatment when compared to placebo, as theophylline improved significantly, but less, the FEV1 (about 80 ml, on average) without affecting any of the other lung function variables. Salmeterol 100 microg was significantly better than theophylline in improving morning PEF. Four patients reported five adverse events while receiving placebo and 2 and 3 patients reported 2 and 3 adverse events, respectively, during salmeterol 50 microg and salmeterol 100 microg phases. None was considered drug related. Five patients experienced 13 adverse events with theophylline treatment, four of which were considered drug related. CONCLUSION: Inhaled salmeterol improves lung function in stable patients with moderate-to-severe and poorly reversible COPD. The magnitude of improvement in FEV1 observed in this study is similar to that found in longer and larger studies on similar populations of patients. In those studies, that improvement was associated with a better quality of life and less symptoms. Theophylline determined a smaller improvement in FEV1 with more unpleasant side effects that both doses of inhaled salmeterol, though there was no significant difference. It is concluded that salmeterol is an effective and well tolerated therapy, potentially preferable to theophylline, at least in the short-term management of stable COPD.