Long-term use of inhaled glucocorticoids in patients with stable chronic obstructive pulmonary disease and risk of bone fractures: a narrative review of the literature.

Patients with chronic obstructive pulmonary disease (COPD) demonstrate a greater osteoporosis prevalence than the general population. This osteoporosis risk may be enhanced by treatment with inhaled corticosteroids (ICSs), which are recommended for COPD management when combined with long-acting bronchodilators, but may also be associated with reduced bone mineral density (BMD). We conducted a narrative literature review reporting results of randomized controlled trials (RCTs) of an ICS versus placebo over a treatment period of at least 12 months, with the aim of providing further insight into the link between bone fractures and ICS therapy. As of 16 October 2017, we identified 17 RCTs for inclusion. The ICSs studied were budesonide (six studies), fluticasone propionate (five studies), mometasone furoate (three studies), beclomethasone dipropionate, triamcinolone acetonide, and fluticasone furoate (one each). We found no difference in the number of bone fractures among patients receiving ICSs versus placebo across the six identified RCTs reporting fracture data. BMD data were available for subsets of patients in few studies, and baseline BMD data were rare; where these data were given, they were reported for treatment groups without stratification for factors known to affect BMD. Risk factors for reduced BMD and fractures, such as smoking and physical activity, were also often not reported. Furthermore, a standardized definition of the term "fracture" was not employed across these studies. The exact relationship between long-term ICS use and bone fracture incidence in patients with stable COPD remains unclear in light of our review. We have, however, identified several limiting factors in existing studies that may form the basis of future RCTs designed specifically to explore this relationship.

Early management of COPD: where are we now and where do we go from here? A Delphi consensus project.

PURPOSE: There is a lack of consensus on the most appropriate early diagnostic strategy, criteria for early access to treatment and follow-up approach for patients with COPD. MATERIALS AND METHODS: A Delphi consensus project investigated the early management of COPD. We formulated two questionnaires for completion by pneumologists in Italy. RESULTS: A total of 207 specialists completed questionnaire 1 and 184 of them questionnaire 2, between November 2016 and October 2017. Early diagnosis of COPD was considered uncommon for 93.2% of the expert panel. Regardless of the definition of "early diagnosis" - a diagnosis made before the clinical manifestation of the disease for most responders (60.4%) - experts were confident of the positive effects of early disease management, which they consider is effective in modifying the natural history of the disease. Lack of awareness of the disease was considered the first limiting factor to early COPD management for 78% of respondents. The most effective steps to reduce functional decline were considered to be smoking cessation, followed by long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA), LAMA, LABA, and finally inhaled corticosteroid/LABA (P<0.01 for each paired comparison). Specialists considered it "inappropriate" for general practitioners to perform both the early diagnosis and therapy of COPD without the involvement of a specialist. CONCLUSION: Early management of COPD is uncommon, and although data on the effects of early disease management on long-term outcomes are limited, Italian experts are confident of the clinical efficacy of this approach.

Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema.

There are only few human translational studies performed in the area of stem cell research in patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary emphysema. Before progress to clinical trials with stem cells we strongly believe that more human translational studies are essential, otherwise, the clinical rationale would be solely based on limited in vitro and animal studies. In the future, stem cell therapy could be a treatment for this incurable disease. As of now, stem cell therapy is still to be considered as an area of active research, lacking any strong rationale for performing clinical trials in COPD. Although stem cells would be likely to represent a heterogeneous population of cells, the different cell subsets and their importance in the pathogenesis of the different clinical phenotypes need to be fully characterised before progressing to clinical trials. Moreover, the potential side effects of stem cell therapy are underestimated. We should not ignore that some of the most deadly neoplasms are arising from stem cells.

TGF-ß Signaling Pathways in Different Compartments of the Lower Airways of Patients With Stable COPD.

BACKGROUND: The expression and localization of transforming growth factor-ß (TGF-ß) pathway proteins in different compartments of the lower airways of patients with stable COPD is unclear. We aimed to determine TGF-ß pathway protein expression in patients with stable COPD. METHODS: The expression and localization of TGF-ß pathway components was measured in the bronchial mucosa and peripheral lungs of patients with stable COPD (n = 44), control smokers with normal lung function (n = 24), and control nonsmoking subjects (n = 11) using immunohistochemical analysis. RESULTS: TGF-ß1, TGF-ß3, and connective tissue growth factor expression were significantly decreased in the bronchiolar epithelium, with TGF-ß1 also decreased in alveolar macrophages, in patients with stable COPD compared with control smokers with normal lung function. TGF-ß3 expression was increased in the bronchial lamina propria of both control smokers with normal lung function and smokers with mild/moderate stable COPD compared with control nonsmokers and correlated significantly with pack-years of smoking. However, TGF-ß3+ cells decreased in patients with severe/very severe COPD compared with control smokers. Latent TGF-ß binding protein 1 expression was increased in the bronchial lamina propria in subjects with stable COPD of all severities compared with control smokers with normal lung function. Bone morphogenetic protein and activin membrane-bound inhibitor expression (BAMBI) in the bronchial mucosa was significantly increased in patients with stable COPD of all severities compared with control subjects. No other significant differences were observed between groups for all the other molecules studied in the bronchial mucosa and peripheral lung. CONCLUSIONS: Expression of TGF-ßs and their regulatory proteins is distinct within different lower airway compartments in stable COPD. Selective reduction in TGF-ß1 and enhanced BAMBI expression may be associated with the increase in autoimmunity in COPD.

Autoimmunity and COPD: Clinical Implications.

COPD is a leading cause of morbidity and mortality worldwide. Long-term cigarette smoking is the cause of > 90% of COPD cases in Westernized countries. However, only a fraction of chronic heavy smokers develop symptomatic COPD by age 80. COPD is characterized by an abnormal immune response in the lower airways, and its progression is associated with infiltration of the lung by innate and adaptive inflammatory immune cells that form lymphoid follicles. There is growing evidence that both cellular- and antibody-mediated autoimmunity has a fundamental role in the pathogenesis of stable COPD. In particular, carbonyl-modified proteins may help to drive autoimmunity in COPD and cause the characteristic small airways abnormalities and even contribute to the pathogenesis of pulmonary emphysema. Although direct, indirect, and circumstantial evidence of a role for autoimmunity in stable patients with COPD has been identified, no cause-and-effect relationship between autoimmunity and the mechanisms of COPD has been firmly established in man. As such, the potential contribution of an autoimmune response to the pathogenesis of COPD exacerbation is still being investigated and represents an area of active research. Many drugs targeting autoimmune responses are already available, and the results of controlled clinical trials are awaited with great interest. The potential for measuring specific serum autoantibodies as biomarkers to predict clinical phenotypes or progression of stable COPD is promising.

Fluticasone furoate and vilanterol for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Current national and international guidelines for the management of patients with stable chronic obstructive pulmonary disease (COPD) recommend the use of inhaled long-acting bronchodilators, inhaled glucocorticoids and their combinations for maintenance treatment of moderate to severe stable COPD. Areas covered: The role of fluticasone furoate (FF) and vilanterol (VI) once daily combination therapy for the regular treatment of patients with stable COPD is discussed in this review. Expert commentary: The regular treatment of moderate to severe stable COPD with once daily FF/VI combination therapy is effective, as seen in in several large placebo-controlled clinical trials involving many thousands of patients. FF/VI improved lung function, decreased respiratory symptoms and decreased the number of COPD exacerbations, including COPD-related hospitalizations. FF/VI combination therapy has also been approved for this indication in most countries. The use of this combination therapy may significantly decrease the economic costs for some National Health Services.

Asthma management in a specialist setting: Results of an Italian Respiratory Society survey.

BACKGROUND: Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources. AIM: to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting. METHOD: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society. RESULTS: The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (κ = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients). CONCLUSIONS: The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately.

Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report.

We present here the case of a 30-year-old man with a long term history of nephrotic syndrome (NS) who developed an episode of acute left main pulmonary artery thrombosis complicated by a lung abscess. During the hospital admission was also identified a concomitant hyperhomocysteinemia. After an atypical resection of the left upper pulmonary lobe and the starting of long term anticoagulation the patient was discharged but did not attend the planned follow up visits until one year later when he was seen again for severe dyspnea and exercise intolerance. At this time chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed by lung perfusion scintigraphy and right heart catheterization. He initially refused the surgical treatment but, after six months, for the presence of worsening dyspnea was referred for bilateral pulmonary endarterectomy followed by a cardio-thoracic rehabilitation program. After a follow-up of seven years the patient is alive and in stable conditions. NS and hyperhomocysteinemia are both known risk factors for pulmonary embolism (PE), but their association with CTEPH is extremely rare. We discuss here the possible mechanisms linking these conditions. CTEPH must be suspected in any patient with NS, with or without hyperhomocysteinemia, and unexplained dyspnea.

Successful management of acute respiratory failure with noninvasive mechanical ventilation after drowning, in an epileptic-patient.

Sea drowning is a common cause of accidental death worldwide. Respiratory complications such as acute pulmonary oedema, which is often complicated by acute respiratory distress syndrome, is often seen. Noninvasive ventilation is already widely used as a first approach to treat acute respiratory failure resulting from multiple diseases. We report a case of a 45 year old man with a history of epilepsy, motor and mental handicap who developed acute respiratory failure secondary to sea water drowning after an epileptic crisis. We illustrate successful and rapid management of this case with noninvasive ventilation. We emphasize the advantages and limitations of using noninvasive ventilation to treat acute respiratory failure due to sea water drowning syndrome.

The management of asthma in the phenotype and biomarker era: The proposal of a new diagnostic-therapeutic model.

Treatment goals in asthma patients are the achievement of a good control of symptoms and the reduction of the risk of exacerbation. However, a "one-size-fits-all" therapeutic strategy is no longer appropriate to effectively pursue these goals, due to the heterogeneity of asthma. To make the treatment scenario even more complex, asthma patients often present comorbidities that may alter response to therapy. In addition, adherence to asthma treatment is poor. Given this complex and heterogeneous picture, the management of asthma is highly challenging. A clear diagnostic-therapeutic model of patients' care and the definition of the specific responsibilities of different healthcare providers appear necessary to improve clinical outcomes and better allocate healthcare resources. We present here a proposal for this model.

Bullous emphysema as first presentation of Ehlers-Danlos syndrome in monozygotic twins.

Ehlers-Danlos syndrome, characterized by hyperextensible skin, hypermobile joints, and fragile vessels, is the most common heritable disorder of connective tissue and has an estimated prevalence of 1 in 5000. Pulmonary involvement with signs of lung destruction (bullous emphysema) as first presentation is unusual. We report a case of monozygotic twins 37 years old men with occasional evidence of bullous emphysema with previously undiagnosed Ehlers-Danlos syndrome type IV. We emphasize the importance of considering uncommon genetic causes of emphysema in young adults, discuss underlining pathophysiological mechanisms and propose a conservative management and follow-up.

Disability in moderate chronic obstructive pulmonary disease: prevalence, burden and assessment - results from a real-life study.

BACKGROUND: The role of disability and its association with patient-reported outcomes in the nonsevere forms of chronic obstructive pulmonary disease (COPD) has never been explored. OBJECTIVES: The aim of this study was to assess, in a cross-sectional real-life study, the prevalence and degree of disability in moderate COPD patients and to assess its association with health status, illness perception, risk of death and well-being. METHODS: Moderate COPD outpatients attending scheduled visits were involved in a quantitative research program using a questionnaire-based data collection method. RESULTS: Out of 694 patients, 17.4% were classified as disabled and 47.6% reported the loss of at least one relevant function of daily living. Disabled patients did not differ from nondisabled patients in terms of working status (p = 0.06), smoking habits (p = 0.134) and ongoing treatment (p = 0.823); however, the former showed a significantly higher disease burden as measured by illness perception, health status and well-being. The stepwise regression analysis showed that the modified Medical Research Council (mMRC) score was the most relevant factor related to COPD disability (F = 38.248; p = 0.001). Patient stratification was possible according to the forced expiratory volume in 1 s (FEV1) value and an mMRC score ≥2, which identified disabled patients, whereas the mMRC values were differently associated with the risk of disability. CONCLUSION: A significant proportion of individuals with moderate COPD reported a limitation of daily life functions, with dyspnea being the most relevant factor inducing disability. Adding the evaluation of patient-reported outcomes to lung function assessment could facilitate the identification of disabled patients.

Fatal pneumomediastinum associated with use of noninvasive mechanical ventilation.

We present a case of fatal pneumomediastinum in a patient with acute respiratory failure caused by acute exacerbated chronic obstructive pulmonary disease (AECOPD) and interstitial lung disease (ILD) precipitated by noninvasive mechanical ventilation (NIMV). To our knowledge, this is the first case reported in the literature. NIMV is very useful to treat acute respiratory failure due to AECOPD improving survival and avoiding endotracheal intubation. Use of NIMV in end stage ILD is not standardized and efficacy is to be proven. No data are reported to manage patient with concomitant COPD and ILD. Pathophysiological mechanisms underlying this fatal complication are explained and suggestions to treat this subgroup of patients discussed.

Recumbent deoxygenation in mild/moderate liver cirrhosis: the "clinodeoxia". The ortho-clino paradigm.

BACKGROUND: While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). We evaluated the effects of postural changes on arterial oxygenation in patients affected by mild/moderate liver cirrhosis. METHODS: We performed pulmonary function tests and arterial blood gas evaluation in sitting and supine positions in 22 patients with mild/moderate liver cirrhosis, biopsy-proved, and 22 matched non-smokers control subjects. RESULTS: Recumbency elicited a decrease of PaO2 (Δ(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p = 0.04) greater in cirrhotics (9.6 ± 5.3%) compared to controls (6.7 ± 3.7%). In the subset of cirrhotics younger than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Δ(sup-sit)PaO2 in recumbency further increased to 12 ± 5.8%, significantly (p = 0.014) greater than in same subgroup of controls (7.1 ± 3.8%). CONCLUSIONS: In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia").

Expiratory CT scan in patients with normal inspiratory CT scan: a finding of obliterative bronchiolitis and other causes of bronchiolar obstruction.

Expiratory CT scan is usually obtained as supplement to normal inspiratory CT scan to recognize air-trapping, which is expression of small airways obstruction. In some patients the air-trapping may be the only sign of an early-stage small airways disease in an otherwise normal lung.The purpose of this article is to illustrate pathologic conditions, namely obliterative bronchiolitis, in which expiratory CT scan can be abnormal despite normal inspiratory CT examination, and to highlight indications for this technique in patients with clinical and functional suspect of bronchiolar obstruction.

1-year prospective real life monitoring of asthma control and quality of life in Italy.

OBJECTIVES: The study aimed at prospectively evaluating the evolution of asthma control in Italy, to evaluate the reasons for lack of asthma control, perceived quality of life (QoL) and association with level of asthma control, the impact of pharmacological treatment, the number of exacerbations and the healthcare resource consumption. METHODS: PRISMA (PRospectIve Study on asthMA control) was an observational study performed in asthmatic patients including a cross-sectional phase and a 12-month prospective phase. Asthma control was assessed with the Asthma Control Test™ (ACT) and QoL was evaluated with EuroQoL-5D questionnaire filled in and collected during 5 clinic visits together with all the other data. RESULTS: The prospective phase included 1017 patients with uncontrolled (55.7%) or partly controlled asthma (44.3%). Out of the 739 patients evaluable after 12 months, 22.2% achieved full asthma control (ACT score = 25) and 58.7% reached a good control (ACT score: 20-24). The improvement in asthma control was associated with improved QoL and reduced hospital visits. The main reasons for lack of asthma control were comorbidities, continued exposure to irritants/triggers and poor adherence to therapy. The frequency of exacerbations was lower in patients with controlled asthma.A fixed combination therapy with an inhaled corticosteroid and a long-acting ß2 agonist was reported by 77.0% of patients. A better asthma control and improved QoL were achieved with extrafine beclomethasone/formoterol compared to either budesonide/formoterol or fluticasone/salmeterol. CONCLUSIONS: An improvement in asthma control and QoL can be achieved during a 1-year monitoring in a real life setting. Extrafine beclomethasone/formoterol was associated with significant benefit in terms of asthma control and QoL compared to large-particles combinations.ClinicalTrials.gov number NCT01110460.

Coping with asthma: is the physician able to identify patient's behaviour?

INTRODUCTION: The strategies patients use to manage their asthma (coping) have been found to be associated with clinical and patient-reported outcomes. OBJECTIVES: The aim of this large cross-sectional survey is to assess the use of coping methods employed by patients with asthma and to explore the ability of general practitioners (GPs) to correctly identify these strategies. METHODS: A modified Coping Orientations to Problem Experienced Questionnaire was completed by patients with asthma and their physicians. RESULTS: The survey was completed by 3089 GPs (69% male; mean age 55 ± 6) and by 6264 patients (52% male; mean age 45 + 14). Active strategies were reported as the predominant method of coping by 51-59% of patients, whilst passive/avoidant techniques accounted for 12-28%. GPs believed the active coping methods were employed primarily by 35-45% of patients and the passive/avoidant methods by 8-26%. Physicians were able to identify the specific strategy used by a patient in 34%-64% of cases. The ability to identify the use of active strategies rather than the passive/avoidant was significantly higher (T test 8,250, p < 0.0001). Coefficient of concordance between GPs' and patients' answers was fair. CONCLUSIONS: These results revealed the extent of maladaptive coping strategies used by patients and the tendency for physicians to underestimate these. These observations may well represent two obstacles in improving asthma clinical outcomes.

Doctor-patient relationship: a resource to improve respiratory diseases management.

BACKGROUND: Many respiratory diseases are chronic conditions that are strongly linked with the patient-physician relationship, disease perception and therapy adherence. The aim of the present study was to evaluate patient's viewpoint about the different aspects involved in their respiratory diseases. METHODS: This is a prospective observational survey. 46 Italian medical centres were involved and equally distributed. The interviews were carried out and were performed by means of a questionnaire which consisted of 32 questions regarding lung disease, modality of access to medical facilities, therapy and level of medical assistance. RESULTS: 1116 patients were enrolled and the most important respiratory symptoms referred were: dyspnoea (69%), chronic phlegm (28%), cough (13%). During programmed visits 98.3% and 98.8% of interviewed patients knew were aware of asthma and COPD respectively, percentage that dropped, during emergency accesses, to 1.7% and 1.1% knew to have asthma and COPD respectively. Primarily were prescribed 1.67 spirometry/patient/year while only the 2% of patients referred to have performed a blood gas analysis. The 18% of patients spontaneously discontinued the therapy, considering it too complex. The average time that patients identified as being used by the doctor to perform the visit was of 22 minutes, with an high mean medical assistance satisfaction score. DISCUSSION: There has been little research examining what factors may influence patient acceptance and participation of chronic respiratory diseases. Our national survey demonstrated that a good patient-physician relationship represents one of the first points in the successful management of respiratory diseases.

Real-life prospective study on asthma control in Italy: cross-sectional phase results.

OBJECTIVES: To estimate the prevalence of partly controlled and uncontrolled asthmatic patients, to evaluate quality of life and healthcare resource consumption. METHODS: Cross-sectional phase followed by a 12-month prospective phase. Asthma Control Test and the EQ-5D were used. RESULTS: 2853 adult patients recruited in 56 Hospital Respiratory Units in Italy were evaluated: 64.4% had controlled asthma, 15.8% partly controlled asthma and 19.8% were uncontrolled. The mean (SD) EQ-5D score was 0.86 (0.17) in controlled, 0.75 (0.20) in partly controlled and 0.69 (0.23) in uncontrolled patients (p<0.001 between groups). The number of patients requiring hospitalization or emergency room visits was lower in controlled (1.8% and 1.6%, respectively) than in partly controlled (5.1% and 11.5%) and uncontrolled (6.4% and 18.6%). A combination of an inhaled corticosteroid and a long-acting beta-2 agonist was the reported therapy by 56.0% of patients, with the rate of controlled asthma and improved quality of life being higher in patients on extrafine beclomethasone/formoterol compared to budesonide/formoterol (p<0.05) and fluticasone/salmeterol (p<0.05 for quality of life). CONCLUSIONS: Asthma control is achieved in a good proportion of Italian patients. Differences may be detected in a real-life setting in favor of extrafine beclomethasone/formoterol combination.