The Impact of Corticosteroids on Human Airway Smooth Muscle Contractility and Airway Hyperresponsiveness: A Systematic Review.

Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the non-genomic effects of CS seem to be mediated by putative non-classic membrane receptors characterized by pharmacological properties that are different from those of classic cytosolic GR. Since pre-clinical findings suggest that inhaled CS (ICS) may also regulate the bronchial contractile tone via putative CS membrane-associate receptors, the aim of this review was to systematically report and discuss the impact of CS on human airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR). Current evidence indicates that CS have significant genomic/non-genomic beneficial effects on human ASM contractility and AHR, regardless of their anti-inflammatory effects. CS are effective in reducing either the expression, synthesis or activity of α-actin, CD38, inositol phosphate, myosin light chain kinase, and ras homolog family member A in response to several pro-contractile stimuli; overall these effects are mediated by the genomic action of CS. Moreover, CS elicited a strong bronchorelaxant effect via the rapid activation of the Gsα-cyclic-adenosine-monophosphate-protein-kinase-A pathway in hyperresponsive airways. The possibility of modulating the dose of the ICS in a triple ICS/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist fixed-dose combination supports the use of a Triple MAintenance and Reliever Therapy (TriMART) in those asthmatic patients at Step 3-5 who may benefit from a sustained bronchodilation and have been suffering from an increased parasympathetic tone.

Distribution of the Clinical Manifestations of Alpha 1 Antitrypsin Deficiency in Respiratory Outpatients from an Area of Northern Italy.

BACKGROUND: Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that affects Caucasians of the European population due to the presence of a deficient allele of the SERPINA1 gene. A frequency of about 1/5,000 individuals has been estimated in Italy. OBJECTIVES: The aim of the study was to evaluate the distribution of the clinical manifestations of severe and intermediate genetic AATD in the geographic area around Parma in Northern Italy. METHOD: 238 subjects were submitted to molecular analysis of the SERPINA1 gene, and data on anthropometric variables, smoking habits, number of packs per year, AAT serum concentration, and clinical manifestations were recorded and presented as mean ± SD or median values (1st quartile; 3rd quartile). RESULTS: The results show a distribution of genetic AATD of 4.1% of the screened population in the area encompassing the city of Parma. PI*MS and PI*MZ were the most common genotypes at 40.9% and 28.2% of the population with genetic AATD, and asthma and emphysema were the most represented clinical manifestations. CONCLUSION: Our study allowed to increase the knowledge of the distribution of genetic AATD in Northern Italy providing information regarding frequencies of genotypes and clinical manifestations of the disorder.

Detection of Small Airway Dysfunction in Asymptomatic Smokers with Preserved Spirometry: The Value of the Impulse Oscillometry System.

PURPOSE: Smoking-induced bronchiolitis with progressive small airway dysfunction (SAD) is a leading cause of chronic obstructive pulmonary disease. We investigated the value of using the impulse oscillometry system (IOS) to detect SAD in asymptomatic smokers with preserved spirometry. PATIENTS AND METHODS: We included 75 asymptomatic smokers (37 females, mean age 47±12 years, 26±17 pack/year) with preserved spirometry [forced expiratory volume at 1st second (FEV1)/forced vital capacity (FVC) ≥0.70 and normal FVC] and 34 never-smokers (19 females, mean age 42±15 years). RESULTS: In smokers, pack/years were significantly related to spirometry and IOS parameters (p < 0.05). The values of the fall in resistance from 5 Hz to 20 Hz (R5 - R20) were significantly and inversely related to the values of the ratio of forced expiratory volume in 3 and in 6 seconds (FEV3/FEV6) (p < 0.05). In addition, the percentage of heavy smokers (≥30 pack/year) with R5 - R20 >0.07 kPa·s·L-1, considered as IOS index of SAD, but not with FEV3/FEV6 less than a lower limit of normal, a spirometry index of SAD, was significantly higher than that of mild smokers (<30 pack/year) and never-smokers (p < 0.05). CONCLUSION: This study demonstrates that IOS has the potential to detect SAD in asymptomatic heavy smokers with preserved spirometry and with FEV3/FEV6 values in the normal range. We confirm that IOS provides parameters which can complement traditional measurements of pulmonary function.

Covid-19 and the role of smoking: the protocol of the multicentric prospective study COSMO-IT (COvid19 and SMOking in ITaly).

The emergency caused by Covid-19 pandemic raised interest in studying lifestyles and comorbidities as important determinants of poor Covid-19 prognosis. Data on tobacco smoking, alcohol consumption and obesity are still limited, while no data are available on the role of e-cigarettes and heated tobacco products (HTP). To clarify the role of tobacco smoking and other lifestyle habits on COVID-19 severity and progression, we designed a longitudinal observational study titled COvid19 and SMOking in ITaly (COSMO-IT). About 30 Italian hospitals in North, Centre and South of Italy joined the study. Its main aims are: 1) to quantify the role of tobacco smoking and smoking cessation on the severity and progression of COVID-19 in hospitalized patients; 2) to compare smoking prevalence and severity of the disease in relation to smoking in hospitalized COVID-19 patients versus patients treated at home; 3) to quantify the association between other lifestyle factors, such as e-cigarette and HTP use, alcohol and obesity and the risk of unfavourable COVID-19 outcomes. Socio-demographic, lifestyle and medical history information will be gathered for around 3000 hospitalized and 700-1000 home-isolated, laboratory-confirmed, COVID-19 patients. Given the current absence of a vaccine against SARS-COV-2 and the lack of a specific treatment for -COVID-19, prevention strategies are of extreme importance. This project, designed to highly contribute to the international scientific debate on the role of avoidable lifestyle habits on COVID-19 severity, will provide valuable epidemiological data in order to support important recommendations to prevent COVID-19 incidence, progression and mortality.

Arachidonic Acid and Docosahexaenoic Acid Metabolites in the Airways of Adults With Cystic Fibrosis: Effect of Docosahexaenoic Acid Supplementation.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of specialized pro-resolving mediators. We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects. Sputum samples from 15 CF and 10 chronic obstructive pulmonary disease (COPD) subjects were collected and analyzed by LC/MS/MS, and blood fatty acid were profiled by gas chromatography upon lipid extraction and transmethylation. Interestingly, CF subjects showed increased concentrations of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and 15-hydroxyeicosatetraenoic acid (15-HETE), when compared with COPD patients, whereas the concentrations of DHA metabolites did not differ between the two groups. After DHA supplementation, not only DHA/arachidonic acid (AA) ratio and highly unsaturated fatty acid index were significantly increased in the subjects completing the study (p < 0.05) but also a reduction in LTB4 and 15-HETE was observed, together with a tendency for a decrease in PGE2, and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels. At the end of the washout period, LTB4, PGE2, 15-HETE, and 17OH-DHA showed a trend to return to baseline values. In addition, 15-HETE/17OH-DHA ratio in the same sample significantly decreased after DHA supplementation (p < 0.01) when compared with baseline. In conclusion, our results show here that in CF patients, an impairment in fatty acid metabolism, characterized by increased AA-derived metabolites and decreased DHA-derived metabolites, could be partially corrected by DHA supplementation.

Quantitative computed tomography detects interstitial lung diseases proven by biopsy.

Background: The Quantitative chest CT (QCT) is emerging as a promising tool in the assessment of interstitial lung disease (ILD). However, the precise relationship between QCT parameters and the fibrosis detectable in lung tissue, remains to be established. Objectives: The aim of this study was to compare QCT and histopathological features in patients with ILD. Moreover we verified if the QCT assessment is similar in patients with or without a ILD diagnosis proven by a biopsy. Methods: Twenty patients affected by ILD who underwent a chest CT and, later, a lung biopsy, were enrolled. Patients were divided according to the histopathological findings (IPF vs sarcoidosis) in two groups (respectively bIPF and bSarc). Other 20 patients with a radiological diagnosis of IPF were included in a control group (rIPF). All CTs were post-processed with a free software (Horos) in order to obtain an ILD quantitative assessment. Results: There were no differences in terms of gender, smoking habit and spirometric values between patients' groups. rIPF subjects were older than the other: 70 vs 59 and 47 years (p<0.001). A different distribution of QCT parameters was observed between bIPF and bSarc (p<0.01) while it was comparable within bIPF and rIPF. Conclusions: QCT parameters were similar in subjects affected by the same type of ILD detected with biopsy and with CT alone. These findings make stronger the assumption that QCT can identify the presence of pulmonary fibrosis and, ultimately, that it can represent an useful and effective tool to assess ILD. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 16-20).

Sarcoidosis in an Italian province. Prevalence and environmental risk factors.

BACKGROUND AND AIM: Sarcoidosis is a systemic granulomatous inflammatory disease whose causes are still unknown and for which epidemiological data are often discordant. The aim of our study is to investigate prevalence and spatial distribution of cases, and identify environmental exposures associated with sarcoidosis in an Italian province. METHODS: After georeferentiation of cases, the area under study was subdivided with respect to Municipality and Health Districts and to the altitude in order to identify zonal differences in prevalence. The bioaccumulation levels of 12 metals in lichen tissues were analyzed, in order to determine sources of air pollution. Finally, the analysis of the correlation between metals and between pickup stations was performed. RESULTS: 223 patients were identified (58.3% female and 41.7% male of total) and the mean age was 50.6±15.4 years (53.5±15.5 years for the females and 46.5±14.4 for the males). The mean prevalence was 49 per 100.000 individuals. However, we observed very heterogeneous prevalence in the area under study. The correlations among metals revealed different deposition patterns in lowland area respect to hilly and mountain areas. CONCLUSIONS: The study highlights a high prevalence of sarcoidosis cases, characterized by a very inhomogeneous and patchy distribution with phenomena of local aggregation. Moreover, the bioaccumulation analysis was an effective method to identify the mineral particles that mostly contribute to air pollution in the different areas, but it was not sufficient to establish a clear correlation between the onset of sarcoidosis and environmental risk factors.

The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. OBJECTIVES: To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. OUTCOMES: Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/ß, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. CONCLUSIONS: The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable COPD and healthy smokers.

We aimed at comparing exhaled and non-exhaled non-invasive markers of respiratory inflammation in patients with chronic obstructive pulmonary disease (COPD) and healthy subjects and define their relationships with smoking habit. Forty-eight patients with stable COPD who were ex-smokers, 17 patients with stable COPD who were current smokers, 12 healthy current smokers and 12 healthy ex-smokers were included in a cross-sectional, observational study. Inflammatory outcomes, including prostaglandin (PG) E2 and 15-F2t-isoprostane (15-F2t-IsoP) concentrations in exhaled breath condensate (EBC) and sputum supernatants, fraction of exhaled nitric oxide (FENO) and sputum cell counts, and functional (spirometry) outcomes were measured. Sputum PGE2 was elevated in both groups of smokers compared with ex-smoker counterpart (COPD: P < 0.02; healthy subjects: P < 0.03), whereas EBC PGE2 was elevated in current (P = 0.0065) and ex-smokers with COPD (P = 0.0029) versus healthy ex-smokers. EBC 15-F2t-IsoP, a marker of oxidative stress, was increased in current and ex-smokers with COPD (P < 0.0001 for both) compared with healthy ex-smokers, whereas urinary 15-F2t-IsoP was elevated in both smoker groups (COPD: P < 0.01; healthy subjects: P < 0.02) versus healthy ex-smokers. FENO was elevated in ex-smokers with COPD versus smoker groups (P = 0.0001 for both). These data suggest that the biological meaning of these inflammatory markers depends on type of marker and biological matrix in which is measured. An approach combining different types of outcomes can be used for assessing respiratory inflammation in patients with COPD. Large studies are required to establish the clinical utility of this strategy.

Effects of Pulmonary Rehabilitation in Patients with Non-Cystic Fibrosis Bronchiectasis: A Retrospective Analysis of Clinical and Functional Predictors of Efficacy.

BACKGROUND: International guidelines recommend the inclusion of patients with bronchiectasis in pulmonary rehabilitation (PR) to improve exercise capacity and health-related quality of life (HRQoL). At present, the effect of PR in these patients has been poorly investigated. OBJECTIVE: The aim of our retrospective analysis was to evaluate the effects and predictors of success for a PR program in patients with bronchiectasis not related to cystic fibrosis (non-CF bronchiectasis). METHODS: One hundred and thirty-five non-CF bronchiectasis inpatients, allocated to a 3-week PR program, were retrospectively evaluated. Exercise capacity (6-min walk distance, 6MWD), dyspnea (Baseline/Transition Dyspnea Index, BDI/TDI), and HRQoL [EuroQol visual analogue scale (EQ-VAS)] were assessed before and after PR. The relationship between baseline parameters and changes in outcome measures after PR was assessed. Both univariate and multiple logistic analyses were performed to evaluate the presence of independent predictors of the efficacy of PR. RESULTS: One hundred and eight patients [49 males, mean age 71 years, mean forced expiratory volume in 1 s (FEV1) 76% predicted] were included. After PR, there was a significant improvement in 6MWD, TDI, and EQ-VAS score (p < 0.001). Changes in 6MWD and EQ-VAS score correlated with baseline FEV1, FEV1/vital capacity (VC), residual volume, transfer factor of the lung for carbon monoxide, and the number of exacerbations in the previous year. Both univariate and multivariate logistic regression analyses showed that male gender, baseline FEV1/VC <70%, and >2 exacerbations in the previous year were independent predictors of PR efficacy in terms of an improvement in 6MWD. CONCLUSIONS: Our study supports the inclusion of patients with bronchiectasis in PR programs. Clinical and functional baseline findings partially predict the response to PR in terms of exercise tolerance. Further prospective, randomized, controlled trials are needed.

Pulmonary arterial hypertension in childhood: an unsual presentation with fibrosing mediastinitis.

Acquired stenosis of normally connected pulmonary veins is a rare condition in children, usually associated with mediastinal processes. It may present later with a less specific clinical picture, symptoms and signs mimicking chronic lung disease. Fibrosing mediastinitis is a rarer disorder of unknown etiology, although several suspected causes such as granulomatous diseases, characterized by fibrous tissue proliferation within the mediastinum, leading to respiratory and cardiac failure by bronchial obstruction or pulmonary hypertension.

Decreased maturation of dendritic cells in the central airways of COPD patients is associated with VEGF, TGF-ß and vascularity.

BACKGROUND: Dendritic cells (DCs) have a pivotal role in the onset and regulation of innate and adaptive immune responses. Moreover, DCs can interact with angiogenic modulators, resulting in modification of their biology and participation in angiogenesis. OBJECTIVES: This study was designed to evaluate the relationship between the density of DCs, vascularity and expression of angiogenic factors [vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß and basic fibroblast growth factor (bFGF)] in the central airways of chronic obstructive pulmonary disease (COPD) patients. METHODS: The study included 20 patients with moderate/severe COPD and 8 healthy control subjects. Bronchial biopsies were evaluated by immunohistochemistry. Specimens were examined for CD83 and CD207 to mark mature and immature DCs, respectively, for collagen IV to evaluate vascularity, and for VEGF, TGF-ß and bFGF. RESULTS: Compared to controls, COPD patients had a significant reduction of CD83+ cells and an increased CD207/CD83 ratio (p < 0.05). Vascularity, VEGF, TGF-ß and bFGF were also significantly increased in COPD patients as compared to controls (p < 0.01). In COPD patients, CD83+ cells were inversely related to VEGF and TGF-ß expression (p < 0.05). Moreover, the CD207/CD83 ratio was positively related to VEGF, TGF-ß and vascularity (p < 0.05). Finally, CD207+ cells were inversely related to FEV1 (p < 0.05). CONCLUSION: Our results show a reduced maturation of DCs in COPD that was related to airway vascularity and angiogenic factors (VEGF and TGF-ß). Additionally, immature DCs were significantly related to disease severity. We propose that the interplay between airway vascular changes, on one hand, and DCs maturation on the other, may play a key role in the pathogenetic mechanisms of COPD.

Overweight is associated with airflow obstruction and poor disease control but not with exhaled nitric oxide change in an asthmatic population.

BACKGROUND: The role of an elevated body mass index (BMI) in asthma remains controversial. OBJECTIVES: To investigate the relationship between overweight (BMI >25 and ≤30), lung function, disease control, and airway inflammation in an asthmatic population. METHODS: We consecutively studied 348 patients (age 43 ± 16 years; 211 females). In all patients, BMI, spirometry, the Asthma Control Test (ACT), and fractional exhaled nitric oxide (FeNO; ppb) were measured. RESULTS: One hundred forty-five patients were overweight and, as compared to those with normal BMI, had lower values of FVC, FEV(1), and FEV(1)/FVC and of FEF(25-75) even when normalized for FVC (p < 0.05 for each comparison). The ratio between the number of patients with well-controlled asthma (ACT ≥20) and that of patients with poorly controlled asthma (ACT < 20) was significantly lower in overweight patients (1.07 vs. 1.84; χ(2) = 6.030, p < 0.01). In overweight patients, the odds ratio of uncontrolled asthma expressed by logistic regression analysis was 1.632 (95% CI = 1.043-2.553), independently of gender, atopy, smoking habit, and inhaled steroid therapy. No difference was observed in FeNO values between overweight and normal weight patients (27.7 ± 2.3 vs. 27.9 ± 2.2 ppb). CONCLUSIONS: Our results show that, in an asthmatic population, overweight is associated with airflow obstruction and poor disease control but not with FeNO change. The findings of the present study support the view that other factors besides airway inflammation alone may explain the relationship between asthma and an elevated BMI.

Flying with respiratory disease.

Patients with respiratory diseases may be at risk during flight because at cruising altitude an important hypobaric hypoxia may occur. The only absolute contraindications to flying in these patients are pneumothorax, bronchogenic cyst and severe pulmonary hypertension. In order to evaluate the risks related to air travel in patients with respiratory diseases, an evaluation of their fitness to fly, including the hypoxia altitude simulation test, is required. The fitness to fly evaluation can identify patients requiring supplemental oxygen during flight which is provided by most airlines when prescribed by the passenger's physician. This review deals with the cardiorespiratory effects of flight, the risks associated with respiratory diseases during air travel and the procedures to follow in order to assess fitness to fly in patients with respiratory disorders.

Lung Diffusion Capacity can Predict Maximal Exercise in Apparently Healthy Heavy Smokers.

Chronic exposure to tobacco smoking may damage lung and heart function. The aim of this study was to assess maximal exercise capacity and its relationship with lung function in apparently healthy smokers. We recruited 15 heavy smokers (age 47 years ± 7, BMI 25 kg/m(2) ± 3, pack/years 32 ± 9) without any cardiovascular or pulmonary signs and symptoms. Fifteen healthy non smoking subjects were enrolled as a control group. All subjects underwent pulmonary function tests, electrocardiograms at rest and graded cycle exercise tests. In smokers and controls, resting lung and cardiac function parameters were in the normal range, apart from diffusing lung capacity (TLCO) values which were significantly lower in smokers (p < 0.05). As compared to controls, smokers presented lower maximal exercise capacity with lower values at peak of exercise of oxygen uptake (peak VO2), workload, oxygen uptake/watt ratio and oxygen pulse (p < 0.05) and higher dyspnoea perception (p < 0.05). Moreover, peak VO2, maximal workload and oxygen pulse at peak exercise were related to and predicted by TLCO (p < 0. 05). Our study confirms that maximal exercise capacity is reduced in apparently healthy heavy smokers, and shows that TLCO explains some of the variance in maximal exercise. Key pointsChronic exposure to tobacco smoking may damage lung and heart function.Smokers present lower diffusion capacity and maximal exercise capacity.In smokers maximal exercise capacity can be predicted by resting diffusion lung capacity.

Pleural involvement in systemic disorders.

The collagen vascular diseases are a heterogeneous group of immunologically-mediated inflammatory disorders. Frequently, these diseases affect organ systems outside the thorax as their primary manifestation, but may involve the pleura as a single presenting feature, as part of multisystem involvement, or as an isolated manifestation of a disease that is otherwise quiescent. In this article, we review the manifestations of respiratory disease caused by rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis/dermatomyositis, mixed connective tissue disease, Sjogren's syndrome, Wegener's granulomatosis, and sarcoidosis.