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The objective of the present work was to analyze volatile compounds in alveolar air in patients with squamous cell lung cancer, lung adenocarcinoma or colon cancer, to prepare algorithms able to discriminate such specific pathological conditions. The concentration of 95 volatile compounds was measured in the alveolar air of 45 control subjects, 36 patients with lung adenocarcinoma, 25 patients with squamous cell lung cancer and 52 patients with colon cancer. Volatile compounds were measured with ion molecule reaction mass spectrometry (IMR-MS). An iterated least absolute shrinkage and selection operator multivariate logistic regression model was used to generate specific algorithms and discriminate control subjects from patients with different kinds of cancer. The final predictive models reached the following performance: by using 11 compounds, patients with lung adenocarcinoma were identified with a sensitivity of 86% and specificity of 84%, nine compounds allowed us to identify patients with lung squamous cell carcinoma with a sensitivity of 88% and specificity of 84%, patients with colon adenocarcinoma could be identified with a sensitivity of 96% and a specificity of 73% using a model comprising 13 volatile compounds. The different alveolar profiles of volatile compounds, obtained from patients with three different kinds of cancer, suggest dissimilar biological&ndash, biochemistry conditions, each kind of cancer has probably got a specific alveolar profile.

Introduction There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem.

Background and aims Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS) which worsen patients’ health and increase healthcare spending. Aim of this study was to assess the clinical and economic effect of adding mepolizumab (MEP) for the treatment of these patients. Methods Patients >18 years old, referred to 8 asthma clinics, starting MEP between May 2017 and December 2018, were enrolled and followed-up for 12 months. Information in the 12 months before mepolizumab were collected retrospectively. The evaluation parameters included: OCS use, number of exacerbations/hospitalizations, concomitant therapies, comorbidity, and annual number of working days lost due to the disease. The primary objective was to compare the annual total cost per patient pre- and post-MEP. Secondary outcomes included rates of exacerbations and number of OCS-dependent patients. Results 106 patients were enrolled in the study: 46 male, median age 58 years. Mean annual cost pre- and post-MEP (cost of biologic excluded) was €3996 and €1,527, respectively. Total savings due to MEP resulted in €2469 (95%CI 1945–2993), 62% due to exacerbations reduction and 33% due to productivity increase. Such savings could fund about 22% of the total cost of MEP for one year. The introduction of MEP induced a clinical benefit by reducing both OCS-dependent patients (OR = 0.12, 95%CI 0.06–0.23) and exacerbation rate (RR = 0.19, 95%CI 0.15–0.24). Conclusions Patients with severe eosinophilic asthma experienced a clinical benefit in asthma control adding MEP to standard therapy. Biologic therapy can be, partially, funded by the savings produced by patients’ improvement.

About 6% of asthma patients suffer from a severe disease corresponding to step 5 of GINA guidelines (https://ginasthma.org/wp-content/uploads/2019/04/GINA 2019). Noticeably, female, obese patients seem to have a late-onset and more severe disease. To the best of our knowledge, clinical and functional features of severe asthma according to gender have been poorly investigated.We aimed at investigating clinical, functional and biological features of patients with severe asthma according to their gender.89 patients (41 males) admitted to the Severe Asthma Clinic of the Careggi University Hospital underwent a clinical examination, quality of life,asthma control and comorbidities evaluation; lung function (spirometry, lung volumes) and laboratory testing (FeNO, blood eosinophilia, alfa1 antitripsin, skin prick tests to major allergens) were measured. Categorical and numerical data obtained in females were compared to the corresponding data in males by using Fisher exact test and unpaired t-test, respectively. Statistical significance was set at p

Background:Interstitial lung disease (ILD) and pulmonary arterial hypertension represent the most frequent causes of morbidity and mortality in SSc, with chest CT representing the gold standard in ILD assessment, while FVC and DLco allow functional assessment.Objectives:As qualitative analysis of given chest CT scans is hampered by low reproducibility, we aimed to perform a quantitative analysis (QA) of CT scans able to investigate the parenchymal and vascular features in SSc-ILD and thus testing the relationship with clinical-functional data.Methods:We prospectively enrolled 80 patients who underwent PFTs and spirometry-gated chest CT scan at TLC on the same day. Clinical, lung functional and diffusion data, as well as disability indexes were collected. CT images were analyzed by a computational platform for texture analysis of ILD patterns (CALIPER) through Imbio LTA. It quantified the extent of normal lung (%N), ground-glass opacities (%GG), reticulation (%RET), honeycombing (%HC), hyperlucent (%HL), absolute (PVV, cm3) and normalized (PVV/LV, %) pulmonary vascular volumes. Cut-offs of normality for %FVC and %DLco of 80% and 70% were tested to differentiate parenchymal and vascular features.Results:73 patients/CT scans were eligible for both software analyses. CALIPER showed GG% as the most frequent radiological pattern (mean 5.5±10.4%). %FVC and % TLC negatively correlated with all ILD patterns, while %DLco with RET% only; PVV and PVV/LV negatively correlated with %FVC and %TLC, while %DLco with PVV/LV only. Positive correlations were found between all ILD patterns and vascular volumes (Table 1).LV (cm3)%N%GG%RET%HC%HLPVV (cm3)% PVV/LVFVC%r.60-.19-.40-.34-.30.35-.26-.44p-.004.01.003.04FEV1%r.58-.02-.38-.25-.24.23-.35-.49p-.002.04.05-.004FEV1/FVCr-.16.33.22.16.21-.35-.15-.08p-.02------TLC%r.71-.14-.42-.37-.48.40-.43-.64p-.001.01.002DLco%r.38-.05-.21-.31-.22.30-.21-.33p.01--.01---.006FVC/DLcor.03-.08-.06-.003-.09.08-.06-.08p--------Cut-offs equal to 80 for %FVC and 70 for %DLco distinguished both parenchymal and vascular features, while 80 for %DLco characterized vascular features only. These results were confirmed also when patients were stratified according to absent/single/combined %FVC and %DLCO impairments with 80% cut-offs (Table 2).FVCFVC ≥80%pDLcoDLco ≥80%pDLco DLco ≥70%p%N82.7 (9.6)86.2 (14.7)-86.6 (12.7)80.8 (15.8)-84.1 (13.9)86.4 (13.5)-%GG10.3 (8.9)2.4 (3.9)5.0 (6.7)3.9 (6.9)-6.2 (7.5)2.4 (4.8).002%RET2.9 (2.9)0.8 (1.3)1.6 (2.1)0.7 (0.9)-1.9 (2.4)0.6 (0.8).007%HC0.4 (0.6)0.1 (0.1)0.2 (0.3)0.1 (0.1)-0.2 (0.4)0.05 (0.2).010%HL3.6 (6.8)8.9 (12.1)-5.4 (8.8)14.1 (15.4).0506.3 (10.1)9.2 (12.7)-PVV125.6 (39.1)90.9 (26.9)101.9 (34.8)84.7 (19.4).016106.9 (38.3)87.5 (20.5).012PVV/LV3.8 (1.6)2.0 (0.7)2.51 (1.3)1.7 (0.6).0022.76 (1.4)1.83 (0.6).001Conclusion:In SSc a cut-off at 80 for %DLco may help identifying vascular changes as automatically assessed on chest CT scan, without any underlying ILD. The 80% cut-off for %DLco may be proposed to identify isolated vascular involvement, while %FVC at 80% or %DLco at 70% to identify significant parenchymal involvement. These results need to be confirmed in larger multi-centric cohorts.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Mariaelena Occhipinti Consultant of: Imbio, Gianna Camiciottoli: None declared, Maurizio Bartolucci: None declared, Gemma Lepri: None declared, Alessio Fabbrizzi: None declared, Alessandra Tottoli: None declared, Anna Bassetto: None declared, Giuglia Ciardi: None declared, Dilia Giuggioli: None declared, Giovanna CUOMO: None declared, Francesco Masini: None declared, Federico Lavorini: None declared, Linda Calistri: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim

Background: It is not clear whether mepolizumab is differently effective in allergic and nonallergic severe eosinophilic asthmatics (SEA) in real life. Objective: We tested mepolizumab effectiveness in allergic/nonallergic SEA in real life. A strict criterion to identify the 2 phenotypes was used. Method: We retrospectively considered 134 consecutive patients divided into allergic, with a positivity to at least 1 allergen to prick tests and/or IgE values ≥100 UI/mL (severe allergic eosinophilic asthma [SAEA]; n: 97–72.4%), and nonallergic, with no prick test results and normal IgE levels n: 37–27.6%). They had taken mepolizumab for at least 6 months. Results: After 10.9 ± 3.7 months, improvements in FEV1%, FEF25–75%, exacerbation numbers, blood eosinophil (BE) counts, fractional exhaled nitric oxide (FENO) (ppb), percentages of patients that stopped/reduced short-acting β2-agonists (SABAs) or oral corticosteroid (OC), observed after treatment, were similar in both groups. Only Asthma Control Test (ACT) increases were higher in SNAEA (8 [5–9]) than in SAEA (5 [2.5–8.5]; p = 0.016). However, no differences were found after treatment in percentages of subjects with ACT ≥20, as well as with FEV1 >80%, FEF25–75 >65%, exacerbations ≤2, BE 1% (β = −0.110; p = 0.266), FEF25–75% (β = −0.228; p = 0.06), BE counts (β = −0.012; p = 0.918), FENO (β = 0.234; p = 0.085), ACT (β = 0.046; p = 0.660), and exacerbations (β = −0.070; p = 0.437). No different associations between lung function and SNAEA occurrence when compared to SAEA condition (FEV1 >80%: OR = 1.04 [95% CI: 0.43–2.55], p = 0.923; FEF25–75 >65%: OR = 0.41 [95% CI: 0.08–2.03], p = 0.272) were detected. Neither all other parameters, such as ACT >20 (OR = 0.73 [95% CI: 0.32–1.63], p = 0.440), presence of exacerbations (OR = 1.35 [95% CI: 0.55–3.27], p = 0.512), SABA discontinuation (OR = 1.16 [95% CI: 0.40–3.39], p = 0.790), and OC cessation/reduction (OR = 3.44 [95% CI: 0.40–29.27], p = 0.258), were differently associated with 1 or the other phenotype. Conclusion: Mepolizumab can be considered as a valid therapeutic choice for either allergic or nonallergic SEA in real life.

ObjectiveTo prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function.MethodsSeventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% ResultsAbsolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%).ConclusionsChest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed.

Purpose To identify a prevalent computed tomography (CT) subtype in patients with chronic obstructive pulmonary disease (COPD) by separating emphysematous from nonemphysematous contributions to total gas trapping and to attempt to predict and grade the emphysematous gas trapping by using clinical and functional data. Materials and Methods Two-hundred and two consecutive eligible patients (159 men and 43 women; mean age, 70 years [age range, 41-85 years]) were prospectively studied. Pulmonary function and CT data were acquired by pulmonologists and radiologists. Noncontrast agent-enhanced thoracic CT scans were acquired at full inspiration and expiration, and were quantitatively analyzed by using two software programs. CT parameters were set as follows: 120 kVp; 200 mAs; rotation time, 0.5 second; pitch, 1.1; section thickness, 0.75 mm; and reconstruction kernels, b31f and b70f. Gas trapping obtained by difference of inspiratory and expiratory CT density thresholds (percentage area with CT attenuation values less than -950 HU at inspiration and percentage area with CT attenuation values less than -856 HU at expiration) was compared with that obtained by coregistration analysis. A logistic regression model on the basis of anthropometric and functional data was cross-validated and trained to classify patients with COPD according to the relative contribution of emphysema to total gas trapping, as assessed at CT. Results Gas trapping obtained by difference of inspiratory and expiratory CT density thresholds was highly correlated (r = 0.99) with that obtained by coregistration analysis. Four groups of patients were distinguished according to the prevalent CT subtype: prevalent emphysematous gas trapping, prevalent functional gas trapping, mixed severe, and mixed mild. The predictive model included predicted forced expiratory volume in 1 second/vital capacity, percentage of predicted forced expiratory volume in 1 second, percentage of diffusing capacity for carbon monoxide, and body mass index as emphysema regressors at CT, with 81% overall accuracy in classifying patients according to its extent. Conclusion The relative contribution of emphysematous and nonemphysematous gas trapping obtained by coregistration of inspiratory and expiratory CT scanning can be determined accurately by difference of CT inspiratory and expiratory density thresholds. CT extent of emphysema can be predicted with accuracy suitable for clinical purposes by pulmonary function data and body mass index. © RSNA, 2018 Online supplemental material is available for this article.

Rationale and Objectives The opened or closed status of the glottis might influence tracheal size changes in inspiratory and expiratory computed tomography (CT) scans. We investigated if the glottis status makes the tracheal collapse differently correlate with lung volume difference between inspiratory and expiratory CT scans. Materials and Methods Forty patients with chronic obstructive pulmonary disease whose glottis was included in the acquired scanned volume for lung CT were divided into two groups: 16 patients with the glottis closed in both inspiratory and expiratory CT, and 24 patients with the glottis open in at least one CT acquisition. Lung inspiratory (Vinsp) and expiratory (Vexp) volumes were automatically computed and lung ΔV was calculated using the following formula: (Vinsp − Vexp)/Vinsp × 100. Two radiologists manually measured the anteroposterior diameter and cross-sectional area of the trachea 1 cm above the aortic arch and 1 cm above the carina. Tracheal collapse was then calculated and correlated with lung ΔV. Results In the 40 patients, the correlations between tracheal Δanteroposterior diameter and Δcross-sectional area at each level and lung ΔV ranged between 0.68 and 0.74 (ρ) at Spearman rank correlation test. However, in the closed glottis group, the correlations were higher for all measures at the two levels (ρ range: 0.84–0.90), whereas in the open glottis group, correlations were low and not statistically significant (ρ range: 0.29–0.34) at the upper level, and moderate at the lower level (ρ range: 0.51–0.55). Conclusions A closed or open glottis influences the tracheal size change in inspiratory and expiratory CT scans. With closed glottis, the tracheal collapse shows a stronger correlation with the lung volume difference between inspiratory and expiratory CT scans.

Background COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes.Objective We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results.Methods We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance.Results The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies.Conclusions Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.

Background The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics. Methods We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below − 950 Hounsfield Units (%LAA-950insp) patients were classified as having no emphysema (NE) with %LAA-950insp

Background: Asthma is one of the most common non-communicable respiratory diseases, affecting about 6% of the general population. Severe asthma, even if afflicts a minority of asthmatics, drives the majority of costs of the disease. The aim of this study is to create a pharmacoeconomic model to predict the costs of corticosteroid-related adverse events in severe asthmatics and applying it to the first published epidemiologic data from the Severe Asthma Network in Italy (SANI) registry. Methods: The analysis was conducted from the perspective of the Italian National Healthcare System (INHS). Model inputs, derived from literature, included: asthma epidemiology data, frequency of adverse events, percentage of severe asthma treated with OCS and adverse event cost (Diagnosis-Related Group (DRG) national tariffs). We estimated costs per different patient groups: non-asthma controls, mild/moderate and severe asthmatics. Final results report estimated direct cost per patient and total direct cost for overall target population, showing economic impact related to corticosteroid complication. Results: Based on epidemiological data input, in Italy, asthmatic subjects resulted about 3,999,600, of which 199,980 with severe asthma. The number of patients with severe asthma OCS-treated was estimated at 123,988. Compared to the non-asthma control cohort and to that with moderate asthma annual cost per severe asthmatic patient resulted respectively about €892 and €606 higher, showing a corticosteroids shadow cost ranging from 45% to 30%.Applying the cost per patient to the target population identified for Italy, the budget impact model estimated a total annual cost related to OCS-related adverse events of €242.7 million for severe asthmatics. In respect with non-asthmatic and moderate population, an incremental expenditure of about € 110.6 million and €75.2, respectively, were shown. Conclusions: Our study provides the first estimates of additional healthcare costs related to corticosteroid induced adverse events in severe asthma patient. Budget impact model results highlighted the relevant economic impact of OCS-related adverse events in severe asthma patients. The future extrapolation of additional data from SANI registry will support the development of a model to investigate the role of corticosteroids sparing drugs. Keywords: Severe asthma, Oral corticosteroids, Adverse events, Pharmacoeconomy, Costs, Diabetes, Glaucoma, Obesity, Bone fracture, Chronic kidney disease

Gianna Camiciottoli,1,2 Francesca Bigazzi,1 Chiara Magni,1 Viola Bonti,1 Stefano Diciotti,3 Maurizio Bartolucci,4 Mario Mascalchi,5 Massimo Pistolesi1 1Section of Respiratory Medicine, Department of Clinical and Experimental Medicine, 2Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, 3Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi,” University of Bologna, Cesena, 4Department of Diagnostic Imaging, Careggi University Hospital, 5Radiodiagnostic Section, Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy Background: In addition to lung involvement, several other diseases and syndromes coexist in patients with chronic obstructive pulmonary disease (COPD). Our purpose was to investigate the prevalence of idiopathic arterial hypertension (IAH), ischemic heart disease, heart failure, peripheral vascular disease (PVD), diabetes, osteoporosis, and anxious depressive syndrome in a clinical setting of COPD outpatients whose phenotypes (predominant airway disease and predominant emphysema) and severity (mild and severe diseases) were determined by clinical and functional parameters. Methods: A total of 412 outpatients with COPD were assigned either a predominant airway disease or a predominant emphysema phenotype of mild or severe degree according to predictive models based on pulmonary functions (forced expiratory volume in 1 second/vital capacity; total lung capacity %; functional residual capacity %; and diffusing capacity of lung for carbon monoxide %) and sputum characteristics. Comorbidities were assessed by objective medical records. Results: Eighty-four percent of patients suffered from at least one comorbidity and 75% from at least one cardiovascular comorbidity, with IAH and PVD being the most prevalent ones (62% and 28%, respectively). IAH prevailed significantly in predominant airway disease, osteoporosis prevailed significantly in predominant emphysema, and ischemic heart disease and PVD prevailed in mild COPD. All cardiovascular comorbidities prevailed significantly in predominant airway phenotype of COPD and mild COPD severity. Conclusion: Specific comorbidities prevail in different phenotypes of COPD; this fact may be relevant to identify patients at risk for specific, phenotype-related comorbidities. The highest prevalence of comorbidities in patients with mild disease indicates that these patients should be investigated for coexisting diseases or syndromes even in the less severe, pauci-symptomatic stages of COPD. The simple method employed to phenotype and score COPD allows these results to be translated easily into daily clinical practice. Keywords: COPD phenotypes, COPD severity, comorbidities

Background:Interstitial lung disease (ILD) and pulmonary arterial hypertension carry a negative impact on SSc prognosis. Chest CT is the gold standard in assessing ILD and helps in evaluating associated vascular involvement.Objectives:As qualitative analysis of CT scans is limited by low reproducibility and time constraints, we aimed at evaluating parenchymal and vascular features in SSc-ILD by quantitative analysis (QA) of CT scans and testing the relationship with clinical-functional data.Methods:We prospectively enrolled 80 patients who underwent PFTs and chest CT scan spirometry gated at TLC on the same day. Clinical, lung functional and diffusion data, as well as disability indexes were collected. CT images were analyzed by a computational platform for texture analysis of ILD patterns (CALIPER), through Imbio LTA. It quantified the extent of normal pattern (NP %), ground glass opacities (GG %), reticulation (RET %), honeycombing (HC %), total ILD extent (ILD EXT %) and hyperlucent (HL %). Low density areas, representing emphysematous area, were also quantified (LDA %). For lung vessel analysis, a software program developed by the Ludwig Boltzmann Institute for Lung Vascular Research was used. This software determined total, arterial, and venous vascular volumes (TV, AV, VV), and relative volumes (TV%, AV%, VV%), as well as density and number for total, arterial and venous vessels.Results:43/80 patients/CT scans were eligible for both software analyses, while 36/43 for arterial and venous separation. TV% and total vessel density were correlated positively with mRSS and negatively with %FVC (r=-0.537 and r=-0.382) and %TLC (r=-0.511 and r=-0.648), while vessel tortuosity correlated positively with %DLco. This was confirmed when separately analyzing arterial vessels, while VV% negatively correlated with %FVC, %TLC and %DLco. There was a positive correlation between %ILD patterns and %vascular volumes, being significant for TV%-AV%, total vessels and arterial density. Conversely, %ILD patterns were negatively correlated with VV and number of veins detected, despite positive correlation between VV% and ILD_EXT%. When clustering patients according to %FVC and %DLco with 80% normal cutoff, %FVC allowed clustering according to significantly different ILD patterns extents and vascular features, while %DLCO for vascular features only. Moreover, the consecutive addition of functional impairment and worsening of ILD (from both normal %FVC and %Dlco, to %DLco impairment only to both %FVC and %Dlco impairment), there was a significant increase in %TV, % AV and %VV, with the exception of decrease in %VV and venous density in patients with double impairment versus DLco single impairment.Conclusion:This is the first study showing in SSc a direct correlation between ILD and the increase in lung vascular volume, which is characterized by increase in arterial volume and density and reduction in venous volume and number. These results might be explained by the reduction of pulmonary volume due to fibrosis. However, also a para-physiological mechanism of redistribution of blood flow in lung areas, less involved by ILD, might be considered. Further studies on lung vessel quantification and distribution are ongoing.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Mariaelena Occhipinti Consultant of: Imbio, Gianna Camiciottoli: None declared, Maurizio Bartolucci: None declared, Michael Pienn: None declared, Gemma Lepri: None declared, Alessio Fabbrizzi: None declared, Alessandra Tottoli: None declared, Giuglia Ciardi: None declared, Dilia Giuggioli: None declared, Giovanna CUOMO: None declared, Francesco Masini: None declared, Horst Olschewski: None declared, Federico Lavorini: None declared, Linda Calistri: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim

Background Severe Asthma Network in Italy (SANI) is a registry of patients recruited by accredited centers on severe asthma. Objective To analyze epidemiological, clinical, inflammatory, functional, and treatment characteristics of severe asthmatics from the SANI registry. Methods All consecutive patients with severe asthma were included into the registry, without exclusion criteria to have real-life data on demographics, asthma control, treatments (including biologics), inflammatory biomarkers, and comorbidities. Results A total of 437 patients (mean age: 54.1 years, 57.2% females, 70.7% atopics, 94.5% in Global Initiative for Asthma severity step V) were enrolled into the study. The mean annual exacerbation rate was 3.75. The mean blood eosinophil level was 536.7 cells/mcL, and the average serum total IgE was 470.3 kU/L. Approximately 64% of patients were on regular oral corticosteroid treatment, 57% with omalizumab and 11.2% with mepolizumab. Most common comorbidities were rhinitis, nasal polyposis, and bronchiectasis. Patients with nasal polyposis had higher age of disease onset, higher blood eosinophil count, and lower frequency of atopy and atopic eczema. Bronchiectasis was associated with more frequent severe exacerbations, higher blood eosinophils, and total IgE. Stratifying patients, those with late-onset asthma were less frequently atopic (with less frequent allergic rhinitis and food allergy), and more frequently with nasal polyposis and higher serum total IgE levels. Conclusions This study revealed a high frequency of relevant comorbidities and that a substantial proportion of patients have late-onset asthma; all these features define specific different disease phenotypes. Severe asthma complexity and comorbidities require multidisciplinary approaches, led by specifically trained pulmonologists and allergists.

Interstitial lung disease (ILD) is common in systemic sclerosis (SSc) patients and despite recent advances in the treatment is, at present, the major cause of death. Today, an early diagnosis of ILD is possible, and is mandatory to improve the prognosis of the disease.Pulmonary function tests and high-resolution computed tomography remain the mainstay for the diagnosis of SSc-ILD, but there is a growing interest in lung ultrasound. Recently, the correlation between severity of fibrosis and some peripheral blood biomarkers has been described.Nonselective immunosuppressors are still the main treatment for ILD, with cyclophosphamide (CYC) most widely used to obtain remission. Novel therapies towards specific molecular and cellular targets have been suggested; in particular, rituximab (RTX) has shown promising results, but further research is needed. It is of paramount importance to define the severity of the disease and the risk of progression in order to define the need for treatment and the treatment intensity. We propose the division of the treatment strategies at our disposal to induce remission into three categories: high intensity (haematopoietic stem cell transplantation), medium intensity (CYC and RTX) and low intensity (azathioprine (AZA) and mycophenolate mofetil (MMF)). After obtaining remission, maintenance treatment with AZA or MMF should be started.In this review we explore new advances in the pathogenesis, diagnosis and treatment of SSc-ILD.

To determine whether the relationship between pulmonary function and computed tomographic (CT) lung attenuation in chronic obstructive pulmonary disease (COPD), which is traditionally described with single univariate and multivariate statistical models, could be more accurately described with a multiple model estimation approach.The study was approved by the local ethics committee. All participants provided written informed consent. The prediction of the percentage area with CT attenuation values less than -950 HU at inspiration (%LAA-950insp) and less than -910 HU at expiration (%LAA-910exp) obtained with single univariate and multivariate models was compared with that obtained with a multiple model estimation approach in 132 patients with COPD.At univariate analysis, %LAA-950insp and %LAA-910exp values higher than the mean value of this cohort (19.1% and 22.0%) showed better correlation with percentage of predicted diffusing capacity of lung for carbon monoxide (Dlco%) than with airflow obstruction (forced expiratory volume in 1 second [FEV1]/vital capacity [VC]). Conversely, %LAA-950insp and %LAA-910exp values lower than the mean value were correlated with FEV1/VC but not with Dlco%. Multiple model estimation performed with two multivariate regressions, each selecting the most appropriate functional variables (FEV1/VC for mild parenchymal destruction, Dlco% and functional residual capacity for severe parenchymal destruction), predicted better than single multivariate regression both %LAA-950insp (R(2) = 0.75 vs 0.46) and %LAA-910exp (R(2) = 0.83 vs 0.63).The relationship between pulmonary function data and CT densitometric changes in COPD varies with the level of lung attenuation impairment. The nonlinear profile of this relationship is accurately predicted with a multiple model estimation approach.

Airflow limitation in COPD results from different mechanisms, including emphysema and small airway disease. Unlike spirometry, computed tomography (CT) can quantify both emphysema extent as well as gas-trapping due to small airway disease. We aimed to predict by clinical and functional data the probability of having emphysema, as assessed on CT. We measured dynamic (FEV1, FVC, VC), static (TLC, FRC, RV) lung volumes, and diffusing capacity (DLco) in 180 COPD patients (GOLD 1-4). By post-processing image analysis of CT scans we measured the percent lung area with density The model included FEV1/VC, FEV1%, DLco%, and BMI as predictors of %LAA-950. The overall accuracy of the model was 81.1%, with a higher accuracy (88.0%) in those subjects with “milder” disease. We classified each subject according to the probability output values, from milder (group 1) to more severe (group 4) emphysema. The four outputs of the model had significantly different %LAA-950 (p The predictive model including FEV1/VC, FEV1%, DLco%, and BMI demonstrated a high accuracy in predicting the emphysema extent in COPD patients, as assessed on CT. The accuracy obtained by the model is suitable for daily clinical purposes as well as for clinical trials.

Background: ACOS describes the co-occurrence of asthma and COPD, although its prevalence and clinical features remain poorly characterized. Aims: To better understand the prevalence and characteristics of ACOS. Methods: An observational study is being performed in subjects with bronchial obstruction at 3 Italian centers. In the first phase, consecutive patients ≥40 years with documented bronchial obstruction are being recruited; eligible patients will enter the second phase, consisting of imaging, functional and clinical evaluation with the MRC dyspnea scale, St. George9s respiratory questionnaire index, Charlson index, and skin prick test. Main inclusion criteria for the evaluation phase are fixed airway obstruction, history of respiratory allergy or asthma, current or past smoking, and a score from 6 to 8 on the Beeh questionnaire. Results: To date, 174 patients have been enrolled. In this interim analysis, 13% had a diagnosis of asthma, 49% COPD, and 37% ACOS. Results are reported in the table. In the COPD group, mean age and the proportion of males was significantly higher than in the ACOS group (*p Conclusions: Preliminary data indicate that among patients with bronchial obstruction, more than 1/3 have features of ACOS. The final analysis will allow full description of the clinical and functional characteristics of patients with ACOS.

Even if severe asthma (SA) accounts for 5–10% of all cases of the disease, it is currently a crucial unmet need, owing its difficult clinical management and its high social costs. For this reason several networks, focused on SA have been organized in some countries, in order to select these patients, to recognize their clinical features, to evaluate their adherence, to classify their biological/clinical phenotypes, to identify their eligibility to the new biologic therapies and to quantify the costs of the disease. Aim of the present paper is to describe the ongoing Italian Severe Asthma Network (SANI). Up today 49 centres have been selected, widespread on the national territory. Sharing the same diagnostic protocol, data regarding patients with SA will be collected and processed in a web platform. After their recruitment, SA patients will be followed in the long term in order to investigate the natural history of the disease. Besides clinical data, the cost/benefit evaluation of the new biologics will be verified as well as the search of peculiar biomarker(s) of the disease.

SUMMARYThe diseases caused by non-tuberculous mycobacteria (NTM), in both AIDS and non-AIDS populations, are increasingly recognized worldwide. Although the American Thoracic Society published the guidelines for diagnosis of NTM pulmonary disease (NTM-PD), the diagnosis is still difficult. In the first part of the study, we collected data on NTM isolates in the Mycobacteriology Laboratory of Careggi Hospital (Florence, Italy) and analysed the epidemiological data of NTM isolates. Then, to analyse the risk factors associated to NTM-PD, we studied the presence of ATS/IDSA criteria for NTM-PD in patients who had at least one positive respiratory sample for NTM and were admitted to the Infectious Disease Unit and the Section of Respiratory Medicine. We selected 88 patients with available full clinical data and, according to ATS/IDSA criteria, classified 15 patients (17%) as NTM-PD cases and 73 as colonized patients (83%). When comparing colonized and NTM-PD patients we did not find significant differences of age, gender and comorbidity. We observed that Mycobacterium avium and M. intracellulare were statistically associated with NTM-PD (P = 0·001) whereas M. xenopi was statistically associated with colonization. Although the number of studied patients is limited, our study did not identify risk factors for NTM-PD that could help clinicians to discriminate between colonization and disease. We underline the need of close monitoring of NTM-infected patients until the diagnosis is reasonably excluded. Further larger prospective studies and new biological markers are needed to identify new useful tools for the diagnosis of NTM-PD.

Airway obstruction and parenchymal destruction underlie phenotype and severity in chronic obstructive pulmonary disease (COPD). We aimed to predict, by clinical and pulmonary function data, the predominant type and severity of pathological changes quantitatively assessed by computed tomography (CT). Airway wall thickness (AWT-Pi10) and percentage of lung area with X-ray attenuation values

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Summary Background Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation caused by small airways increased resistance and/or terminal airspaces emphysematous destruction. Spirometric detection of not fully reversible airflow limitation unifies under the acronym COPD, a spectrum of heterogeneous conditions, whose clinical presentations may be substantially different. In a cross-sectional study we aimed to ascertain whether COPD phenotypes reflecting different mechanisms of airflow limitation could be clinically identified. Methods Multidimensional scaling was used to visualize as a single point in a two-dimension space the multidimensional variables derived from each of 322 COPD patients (derivation set) by clinical, functional, and chest radiographic evaluation. Cluster analysis assigned then a cluster membership to each patient data point. Finally, using cluster membership as dependent variable and all data acquired as independent variables, we developed multivariate models to prospectively classify another group of 93 COPD patients (validation set) in whom high-resolution computerized tomography (HRCT) density parameters were measured. Results A multivariate model based on nine variables acquired from the derivation set by history (sputum characteristics), physical examination (adventitious sounds, hyperresonance), FEV 1 /VC, and chest radiography (increased vascular markings, bronchial wall thickening, increased lung volume, reduced lung density) partitioned the validation set into two groups whose clinical, functional, chest radiographic, and HRCT characteristics corresponded to either an airways obstructive or a parenchymal destructive COPD phenotype. Conclusion Patients with COPD can be assigned a clinical phenotype reflecting the prevalent mechanism of airflow limitation. The standardized identification of the predominant phenotype may permit to clinically characterize COPD beyond its unifying spirometric definition.

Background: To ascertain if analysis of lung density histograms in thin-section CT was more reproducible than visual assessment of lung changes in systemic sclerosis (SSc), and if such density histogram parameters as mean lung attenuation (MLA), skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment. Methods: The intraoperator and interoperator reproducibility of visual and densitometric lung CT analysis in 48 SSc patients examined with CT were evaluated by means of weighted κ statistics. Univariate and multivariate regression analyses were applied to evaluate the relationship of visual and densitometric CT measurements with functional parameters including functional residual capacity (FRC), FVC, FEV 1 , diffusion capacity of the lung for carbon monoxide (D lco ), 6-min walking testing (6MWT), and health-related quality of life questionnaire (QLQ) parameters. Results: The intraoperator and interoperator reproducibility of MLA (intraobserver weighted κ = 0.97; interobserver weighted κ = 0.96), skewness (intraobserver weighted κ = 0.89; interobserver weighted κ = 0.88), and kurtosis (intraobserver weighted κ = 0.89; interobserver weighted κ = 0.88) were higher than those of visual assessment (intraobserver weighted κ = 0.71; interobserver weighted κ = 0.69). In univariate analysis, only densitometric measurements were correlated with some exercise and QLQ parameters. In multivariate analysis, MLA (square regression coefficient corrected [ R 2 c] = 0.70), skewness ( R 2 c = 0.78), and kurtosis ( R 2 c = 0.77) were predicted by FRC, FVC, D lco , 6MWT, and QLQ parameters, while visual assessment was associated only with FRC and FVC ( R 2 c = 0.40). Conclusions: In SSc, densitometric analysis is more reproducible than visual assessment of lung changes in thin-section CT and more closely correlated to pulmonary function testing, 6MWT, and QLQ. Density histogram parameters may be useful for cross-sectional and longitudinal studies of lung involvement in SSc.

Exacerbations are recommended (GOLD2011) as a new dimension to stage COPD and guide its therapeutic approach. We investigated: 1) the relationship of exacerbations with clinical examination, pulmonary function and lung CT changes; 2) the stability of exacerbation frequency in 133 COPD outpatients over two years of follow-up. Exacerbation frequency occurring in the year prior and the year following a chest CT scan was collected by a standardized questionnaire. Patients with ≥2 episodes/year were considered “frequent exacerbators” . By principal component analysis of CT values of parenchymal destruction (%LAA-950) and airway wall thickness (AWT-Pi10) we assessed quantitatively the CT predominant phenotype (airway disease or emphysema) and the overall severity of COPD (Camiciottoli et al ERJ 2013). Patients with more severely impaired lung function, higher BODE score and more severe CT changes had more frequent exacerbations in the year prior the examination. Exacerbation frequency was not significantly different in patients with airways disease or emphysema CT predominant phenotype. Fifty% of the 42 “frequent exacerbators” in the first year became “infrequent exacerbators” in the second year, while only 5% of the 91 “infrequent exacerbators” became “frequent exacerbators”. Exacerbations frequency does not reflect the predominant mechanism of airflow limitation as determined by quantitative CT. Although exacerbations frequency could be a reliable index of COPD severity, the so called “frequent exacerbator phenotype” is not a stable disease characteristic and its prevalence may be influenced by medical treatment or other sociological interactions. Larger population longitudinal studies are needed to clarify this point.

Objective: To correlate lung density measurements with the results of visual assessment of thin-section computed tomography (CT) and of pulmonary function tests (PFT) in Systemic Sclerosis (SSc). Methods: Thirty-nine SSc patients underwent sequential thin-section CT and spiral low-dose whole-lung acquisitions. The thin-section CT scans were evaluated with a dedicated visual scale. Mean lung density, skewness, and kurtosis were calculated from the lung density histogram. In addition from the spiral low-dose acquisition, the lung volume was computed. The visual score, the densitometric parameters, and the lung volume were correlated with the PFT. Results: Mean lung density, skewness, and kurtosis computed from thin-section (R = 0,66; R = -0,74; R = -0,75) and low-dose volumetric (R = 0,72; R = -0,71; R = -0,71) CT and the lung volume (R = -0.54) correlated with the visual score. Densitometric values and lung volume consistently better correlated with PFT than the visual score. Conclusions: In SSc the histogram results are more closely correlated to PFT than the visual score. The low-dose spiral CT seems ideal for longitudinal studies.

Study objectives The aim of this study was to investigate the relationship between high-resolution CT (HRCT) lung attenuation measurements, acquired under spirometric control of inspiratory and expiratory lung volume, and pulmonary dysfunction as well as dyspnea severity in patients with COPD. Patients and design In 51 patients with COPD, we compared by linear regression, univariate and multivariate logistic regression airflow limitation (FEV 1 /vital capacity [VC]), hyperinflation (percentage of predicted residual volume [RV%]), parenchymal loss (percentage of predicted diffusing capacity of the lung for carbon monoxide [D lco %]), and Medical Research Council (MRC) dyspnea scale with relative area with attenuation values 950 ] and exp ]). Results All HRCT attenuation measurements were significantly related with functional abnormalities and dyspnea severity. In multivariate logistic models, with 1 indicating worse changes in dichotomous outcome variables, MeanCT exp independently predicted FEV 1 /VC (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11 to 0.56), RV% (OR, 0.57; 95% CI, 0.42 to 0.77), and MRC dyspnea scale (OR, 0.63; 95% CI, 0.48 to 0.82), while RAI 950 independently predicted D lco% (OR, 1.90; 95% CI, 1.37 to 2.65). Conclusions Spirometrically gated measurements of HRCT lung attenuation reflect differently functional changes and dyspnea perception in COPD. Inspiratory measurements assess the extent of emphysematous tissue loss, and expiratory measurements may reflect airflow limitation and lung hyperinflation with attendant dyspnea perception. Pulmonary dysfunction in COPD cannot be assessed by a single modality of lung attenuation measurement.

Purpose: The purpose of this work was to evaluate feasibility of spirometric-gated high-resolution computed tomography (HRCT) in patients with chronic obstructive pulmonary disease (COPD) and to compare the lung density CT measurements obtained with and without spirometric control of lung volume. Method: Twenty-nine patients with COPD underwent pulmonary function tests and spirometric-gated (3 slices at 10% and 90% of vital capacity) and -ungated (12 slices at maximum expiration and inspiration) HRCT in the same day. Four lung density measurements (inspiratory pixel index, expiratory pixel index, inspiratory and expiratory mean lung density) derived from gated and ungated acquisitions were compared using the nonparametric Wilcoxon test, the line of equality, and the Bland and Altman test. Results: The vital capacity measured at pulmonary function tests and on the CT table showed a substantial agreement. All but one patient completed the gated and ungated examination, but only 8 (28%) of 28 patients reached the expiratory and inspiratory gating level for CT acquisitions at the first attempt. Only the inspiratory mean lung density derived from the 3 gated and 12 ungated slices showed borderline agreement. Other CT measurements, and notably all those from the 3 gated and ungated scans, acquired at the same anatomic level, did not agree. Conclusions: Although the procedure can be difficult for individual patients, spirometric gating significantly influences the lung density CT measurements and might improve standardization of CT evaluation of COPD. Index Terms: high-resolution computed tomography, chronic obstructive pulmonary disease, spirometric gating

The most recent guidelines define COPD in a multidimensional way, nevertheless the diagnosis is still linked to the limitation of airflow, usually measured by the reduction in the FEV1/FVC ratio below 70%. However, the severity of obstruction is not directly correlated to symptoms or to invalidity determined by COPD. Thus, besides respiratory function, COPD should be evaluated based on symptoms, frequency and severity of exacerbations, patient’s functional status and health related quality of life (HRQoL). Therapy is mainly aimed at increasing exercise tolerance and reducing dyspnea, with improvement of daily activities and HRQoL. This can be accomplished by a drug-induced reduction of pulmonary hyperinflation and exacerbations frequency and severity. All guidelines recommend bronchodilators as baseline therapy for all stages of COPD, and long-acting inhaled bronchodilators, both beta-2 agonist (LABA) and antimuscarinic (LAMA) drugs, are the most effective in regular treatment in the clinically stable phase. The effectiveness of bronchodilators should be evaluated in terms of functional (relief of bronchial obstruction and pulmonary hyperinflation), symptomatic (exercise tolerance and HRQoL), and clinical improvement (reduction in number or severity of exacerbations), while the absence of a spirometric response is not a reason for interrupting treatment, if there is subjective improvement in symptoms. Because LABA and LAMA act via different mechanisms of action, when administered in combination they can exert additional effects, thus optimizing (i.e. maximizing) sustained bronchodilation in COPD patients with severe airflow limitation, who cannot benefit (or can get only partial benefit) by therapy with a single bronchodilator. Recently, a fixed combination of ultra LABA/LAMA (indacaterol/glycopyrronium) has shown that it is possible to get a stable and persistent bronchodilation, which can help in avoiding undesirable fluctuations of bronchial calibre.

Objective To investigate the prevalence and features of asymptomatic pulmonary involvement in juvenile dermatomyositis (JDM). Methods Twelve JDM patients underwent pulmonary function tests at baseline, 12 and 24 months. Disease activity, duration, serum lactate dehydrogenase (LDH) values and antinuclear antibody (ANA) titres were also evaluated. Results Five patients showed lung impairment at baseline and four at 12 and 24 months. Forced expiratory volume in 1s, forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO) and alveolar volume were the most frequently altered variables, indicating a restrictive pattern and impairment of diffusion. The prevalence and features of pulmonary alterations did not change during follow-up. FVC values were significantly lower in active JDM patients and were inversely related to LDH. DLCO values were significantly lower in ANA-positive patients. About half of the patients of this small case series of JDM had asymptomatic lung disease. Conclusions We suggest that lung function should be evaluated at disease onset and regularly during follow-up, as pulmonary function tests can detect otherwise unpredictable pulmonary involvement.

We evaluated lung function in a group of patients affected by juvenile rheumatoid arthritis (JRA), without clinical and/or radiological signs of respiratory involvement. We compared the effects on pulmonary function of methotrexate (MTX) therapy combined with non-steroid anti-inflammatory drugs (NSAIDs) to those of NSAIDs alone and correlated lung function to subtype onset, disease duration and disease activity. Our patients were 27 JRA children, subdivided into two groups according to the therapy (group A = 14 patients, treated with a low dose of MTX and NSAIDs; group B = 13 patients, treated with NSAIDs alone). Clinical evaluation, haematological data and pulmonary function tests (PFTs) were obtained in each group at baseline (time 0) and at 1 year (time 1). At time 0 and time 1 PFTs were altered in 51.8% of JRA patients. The restrictive pattern (reduced forced vital capacity, FVC) was the most frequent feature, observed in 22.2% of patients. In group A the mean values of FVC, FEV1 (forced expiratory flow in 1 s), FRC (functional residual capacity), TLC (total lung capacity) and DLCO (diffusing lung capacity of carbon monoxide) were significantly lower compared to those of group B, at time 0 and at time 1. No functional parameter was correlated to subtype, duration or activity of the disease. Our study confirms that abnormalities in PFTs may be detected in JRA patients, even in the absence of clinical and/or radiological signs of lung disease; MTX in combination with NSAIDs does not seem to affect lung function at 1 year more than NSAIDs alone.

Respiratory responses to bronchoconstriction in asthma have been partially assessed and their significance is unclear. In 44 mild asthma patients we investigated respiratory responses during increasing levels of methacholine-induced bronchoconstriction. Inspiratory muscle activity, tidal volume, inspiratory and expiratory times were continuously monitored; breathing discomfort was rated. Mean inspiratory flow, respiratory frequency and ventilation were calculated. Lung function was assessed prior to and at maximum bronchoconstriction. Bronchoconstriction "dose-dependently" increased inspiratory muscle activity and breathing discomfort (P0.01). In 37 patients (84.1%), the increase in inspiratory muscle activity was associated with increases in mean inspiratory flow and ventilation (P0.01) because of selective rises in breathing depth (volume responders), or rate (frequency responders) or both (dual responders). In seven patients (15.9%) ventilation was unchanged. Individual respiratory responses were reproducible. With bronchoconstriction, frequency responders displayed greater hyperinflation and stronger breathing discomfort than volume responders (P0.01). Analysis of the responses to induced bronchoconstriction disclosed distinctive and reproducible respiratory adjustments that may identify functionally different asthma subpopulations.

We aimed to ascertain whether monitoring changes in transcutaneous (tc) oxygen partial pressure (PO2) may be used to determine the slope of the dose-response curves to inhaled methacholine. In 10 adult asthmatic patients, FEV1 and tcPO2 were simultaneously measured during inhalation of doubling methacholine concentrations. In each patient, the slopes of the methacholine dose-response curves for FEV1 and tcPO2 were similar and strongly correlated (r = 0.72; p < 0.05). The results indicate that tcPO2 monitoring represents a useful, reliable tool for analysis of the slope of dose-response curves to inhaled methacholine in asthmatic patients. It can also be used to investigate the pathophysiological implications of bronchial hyperreactivity.

COPD is a heterogeneous disorder whose assessment is going to be increasingly multidimensional. Grading systems such as BODE (Body-Mass Index, Obstruction, Dyspnea, Exercise), mBODE (BODE modified in grading of walked distance), ADO (Age, Dyspnea, Obstruction) are proposed to assess COPD severity and outcome. Computed tomography (CT) is deemed to reflect COPD lung pathologic changes. We studied the relationship of multidimensional grading systems (MGS) with clinically determined COPD phenotypes and CT lung density. Seventy-two patients underwent clinical and chest x-ray evaluation, pulmonary function tests (PFT), 6-minute walking test (6MWT) to derive: predominant COPD clinical phenotype, BODE, mBODE, ADO. Inspiratory and expiratory CT was performed to calculate mean lung attenuation (MLA), relative area with density below-950 HU at inspiration (RAI(-950)), and below -910 HU at expiration (RAE(-910)). MGS, PFT, and CT data were compared between bronchial versus emphysematous COPD phenotype. MGS were correlated with CT data. The prediction of CT density by means of MGS was investigated by direct and stepwise multivariate regression. MGS did not differ in clinically determined COPD phenotypes. BODE was more closely related and better predicted CT findings than mBODE and ADO; the better predictive model was obtained for CT expiratory data; stepwise regression models of CT data did not include 6MWT distance; the dyspnea score MRC was included only to predict RA-950 and RA-910 which quantify emphysema extent. BODE reflect COPD severity better than other MGS, but not its clinical heterogeneity. 6MWT does not significantly increase BODE predictivity of CT lung density changes.

Background Multidetector spiral computed tomography (CT) has opened the possibility of quantitative evaluation of emphysema extent in the whole lung. Visual assessment can be used for such a purpose, but its reproducibility has not been established. Purpose To assess agreement of detailed assessment of pulmonary emphysema on whole-lung CT using a visual scale. Material and Methods Thirty patients with chronic obstructive pulmonary disease underwent whole-lung inspiratory CT. Four chest radiologists rated the same 22 ± 2 thin sections using a visual scale which defines a range of emphysema extent between 0 and 100. Two of them repeated the rating two months later. Inter- and intra-operator agreement was evaluated with the Bland and Altman method. In addition, the percentage of emphysema at –950 Hounsfield units in the whole lung was determined using fully automated commercially available software for 3D densitometry. Results In three of six operator pairs and in one of two intra-operator pairs the Kendall τ test showed a significant correlation between the difference and the average magnitude of visual scores. Among different operators the half-width of 95% limits of agreement (95% LoA) was wide ranging between a score of 14.2–27.7 for an average visual score of 20 and between 18.5–36.8 for an average visual score of 80. Within the same operator the half-width of 95% LoA ranged between a score of 10.9–21.0 for an average visual score of 20 and between 25.1–30.1 for an average visual score of 80. The visual scores of the four radiologists were correlated with the results of densitometry ( P < 0.001; r = 0.65–0.81). Conclusion The inter- and intra-operator agreement of detailed assessment of emphysema in the whole lung using a visual scale is low and decreases with increasing emphysema extent.

We assessed with computed tomography (CT) densitometry the prevalence of emphysema in 266 (175 men and 91 women; mean age 64 +/- 4 years) smokers and former smokers enrolled in the ITALUNG trial of lung cancer screening with low-dose thin-slice CT. Whole-lung volume and the relative area at -950 Hounsfield units (RA(950)) and mean lung attenuation (MLA) in 1 of every 10 slices (mean, 24 slices per subject) were measured. Lung volume, MLA and RA950 significantly correlated each other and with age. Average RA950 >6.8% qualifying for emphysema was present in 71 (26.6%) of 266 subjects, with a higher prevalence in men than in women (30.3% vs 19.8%; p = 0.003). Only in smokers was a weak (r = 0.18; p = 0.05) correlation between RA950 and packs/year observed. In multiple regression analysis, the variability of RA950 (R2 = 0.24) or MLA (R2 = 0.34) was significantly, but weakly explained by age, lung volume and packs/year. Other factors besides smoking may also have a significant role in the etiopathogenesis of pulmonary emphysema.

We compared whole-lung densitometry with visual evaluation of pulmonary emphysema. Thirty patients with chronic obstructive pulmonary disease underwent multi-detector CT (150 mAs and 0.75 collimation) with double reconstruction: thick (5-mm) slices with smooth filter for whole-lung densitometry and thin (1 mm) slices with sharp filter for visual assessment (one of every ten slices). Densitometry and visual assessment were performed by three operators each, and the time required for assessment, the inter-observer agreement and the correlation with the results of the diffusion capacity of carbon monoxide (DL(CO)) in the same patients were computed. The average time for densitometry (8.49 +/- 0.13 min) was significantly longer (p < 0.0001) than that for visual evaluation (5.14 +/- 0.11 min). However, the inter-operator agreement ranged between "moderate" to "almost perfect" for densitometry (kappa range 0.58-0.87) and "slight" for visual (kappa = 0.20) assessment. The correlation coefficients of DL(CO) with relative area at -960 and -970 Hounsfield units (HU) (both r = -0.66) and of the first percentile point of lung density (r = 0.66) were slightly stronger than that of the visual score (r = -0.62). Densitometry should be preferred to visual assessment because it enables a more reproducible evaluation of the extent of pulmonary emphysema, which can be carried out on the entire lung in a reasonable amount of time.

Background: Induced sputum (IS) is a noninvasive tool, which can be used to collect cellular and soluble materials from lung airways. Objective: To evaluate if IS may be a useful and safe tool for the detection of airway inflammation in patients with interstitial lung disease (ILD) in systemic sclerosis (SSc). Methods: Sixty-eight patients with SSc and ILD as well as 18 healthy individuals (controls) were selected and submitted to IS examination. In 34 of 68 patients with SSc, bronchoalveolar lavage (BAL) was also performed. Safety of IS was assessed by comparison of forced expiratory volume in the first second (FEV1), FEV1/forced vital capacity ratio and peak expiratory flow before and after the IS procedure. Cell composition in samples collected by BAL and IS was correlated, and IS total and differential cell count in SSc patients and controls were compared. Results: The total number of cells was significantly higher in IS samples of SSc patients compared to those of healthy controls. Mean percentage of neutrophils was also higher in SSc patients (41.79 ± 23.89 vs. 27.37 ± 17.90), as well as lymphocytes (17.42 ± 19.70 vs. 3.13 ± 2.28) and eosinophils (2.35 ± 4.43 vs. 0.41 ± 0.46). On the other hand, mean percentage of macrophages was higher in healthy individuals (69.10 ± 19.15 vs. 36.96 ± 20.68). In fluid recovered by BAL, the most frequent cells were macrophages (67.89% ± 17.26), while neutrophils (14.77 ± 17.18%) and lymphocytes (15.62 ± 13.46%) were less frequent and eosinophils (1.66 ± 2.08%) were rare. A similar pattern of cell composition was found in IS samples (41.15 ± 21.67% of macrophages, 39.72 ± 23.15% of neutrophils, 15.28 ± 19.46% of lymphocytes and 2.56 ± 5.03% of eosinophils). Strength of correlation between BAL and IS was significant for macrophages and neutrophils. After IS procedure was performed, improvement of FEV1 (mean value before IS was 85.09 ± 14.44 and 88.93 ± 16.40 after IS) and FEV1/forced vital capacity (mean value before IS was 98.53 ± 12.11 and 105.22 ± 10.78 after IS) was observed. Conclusion: The IS method may allow a noninvasive assessment of cell composition in airway fluid and may contribute to the better understanding of upper/medium airway inflammation in SSc. Future studies are needed to verify whether IS can replace invasive procedures for the detection and monitoring of lung inflammation in SSc.

This paper is a post-hoc analysis of a previous study performed to investigate the relationship between computerized tomography (CT) and lung function in 51 outpatients with mild-to-moderate COPD. We studied whether changes in lung function and radiographic patterns may help to explain dyspnea, the most disturbing symptom in patients with COPD. The Medical Research Council (MRC) dyspnea scale shows, by univariate analysis, a similar strength of association to CT expiratory lung density and to DL(CO), a functional index of lung parenchymal loss. The MRC dyspnea scale shows a somewhat less strength of association with a small vertical heart on plain chest films. In multivariate analysis, the model with the strongest association to the MRC dyspnea scale (r = 0.76, p0.0001) contains 4 explanatory variables (DL(CO), FRC, PaCO(2), and radiographic pattern of pulmonary hypertension). We suggest that diffusing capacity reflects the emphysematous component of hyperinflation, associated by definition with destruction of terminal airspace walls, as distinct from the air trapping component, which is ascribed to airway obstruction and associated with FRC. PaCO(2) mainly reflects the ventilatory components, i.e., ventilatory drive and ventilatory constraints, of pulmonary gas exchange in COPD, while radiographic pattern of pulmonary hypertension likely reflects hypoxic vascular changes, which depend mainly on ventilation/perfusion mismatch and give rise to pulmonary arterial hypertension that may contribute per se to dyspnea. In conclusion, our analysis points out that chronic effort dyspnea variance may account for up to 58% (r(2) = 0.58) by lung function tests and radiographic patterns. Thus, about 42% of the MRC dyspnea variance remains unexplained by this model. On the other hand, dyspnea ascertainment is dependent on subjective behavior and evaluation and in tests is influenced by individual performance and perception. For example in the 6-minute walk test, a similar or higher proportion (60%) of the overall variance is unexplained.

For inhaled medications, bioequivalence testing is becoming increasingly important owing to the availability of many inhalation devices. We evaluated agreement between the Finney bioassay and the Emax model in the assessment of bioequivalence of salbutamol administered via a metered-dose inhaler with a spacer (pMDI+ Volumatic) or via a dry-powder inhaler (Diskus) in asthmatic patients with methacholine-induced bronchoconstriction. Eighteen patients inhaled methacholine until FEV 1 decreased by approximately 35% of control. Following inhalation of placebo, 200 and 400 mcg salbutamol through the pMDI+ Volumatic or the Diskus, changes in FEV 1 were repeatedly measured over a 60-min observation period. Bioequivalence of salbutamol administered via the two inhalation devices was assessed by calculating the relative potency of each device by using the Finney 2-by-2 parallel regression analysis and the non-linear, Emax model. Agreement between these methods in calculating relative potency was evaluated by using the Bland-Altman method. After salbutamol FEV 1 values were similar irrespective of the device employed, and greater (P0.01) than those after placebo. However, assessment of relative potencies obtained with both the Finney (1.97, 90% CI 1.62-2.32) and the Emax (2.25, 90% CI 1.90-2.60) methods revealed that twice the salbutamol dose was needed to reverse methacholine-induced bronchoconstriction when the drug was inhaled via the Diskus than via the pMDI+ Volumatic. The mean difference in relative potency (-0.28, 90% CI -0.001 to -0.56) calculated with both methods did not significantly differ from zero, and none of the individual differences exceeded the limits of agreement. The Finney and the Emax methods provide comparable results in the evaluation of bioequivalence of different salbutamol formulations. The pMDI+ Volumatic is twice as efficient as the Diskus in lung delivery of salbutamol in asthma patients.

Gianna Camiciottoli,1 Stefano Diciotti,2 Francesca Bigazzi,1 Simone Lombardo,3 Maurizio Bartolucci,4 Matteo Paoletti,1 Mario Mascalchi,3 Massimo Pistolesi1 1Section of Respiratory Medicine, Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy; 2Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi,” University of Bologna, Cesena, Italy; 3Radiodiagnostic Section, Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy; 4Department of Diagnostic Imaging, Careggi University Hospital, Florence,Italy Abstract: A substantial proportion of patients with chronic obstructive pulmonary disease (COPD) develops various degree of intrathoracic tracheal collapsibility. We studied whether the magnitude of intrathoracic tracheal collapsibility could be different across clinical phenotypes and sex in COPD. Intrathoracic tracheal collapsibility measured at paired inspiratory–expiratory low dose computed tomography (CT) and its correlation with clinical, functional, and CT-densitometric data were investigated in 69 patients with COPD according to their predominant conductive airway or emphysema phenotypes and according to sex. Intrathoracic tracheal collapsibility was higher in patients with predominant conductive airway disease (n=28) and in females (n=27). Women with a predominant conductive airway phenotype (n=10) showed a significantly greater degree of collapsibility than women with predominant emphysema (28.9%±4% versus 11.6%±2%; P