Dina Visca

Serum Interleukin 6 Is Predictive of Early Functional Decline and Mortality in Interstitial Lung Disease Associated with Systemic Sclerosis

Objective. Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). Methods. A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. Results. In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD. Conclusion. In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

Fecal calprotectin concentrations in alcoholic patients: a longitudinal study

Objectives Excessive alcohol consumption often results in intestinal damage, mediated by inflammatory processes, mainly characterized by an increased influx of leukocytes. Fecal calprotectin is a granulocyte cytosolic protein, representing as a promising marker of subclinical intestinal inflammation. In this study, we assessed fecal calprotectin concentrations (FCCs) in current drinking alcoholics, both at the baseline, and then during a subsequent 84-day period. Moreover, FCCs in the alcoholics were compared with the FCCs in healthy controls. Methods Twenty-eight, active-drinking alcoholics were enrolled in this study and compared with 40 healthy volunteers as the control group. In alcoholics, FCCs were determined at the beginning of the study (baseline; T0) and then every 2 weeks (T1–T6) during the following 84-day period. Potential differences in FCCs were analyzed between alcoholics and healthy controls, and during the 84-day period within the group of alcoholics. In addition, an analysis of FCCs was conducted in three subgroups of alcoholics, considering their drinking status during the 84-day period (abstinent, relapsed, and active). Results At baseline, no significant differences in median FCCs were found between alcoholics and controls. No significant changes of median FCCs were found, comparing baseline FCCs and FCCs during the 84-day period (T1-T6) in the whole group of alcoholics, nor in the three subgroups of alcoholics. Conclusion FCCs in active-drinking alcoholics are not significantly different, compared with the healthy controls. Moreover, FCCs do not significantly differ according to the alcohol drinking status. These results may suggest the absence of a subclinal intestinal inflammation involving neutrophils in the alcoholics.

Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial

BACKGROUND In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the Kings Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was associated with significant improvements in total K-BILD scores (mean 55·5 [SD 13·8] on oxygen vs 51·8 [13·6] on no oxygen, mean difference adjusted for order of treatment 3·7 [95% CI 1·8 to 5·6]; p<0·0001), and scores in breathlessness and activity (mean difference 8·6 [95% CI 4·7 to 12·5]; p<0·0001) and chest symptoms (7·6 [1·9 to 13·2]; p=0·009) subdomains. However, the effect on the psychological subdomain was not significant (2·4 [-0·6 to 5·5]; p=0·12). The most common adverse events were upper respiratory tract infections (three in the oxygen group and one in the no-treatment group). Five serious adverse events, including two deaths (one in each group) occurred, but none were considered to be related to treatment. INTERPRETATION Ambulatory oxygen seemed to be associated with improved HRQOL in patients with interstitial lung disease with isolated exertional hypoxia and could be an effective intervention in this patient group, who have few therapeutic options. However, further studies are needed to confirm this finding. FUNDING UK National Institute for Health Research.

Eligibility for the shorter regimen for multidrug-resistant tuberculosis in Mexico

We read with interest the articles by Sotgiu et al. [1] and Dalcolmo et al. [2], which initiated a debate on the suitability of the shorter regimen for multidrug-resistant (MDR) tuberculosis (TB) cases in different settings [2–6]. The shorter World Health Organization (WHO) regimen [7, 8] is composed of an initial phase of 4–6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol. Comparing phenotypic and genotypic results in Mexico: guidance for the adoption of the shorter MDR-TB regimen http://ow.ly/MOxJ30hXkjd

Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD

Proceedings of the European Seminars in Respiratory Medicine course, Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD, held in Taormina, Italy, on 3-4 March, 2017.

Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review

The World Health Organization (WHO) estimated that 490 000 cases of multidrug-resistant (MDR) tuberculosis (TB) (defined as TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin) occurred in 2016. Among them, ∼6.2% had extensively drug-resistant (XDR) TB (i.e. TB caused by MDR strains with additional resistance to fluoroquinolones and at least one second-line injectable drug) [1]. Efficacy and safety of co-administered bedaquiline and delamanid in MDR-TB patients http://ow.ly/Ctvj30kreEP

Airway inflammatory phenotypes: Making sputum cell evaluation more accessible for clinical use

Airway inflammation is a characteristic of the majority of asthmatic and chronic obstructive pulmonary disease (COPD) patients who show a predominant inflammatory phenotype. After the standardization of induced sputum procedure, several years ago, because of the lack of laboratory facilities, only a few dedicated laboratories are performing now this methodology to assess airway inflammation. Numerous studies have tried to identify airway inflammation surrogate markers however, sputum cell assessment provides information on both neutrophils and eosinophils simultaneously, which is crucial for a tailored therapy for COPD and asthmatic patients. We think that a more rapid and feasible technique for sputum cell evaluation might increase availability and use in routine practice of this procedure, particularly in periphery centres. Induced sputa were consecutively collected from 44 subjects (ie, 47.7%, with COPD; 52.2%, with asthma). Sputum was induced with 4.5% hypertonic saline solution and plugs were selected from saliva, gently mixed, divided into 2 parts, randomly coded and analysed with the 2 techniques (ie, processed or smeared samples). Processed sputum was treated with 0.1% dithiothreitol (DTT) according to the International Guidelines for sputum processing. Cells were counted and cytospins were stained with Diff-Quick solutions. For the second technique, selected plugs were gently smeared, avoiding excessive pressure of the material onto the slide. Slides were air dried and, then, stained with MayGrunwald/Geimsa. Differential cell count was performed following a blinded procedure, counting at least 500 nonsquamous cells. Quantitative variables were summarized with medians and interquartile ranges. Spearman correlations and Wilcoxon test for paired samples were carried out. The IRB of ICS Maugeri approved this study, conformed to the declaration of Helsinki. An informed consensus was signed by each patient to perform sputum induction. Sputum samples were smeared by health-care workers in a few minutes (processing procedure was longer: 30–45 minutes). Sputum differential cell counts were computed for both diagnostic techniques, but only neutrophil and eosinophil data were compared. No difference was found between sputum neutrophils and eosinophils evaluated with the 2 methodologies. When data were analysed divided according to patient’s diagnosis, sputum neutrophils were slightly higher in the smeared than in the processed samples of COPD patients 80.7% (67.4–94.4) and 74.2% (61.6–86.3) respectively, P5 .02. Smeared samples presented lower squamous cells than processed samples, 1.3% (0.6-3.6) and 2.4% (0.9-9.2) respectively. Sputum neutrophil and eosinophil counts, evaluated with the 2 techniques, were highly correlated (rho5 0.82, P< .0001; rho5 0.91, P < .0001 respectively). When sputa were classified according to the type of inflammation as neutrophilic(neutrophils 61%), eosinophilic(eosinophils 3%), mixed granulocytic(neutrophilic1 eosinophilic) or pauci granulocytic(neutrophils <61% and eosinophils <3%), we obtained the same inflammatory pattern in 38/44 samples (Table 1). Small amounts of plugs were suitable for smearing and not for processing. Cell viability and plug weight did not affect any data comparisons. Smearing technique could be affected by the characteristics of the sample, if sputum is homogenous, as in most COPD patients, every part taken to be smeared is likely similar to another, while when the sample is composed by many small and different plugs, particular care should be paid in selecting the material to be smeared and more slides should be prepared to obtain reliable data. The first studies using induced sputum to assess airway inflammation were performed smearing the samples, but to the best of our knowledge no study compares the results obtained processing and smearing the samples. Smearing sputum provides information similar to those obtained processing the sample, particularly on eosinophils and neutrophils. Difference in neutrophilic cell counts between the 2 methods in COPD patients could be explained with neutrophil fragility: part of these cells could be damaged by the processing procedure with DTT and by the centrifugation steps. Although present at low percentages, squamous cells were significantly higher in processed than in smeared

S57 Predictors of uptake of ambulatory oxygen on completion of the ambox trial, a study to assess effects of ambulatory oxygen on quality of life in patients with fibrotic interstitial lung disease

Background There are no ILD specific guidelines on the use of ambulatory oxygen. The AmbOx trial is a multicenter, randomised, cross-over controlled trial (NCT02286063), to assess quality of life during two weeks on ambulatory oxygen compared to two weeks off oxygen, in patients with fibrotic ILD. Methods Individuals with fibrotic ILD whose oxygen saturation was normal at rest, but dropped to ≤88% on a 6MWT, with stable symptoms during a two week run-in period, were recruited and randomised. Primary outcome: health status assessed by King’s Brief ILD questionnaire (KBILD). A simple question on whether breathlessness had changed (better, same, worse) over the previous two weeks was a key secondary outcome. Patients‘ experiences with portable oxygen were explored through interviews in a subgroup. At the end of the four week trial period, patients were asked if they wished to continue with the ambulatory oxygen. Results Out of 84 randomised patients, 76 completed the trial. Mean age 64.5±1.1 years, 58 males, 53 ever smokers, FVC 73.3%±19.1%, DLCO 38.7%±12.8%. 43 patients had possible/definite IPF. Ambulatory oxygen, compared to no oxygen, was associated with improvements in total KBILD score (p<0.0001). At the end of the two weeks on oxygen, the majority of patients reported improved breathlessness (better:52/76 – same:23/76 – worse:1/76), compared to the two weeks on no oxygen (better 1/76 – same:57/76 – worse:18/76). On trial completion, 51/76 (67%) of patients chose to continue on ambulatory oxygen. On multivariate analysis, factors independently predictive of the patient’s decision to continue, included younger age (64.8 vs 72.8 years, p=0.002), more severe disease (CPI 55.5 vs 49.1, p=0.003) and patient’s global assessment of improvement in breathlessness (OR 3.2, p=0.018). Despite symptomatic improvements in the majority, ambulatory oxygen was also associated with a number of patient-reported challenges, explored in the patient interviews.

Is bronchodilator the correct treatment for COPD subjects before EBUS

Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a reliable and commonly established technique, enabling real-time guidance of transbronchial needle aspiration of mediastinal and hilar structures and parabronchial lung masses. As EBUS-TBNA became more available and adopted by clinicians, questions emerged about the optimal performance of the procedure. Although EBUS is considered safe, there are few complications that could occur during the test, correlated with both the procedure itself and the patients characteristics. Moreover, this technique is often addressed to patients with overlapping airways diseases, which might have higher risk of complications during the procedure. Chronic obstructive pulmonary disease (COPD) patients could experience EBUS-TBNA with a relative high frequency due to their risk of developing lung cancer. The irreversible bronchial constriction characteristic of the disease raises some questions on premedication before bronchoscopic procedures. It is mandatory to optimize every aspect of the procedure in order to minimize the risk of complications, especially for fragile patients. Whether the use of inhaled bronchodilators before the procedure could improve the outcome of the procedure in COPD patients is reviewed in this article. No clear indication emerged from the literature suggesting the need of more studies in order to clarify this point.

P32 Role of non acid and proximal reflux in scleroderma-associated interstitial lung disease

Background Oesophageal involvement is extremely common in patients with scleroderma. This prospective observational study (NCT02136394) addresses the relationship between gastro-oesophageal reflux (GORD) and scleroderma-associated interstitial lung disease (SSc-ILD), and evaluates the clinical utility of noninvasive tests of microaspiration. Materials and methods We present preliminary results of the first 27 enrolled patients (median age 59 [min/max 35/79], median FVC = 74% [38/128%], median DLCO = 39% [21/72%], female 70%, diffuse SSc 33%). Collected clinical data included 24 hr impedance (carried out off PPI), respiratory (K-BILD and Leicester cough questionnaires) and GORD symptom questionnaires (UCLA SCTC GIT 2.0 Questionnaire, Reflux Disease Questionnaire RDQ), as well as full lung function test data. Pepsin levels were measured in saliva in all patients, and in a subset of 6 patients in bronchoalveolar lavage (BAL). Results Non acid reflux and proximal reflux were detected in 54% and 49% of patients, respectively. In the subgroup of patients with normal DeMeester score (i.e. global impedance index of acid exposure), 66% had non acid reflux episodes. The DeMeester score (median 14.2 [min/max 0.8/156]) was correlated with total scores GORD questionnaire scores (e.g. RDQ, r = 0.68 p = 0.003; GIT 2.0, r = 0.68 p = 0.004), but not with K-BILD, Leicester questionnaire, or saliva pepsin. Proximal reflux episodes were moderately correlated with the Leicester total score (r = -0.76 p = 0.002) and with saliva pepsin (r = 0.46 p = 0.05). Saliva pepsin (median concentration 2.34 ng/ml [2.34/12.4]) was correlated with the impedance cough index association (r = 0.53, p = 0.02). BAL pepsin was present in all six cases (median concentration 2.34 ng/ml [2.34/12.4]) and was correlated with FVC (r = -0.8, p = 0.04). Lung function test parameters were not correlated with saliva pepsin, but were significantly, if loosely, correlated with impedance measures of acid exposure in the recumbent position (e.g.% time of exposure, r = -0.43 p = 0.04). Conclusions Proximal and non acid reflux are highly prevalent in the SSc-ILD population and are associated with a high symptom burden. Pepsin is measurable in BAL of SSc-ILD patients and suggests microaspiration into the lungs, although larger numbers are needed to confirm these findings and define whether saliva pepsin measurement could represent a useful non invasive marker of microaspiration.