Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial.

BACKGROUND: The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension. METHODS: We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40-80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing. FINDINGS: Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI -11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group. INTERPRETATION: Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil. FUNDING: F Hoffmann-La Roche.

Combined pulmonary fibrosis and emphysema characteristics in a Greek cohort.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) has recently received great attention, with studies suggesting that it presents a distinct clinical entity while others have challenged this hypothesis. This nationwide study aimed to describe a large cohort of Greek CPFE patients and to examine potential prognostic factors for survival. METHODS: This retrospective study included 97 patients with CPFE. Demographic and clinical data, pulmonary function tests, echocardiography results and bronchoalveolar lavage analysis were recorded. RESULTS: Most patients were male (94.8%) and 92% were current or ex-smokers. Spirometry results were abnormal (forced vital capacity (FVC) 72.9±19.9% pred and forced expiratory volume in 1 s/FVC 82.9±9.7%) with reduced diffusing capacity of the lung for carbon monoxide (D LCO) (42.3±17.4% pred). Mean systolic pulmonary arterial pressure was 41.9±19.7 mmHg and pulmonary hypertension was present in 58.8% of patients. Mean 6-min walk distance was 335.4±159.4 m. Mean emphysema score was 14.23±8.69% and mean interstitial lung disease (ILD) extent was 39.58±19.82%. Mean survival was 84 months (95% CI 72-96 months). Patients with D LCO ≥39% pred had better survival than patients with D LCO <39% pred (p=0.031). Patients with ILD extent ≥30% had worse survival than patients with ILD extent <30% (p=0.037). CONCLUSIONS: Our results indicate that CPFE patients have preserved lung volumes associated with disproportionately reduced D LCO, while reduced D LCO and increased ILD extent was associated with worse prognosis.

Ventilator-associated pneumonia or endotracheal tube-associated pneumonia? An approach to the pathogenesis and preventive strategies emphasizing the importance of endotracheal tube.

Ventilator-associated pneumonia is the most common nosocomial infection in the intensive care unit, and it is associated with prolonged hospitalization, increased health care costs, and high attributable mortality. During the past several decades, numerous studies focused on the crucial role of the endotracheal tube (ETT) in the pathogenesis of ventilator-associated pneumonia. Tracheal intubation thwarts the cough reflex, compromises mucocilliary clearance, injures the tracheal epithelial surface, provides a direct conduit for rapid access of bacteria from upper into the lower respiratory tract, and allows the formation of biofilm on the ETT surface. The combination of these factors puts the mechanically ventilated patient at great jeopardy of developing ventilator-associated pneumonia. Many preventive strategies have arisen from this understanding: control of intracuff pressure, aspiration of subglottic secretions, decontamination of subglottic area, use of antiseptic impregnated ETTs, and elimination or prevention of the ETT biofilm formation. The authors review the role of ETT management for the prevention of the ventilator-associated pneumonia.

Investigation of IL-18 and IL-12 in induced sputum of patients with IPF before and after treatment with interferon gamma-1b.

BACKGROUND AND AIM: Interleukin-18 (IL-18) has been identified as an interferon-gamma (IFN-gamma) mediator, promoting a T helper 1 (Th1) response. Th1 response is characterized by increased expression of IFN-gamma, interleukin-12 (IL-12) and interleukin-18 (IL-18). The present study aims to evaluate the role of Th1 cytokines by monitoring changes in Induced Sputum (IS) samples, before and after treatment with IFN-gamma-1b in patients with IPF. PATIENTS AND METHODS: Fifteen patients with histologically confirmed IPF/UIP (12 male, 3 female) of median age 65 yr were prospectively studied. Ten healthy subjects (5 female, 5 male) of median age 61 yr served as control group. Patients were assigned to receive IFN-gamma-1b 200 microg (15 patients) subcutaneously three times per week for 12 months. Induced sputum (IS) IL-12 and IL-18 levels were measured before and after IFN-gamma-1b treatment in IPF patients as well as in healthy controls, using ELISA immunoassay. RESULTS: The IL-18 levels were significantly higher in IPF samples before treatment than in healthy controls (57.05 +/- 6.9 pg/ml vs. 41.07 +/- 8.16 pg/ml, p < 0.05). A statistically significant decrease was detected in the IL-18 levels after IFN-gamma-1b treatment (57.05 +/- 6.9 vs. 42.8 +/- 5.1 pg/ml, p = 0.04). The IL-12 supernatant levels measured before and after IFN-gamma-1b treatment were not significantly different. CONCLUSIONS: Our results may illustrate the potential role of IL-18 as an inflammatory molecule in the pathogenesis of IPF. Moreover, decrease of IL-18 levels in IPF patients, after 12 months of therapy could possibly be explained as IL-18 downregulation after IFN-gamma-1b treatment. Extended studies are needed to determine the precise role of IL-12 and IL-18 during IPF.

Induced sputum versus bronchoalveolar lavage fluid in the evaluation of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Induced sputum (IS) has been proposed as a useful noninvasive method for the assessment of airway diseases. Bronchoalveolar lavage fluid (BALF), an important tool for evaluating interstitial lung diseases, has limited utility due to its invasiveness and the difficulties of performing it in severely ill patients, while it is impractical for follow-up evaluation. OBJECTIVES: The aim of this study was to investigate the differences and the possible correlation of cell differential and lymphocyte subpopulations between BALF and IS samples in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We studied prospectively 20 patients (18 male, 2 female) of median age 67 years (range 40-75) with IPF and 10 normal subjects (5 female, 5 male) of median age 59 years (range 36-70). IS was performed with hypertonic saline solution using an ultrasonic nebulizer (Ultraneb 2000). BALF was performed by a conventional procedure using fiberoptic bronchoscopy within 3 days from IS. May-Grunewald-Giemsa-stained preps were differentially counted and T-lymphocyte subsets were analyzed by a flow-activated cell sorter. RESULTS: The percentage of macrophages was significantly lower in IS than in BALF (p < 0.0001), while the neutrophils were lower in BALF (p < 0.0001). A significant correlation was found between BALF and IS eosinophil counts (r = 0.54, p = 0.01) and CD4+/CD8+ ratio (r = 0.74, p < 0.0001). CONCLUSION: Our data suggest that different information is obtained by IS and BALF and thus, the two methods are complementary in IPF.

Th1 cytokine pattern (IL-12 and IL-18) in bronchoalveolar lavage fluid (BALF) before and after treatment with interferon gamma-1b (IFN-gamma-1b) or colchicine in patients with idiopathic pulmonary fibrosis (IPF/UIP).

BACKGROUND AND AIM: Characterization of the biologic effects of Th1 cytokines will enhance the understanding of idiopathic pulmonary fibrosis (IPF) pathogenesis and treatment selection. Th1 response is characterized by increased expression of IFN-gamma, interleukin (IL)-12 and IL-18. The present study aims to evaluate the role of Th1 cytokines and their possible changes in the bronchoalveolar lavage fluid (BALF), before and after treatment with IFN-gamma-1b or colchicine. PATIENTS AND METHODS: We studied prospectively 10 patients (8 male, 2 female) of median age 67 yr with histologically confirmed IPF/UIP. Patients were randomly assigned to receive either IFN-gamma-1b 200 microg sc (5 patients) or colchicine 1 mg qd (5 patients) plus prednisone 10 mg qd. BALF IL-12 and IL-18 levels were measured before and after treatment. RESULTS: BALF IL-12 levels before and after treatment did not differ significantly between the two treatment groups. However, BALF IL-18 levels were significantly decreased after treatment with IFN-gamma-1b (mean +/- SD, 58.4 +/- 15.6 pg/mL vs 42.8 +/- 4.90 pg/mL, p < 0.05). A significant difference was also found after treatment with colchicine (mean +/- SD, 66.8 +/- 36.9 pg/mL vs 42.6 +/- 1.08 pg/mL, p < 0.01). A significant correlation was found between IL-18 BALF levels and the BALF neutrophils (r = 0.75, p = 0.024). CONCLUSION: Our data suggest the potential role of IL-18 as an inflammatory marker in the pathogenetic pathway of IPF such as its possible downregulation by IFN-gamma-1b treatment. Further studies are needed in a higher number of patients in order to define the precise role of both cytokines during the immunoregulatory response with IFN-gamma-1b.