Antonio Xaubet

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Pulmonary Sarcoidosis: Typical and Atypical Manifestations at High-Resolution CT with Pathologic Correlation

Sarcoidosis is a multisystem disorder that is characterized by noncaseous epithelioid cell granulomas, which may affect almost any organ. Thoracic involvement is common and accounts for most of the morbidity and mortality associated with the disease. Thoracic radiologic abnormalities are seen at some stage in approximately 90% of patients with sarcoidosis, and an estimated 20% develop chronic lung disease leading to pulmonary fibrosis. Although chest radiography is often the first diagnostic imaging study in patients with pulmonary involvement, computed tomography (CT) is more sensitive for the detection of adenopathy and subtle parenchymal disease. Pulmonary sarcoidosis may manifest with various radiologic patterns: Bilateral hilar lymph node enlargement is the most common finding, followed by interstitial lung disease. At high-resolution CT, the most typical findings of pulmonary involvement are micronodules with a perilymphatic distribution, fibrotic changes, and bilateral perihilar opacities. Atypical manifestations, such as masslike or alveolar opacities, honeycomb-like cysts, miliary opacities, mosaic attenuation, tracheobronchial involvement, and pleural disease, and complications such as aspergillomas, also may be seen. To achieve a timely diagnosis and help reduce associated morbidity and mortality, it is essential to recognize both the typical and the atypical radiologic manifestations of the disease, take note of features that may be suggestive of diseases other than sarcoidosis, and correlate imaging features with pathologic findings to help narrow the differential diagnosis.

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis.

Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% (P<0.01) and 74% (P<0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX(600), a competitive inhibitor of ACE-2 (P<0.05). Administration of either ACE-2 siRNA or DX(600) significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX(600)-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

Systemic inflammatory response after bronchoalveolar lavage in critically ill patients

Bronchoscopic bronchoalveolar lavage (BAL) may be followed by a systemic inflammatory response. Previous reports have suggested pneumonia as a predisposing condition and systemic cytokines as possible mediators. To test this hypothesis, systemic levels of interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were studied before and at 12 h and 24 h after bronchoscopically guided BAL in 30 mechanically ventilated patients (median age 67 (range 54-76) yrs, simplified acute physiology score II (SAPS II) 33 (12-56)), 20 of whom had pneumonia and 10 of whom were control patients without pneumonia. Arterial oxygen partial pressure to inspired oxygen fraction ratio (Pa,O2/FI,O2), body temperature, mean arterial pressure, and cardiac frequency were recorded. The majority of patients (28/30, 93%) received antibiotic treatment prior to the procedure. Pa,O2/FI,O2 ratio was lower at 12 h compared to baseline in patients with pneumonia (baseline median 192 (range 65-256); 12 h 160 (66-190) mmHg, p<0.001) and ventilated controls (baseline 293 (205-473); 12 h 226 (153-330) mm Hg p=0.011), but returned to baseline levels at 24 h (pneumonia: 194 (92-312), p=0.991; controls: 309 (173-487) mmHg, p=0.785). No changes in other clinical variables were observed. Systemic TNF-alpha levels before BAL (pneumonia: 35 (10-88); controls: 17 (0-33) pg x mL(-1)) did not increase at 12 h (pneumonia: 35 (0-64); p=0.735; controls: 16 (0-21) pg x mL(-1), p=0.123 comparison to baseline) or 24 h (pneumonia: 31 (0-36), p=0.464; controls: 19 (0-43) pg x mL(-1), p=0.358). No changes of IL-1beta (baseline: pneumonia 0 (0-13); controls 1 (0-32) pg x mL(-1)) or IL-6 (baseline: pneumonia, 226 (9-4300); controls, 53 (0-346) pg x mL(-1)) were detected. No deterioration of clinical variables and no increase in systemic cytokine release has been observed after bronchoalveolar lavage, in critically ill patients. The potential cytokine increase is probably too small, in relation to the pre-existing inflammatory response, to yield clinical significance in this population otherwise antibiotic therapy may have been protective.