Paul De Vuyst

Lung function in idiopathic pulmonary fibrosis - extended analyses of the IFIGENIA trial

BackgroundThe randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.MethodsWe analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.ResultsIn trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.ConclusionThis descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.Trial RegistrationRegistered at http://www.ClinicalTrials.gov; number NCT00639496.

'Black Spots' and hyaline pleural plaques on the parietal pleura of 150 urban necropsy cases.

The absence of any direct connection between the lung and the parietal pleura raises questions about the mechanisms of pleural migration and retention of inhaled particles. It has been suggested that specific areas of parietal pleura absorb and retain inorganic particles from the pleural space, including carbon pigments and asbestos fibers, and could be starting points for pathologic changes induced by mineral fibers. These particle-collecting structures have been called “black spots.” To study their distribution, macroscopic appearance, and possible relationship with pleural plaques, the parietal pleura of 150 consecutive necropsies of urban dwellers (mean age 67.7 ± 12.9 years) were examined. The size and intensity of spots were scored and recorded on a computer scheme together with information of the presence of pleural plaques. Black spots were observed in 92.7% of the cases. They were mainly located in the lower costal and diaphragmatic zones and could correspond to the anatomic distribution of structures involved in pleural cavity clearance. Scores correlated with sex and age. There was no relationship between the predominant locations of black spots and hyaline pleural plaques.

ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia.

Viral diseases of the respiratory tract, which include influenza pandemic, children acute bronchiolitis, and viral pneumonia of the elderly, represent major health problems. Plasmacytoid dendritic cells play an important role in anti-viral immunity, and these cells were recently shown to express ChemR23, the receptor for the chemoattractant protein chemerin, which is expressed by epithelial cells in the lung. Our aim was to determine the role played by the chemerin/ChemR23 system in the physiopathology of viral pneumonia, using the pneumonia virus of mice (PVM) as a model. Wild-type and ChemR23 knock-out mice were infected by PVM and followed for functional and inflammatory parameters. ChemR23−/− mice displayed higher mortality/morbidity, alteration of lung function, delayed viral clearance and increased neutrophilic infiltration. We demonstrated in these mice a lower recruitment of plasmacytoid dendritic cells and a reduction in type I interferon production. The role of plasmacytoid dendritic cells was further addressed by performing depletion and adoptive transfer experiments as well as by the generation of chimeric mice, demonstrating two opposite effects of the chemerin/ChemR23 system. First, the ChemR23-dependent recruitment of plasmacytoid dendritic cells contributes to adaptive immune responses and viral clearance, but also enhances the inflammatory response. Second, increased morbidity/mortality in ChemR23−/− mice is not due to defective plasmacytoid dendritic cells recruitment, but rather to the loss of an anti-inflammatory pathway involving ChemR23 expressed by non-leukocytic cells. The chemerin/ChemR23 system plays important roles in the physiopathology of viral pneumonia, and might therefore be considered as a therapeutic target for anti-viral and anti-inflammatory therapies.

Imaging of occupational and environmental disorders of the chest

The Basics for Understanding Imaging: Epidemiolog.- Responses of the Respiratory System to Inhaled Agents (Airways, Lung, and Pleura).- Mineral Dusts and Fibers.- Bioaerosols and Organic Dusts.- Chemicals and Pollutants (Including Acute Lung Injury and Long-Term Sequellae).- Diagnostic Techniques.- Imaging Techniques.- ILO Classification.- Lung Function Studies.- Mineralogic Analyses.- Immunological Methods.- Imaging: Lung Effects of Cigarette Smoking.- Silicosis.- Coal Workers Pneumoconiosis.- Asbestosis.- Benign Asbestos-Related Pleural Diseases.- Malignant Mesothelioma.- Berylliosis.- Hard-Metal and Cobalt Disease.- Dental Technicians Pneumoconiosis.- Other Uncommon Pneumoconioses.- Hypersensitivity Pneumonitis.- Subject Index.- List of Contributors

PET/CT with 18F-FDG– and 18F-FBEM–Labeled Leukocytes for Metabolic Activity and Leukocyte Recruitment Monitoring in a Mouse Model of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. Methods: C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with 18F-FDG– or 18F-4-fluorobenzamido-N-ethylamino-maleimide (18F-FBEM)–labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. Results: In bleomycin-treated mice, a higher metabolic activity was measured on 18F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by 18F-FBEM–labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. Conclusion: 18F-FDG– and 18F-FBEM–labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected.

Asbestos Exposure During Uncontrolled Removal of Sprayed-on Asbestos

Asbestos-containing materials in place in buildings, especially sprayed-on asbestos, are still an important health threat. Clearance of these materials has to be operated by specifically trained workers wearing specific individual protection suits after containment of the contaminated area. Good work practices are, however, not always applied. We report the case of two workers hired for ∼1 week to remove sprayed-on amosite asbestos during the remodeling of a former industrial hall. Regulatory protective equipments were not used. A legal action was initiated after disclosure of the working conditions. Medical examinations were performed 18 and 22 months after exposure. Workers denied any other asbestos exposure. Lung function tests and chest computed tomography scans were normal. Very high levels of asbestos fibers and bodies were discovered on mineralogical analysis of bronchoalveolar lavage fluid (BALF) by phase contrast light microscopy and analytical electron microscopy. All fibers were amosite. An extrapolation considering duration of exposure, breathing pattern, and BALF fiber content suggests that the workers were exposed to airborne fiber concentrations in the range from several tens to about a hundred World Health Organization fibers per milliliter air. In conclusion, exposures to historical airborne fiber levels prevailing half a century ago may still occur today when the work regulations are not applied. In these conditions, even very short exposures may result in considerable lung fiber retention in case of amphibole exposure with the subsequent risk for developing asbestos-related diseases. Fiber analysis in BALF is useful to clarify such exposures.