The Experts below are selected from a list of 1080 Experts worldwide ranked by ideXlab platform

R M Du Bois - One of the best experts on this subject based on the ideXlab platform.

  • idiopathic pulmonary fibrosis cryptogenic Fibrosing Alveolitis
    Clinical and Experimental Medicine, 2003
    Co-Authors: J M Fellrath, R M Du Bois
    Abstract:

    Idiopathic pulmonary fibrosis (IPF), synonymous with cryptogenic Fibrosing Alveolitis (CFA), is a progressive and usually fatal disease of unknown cause characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Historically, IPF/CFA encompassed a heterogeneous group of different histological and clinical entities arising in an idiopathic setting. Recently, the American Thoracic Society (ATS) and European Respiratory Society (ERS) core committee has redefined diagnostic criteria for both IPF/CFAand idiopathic interstitial pneumonias confining the term IPF/CFA to patients with a histological pattern of usual interstitial pneumonia on lung biopsy. This review attempts to refine the clinico-radiological-pathological features that together define IPF/CFA as it is understood today, and to summarize the rationale of new therapeutic approaches based on the current understanding of the pathogenetic mechanisms.

  • cryptogenic Fibrosing Alveolitis idiopathic pulmonary fibrosis
    The European respiratory journal. Supplement, 2001
    Co-Authors: R M Du Bois, Au Wells
    Abstract:

    Cryptogenic Fibrosing Alveolitis (CFA), synonymous with idiopathic pulmonary fibrosis (IPF), remains a life-threatening disease: 50% of patients die within 5 yrs. Historically, many diseases that are now considered to be quite distinct have been "labelled" as CFA. More recently, high-resolution computed tomography and new appreciation of the histopathological patterns of idiopathic interstitial pneumonias have enabled disease variants to be defined according to their different responses to therapy and survival. CFA is believed to be induced by an external agent, although it is not clear whether CFA represents the final common outcome of numerous pathogenetic mechanisms or has a single cause. In addition, there are currently no prospective double-blind, placebo-controlled trials of treatment showing superiority of one drug regimen over another. This review attempts to dissect the different patterns of cryptogenic Fibrosing Alveolitis, illustrate the major features of each, and refine the clinico-radiological-pathological descriptors that together define cryptogenic Fibrosing Alveolitis as it is understood today.

  • different cytokine profiles in cryptogenic Fibrosing Alveolitis and Fibrosing Alveolitis associated with systemic sclerosis a quantitative study of open lung biopsies
    European Respiratory Journal, 1999
    Co-Authors: S Majumdar, R M Du Bois, C M Black, Panagiotis Pantelidis, T Ansari, Mariusz J Gizycki, Peter K. Jeffery
    Abstract:

    Differences in the inflammatory response and prognosis of cryptogenic Fibrosing Alveolitis (CFA) and that associated with systemic sclerosis (FASSc) are beginning to emerge. It is hypothesized that these differences may be reflected in a distinct pattern of T-helper (Th)-1 and Th-2-type cytokines. Open lung biopsies were obtained from clinically well-documented cases of CFA and FASSc and, as a control, compared with grossly and histologically normal parenchyma obtained from smokers whose lungs were resected for cancer (n=5 in each group). In situ hybridization (ISH) was applied to the samples using anti-sense and sense 35S-labelled riboprobes to detect messenger ribonucleic acid (mRNA) for interleukins (IL)-2, IL-4, IL-5 and interferon (IFN)-gamma. Between 52-91% of cells expressing the cytokines studied were present in the alveolar interstitium rather than in lumenal cells or the alveolar epithelial lining. The highest values for all four cytokines were present in the patients with FASSc, i.e., 22-39 ISH positive cells x mm(-2) alveolar tissue compared with 1-19 cells x mm(-2) and 4-5 cell x mm(-2) in CFA and control subjects, respectively. Whereas the proportions of the four cytokines in FASSc were similar to the control subjects, IL-4 and IL-5 predominated significantly in CFA (p<0.001). For example, the ratio of IL-5 to IFN-gamma was 22:1 in CFA, significantly higher than in the cases with FASSc (2:1) or the control subjects (4:1) (p<0.05). In conclusion, cryptogenic Fibrosing Alveolitis is an inflammatory condition which is characterized, like asthma, by a predominance of gene expression for T-helper-2-type regulatory cytokines, whereas cryptogenic Fibrosing Alveolitis associated with systemic sclerosis appears to have a distinct mixed T-helper-1/T-helper-2 functional phenotype and a greater number of cells expressing each of these pro-inflammatory cytokines.

  • exhaled nitric oxide is increased in active Fibrosing Alveolitis
    Chest, 1999
    Co-Authors: Paolo Paredi, R M Du Bois, Panagiotis Pantelidis, Sergei A Kharitonov, Stelios Loukides, Peter J Barnes
    Abstract:

    Study objectives Interstitial inflammation is a major aggravating factor in Fibrosing lung disease associated with scleroderma (FASSc) and cryptogenic Fibrosing Alveolitis (CFA). Exhaled nitric oxide (NO) production is increased in asthma and bronchiectasis and reflects the degree of inflammation. We investigated whether measuring levels of exhaled NO is valuable in assessing disease activity in patients with CFA and patients with FASSc. Measurements and results NO levels were measured in 11 patients with CFA (mean age ± SEM, 58 ± 12 years old; 5 were male) and 17 patients with FASSc (mean age, 48 ± 9 years old; 5 were male), and they were compared to BAL cell counts and lung function. Patients with CFA and FASSc had elevated NO levels (11.2 ± 1.0 parts per billion [ppb] and 9.8 ± 1.0 ppb, respectively; p > 0.05), whereas in a group of 13 nonsmoking normal subjects, the NO levels were not elevated (6.9 ± 0.5 ppb; p 14%, neutrophils > 4%, or eosinophils > 3%) had significantly higher NO levels (13.2 ± 1.8 ppb), and neutrophil (16.5 ± 4.0%) and lymphocyte (26.8 ± 3.4%) BAL cell counts than did patients with FASSc who had inactive BAL (6.7 ± 1.2 ppb; 1.3 ± 1.0% and 7.5 ± 1.3%, respectively; p Conclusions We conclude that exhaled NO may be a useful addition to BAL cell counts in disease monitoring.

  • t cell receptor gene usage in patients with Fibrosing Alveolitis and control subjects
    European Journal of Clinical Investigation, 1999
    Co-Authors: P A Lympany, C M Black, A.m. Southcott, K I Welsh, A W Boylston, R M Du Bois
    Abstract:

    BACKGROUND Fibrosing Alveolitis is characterized by inflammation, fibrosis and increased numbers of activated CD4+ T-cells in the lower respiratory tract. The aims of this study were to compare the T-cell antigen receptor repertoire in the lungs of subjects with Fibrosing Alveolitis systemic sclerosis (FASSc) with cryptogenic Fibrosing Alveolitis (CFA) and normal control subjects, to determine whether FASSc is driven by a specific T-cell trigger and is determined by a T-cell driven immune response, and to assess the clonality of CD4+ and CD8+ TcR usage in subjects with FASSc. MATERIALS AND METHODS We used reverse transcription polymerase chain reaction with specific V alpha- and V beta-chain primers to identify the TcR gene usage in biopsy material, bronchoalveolar lavage fluid or peripheral blood from our subjects. RESULTS We found individual-specific restriction of V alpha- and V beta-chain usage in lung biopsies from patients and control subjects. To establish whether this was due to expression bias in the CD4+ or CD8+ T-cells and was restricted to the lung, the alpha beta-T-cell receptor chain usage was assessed in T-cell subsets separated from the lungs of patients with Fibrosing Alveolitis and was compared with that of the peripheral blood. There was no consistent difference in the expression of any variable family chain among the population studied, although there was a significant difference between lung and peripheral blood lymphocyte V beta-families in CD8+ T-cells (P = 0.0007). CONCLUSION We conclude that there is individual TcR V alpha- and V beta-expression bias in subjects with Fibrosing Alveolitis.

Au Wells - One of the best experts on this subject based on the ideXlab platform.

  • cryptogenic Fibrosing Alveolitis idiopathic pulmonary fibrosis
    The European respiratory journal. Supplement, 2001
    Co-Authors: R M Du Bois, Au Wells
    Abstract:

    Cryptogenic Fibrosing Alveolitis (CFA), synonymous with idiopathic pulmonary fibrosis (IPF), remains a life-threatening disease: 50% of patients die within 5 yrs. Historically, many diseases that are now considered to be quite distinct have been "labelled" as CFA. More recently, high-resolution computed tomography and new appreciation of the histopathological patterns of idiopathic interstitial pneumonias have enabled disease variants to be defined according to their different responses to therapy and survival. CFA is believed to be induced by an external agent, although it is not clear whether CFA represents the final common outcome of numerous pathogenetic mechanisms or has a single cause. In addition, there are currently no prospective double-blind, placebo-controlled trials of treatment showing superiority of one drug regimen over another. This review attempts to dissect the different patterns of cryptogenic Fibrosing Alveolitis, illustrate the major features of each, and refine the clinico-radiological-pathological descriptors that together define cryptogenic Fibrosing Alveolitis as it is understood today.

  • Bronchoalveolar lavage cellularity: lone cryptogenic Fibrosing Alveolitis compared with the Fibrosing Alveolitis of systemic sclerosis.
    American journal of respiratory and critical care medicine, 1998
    Co-Authors: Au Wells, M B Rubens, C M Black, Jeremy Cailes, D M Hansell, P L Haslam, R M Du Bois
    Abstract:

    Lone cryptogenic Fibrosing Alveolitis (CFA) is histologically identical to Fibrosing Alveolitis associated with systemic sclerosis (FASSc), but it has a much worse prognosis after matching for disease severity at presentation. The aims of this study were to gain insights into possible pathogenetic mechanisms contributing to this prognostic difference, by comparing bronchoalveolar lavage (BAL) cellularity in the two diseases, and to evaluate the relationships between BAL findings and the regional and global extent of disease, quantified by thin-section computed tomography (CT) and lung function indices. Patients with CFA were distinguished by more extensive Fibrosing Alveolitis on CT (p < 0.02) and by higher counts of neutrophils (total per ml, p < 0.02; percentage p < 0.03) and eosinophils (total per ml, p < 0.002; percentages, p < 0.02) in BAL fluid. After adjustment for functional and morphologic measures of disease extent, eosinophil percentages and total counts were increased in CFA (p < 0.05 in all 12 multivariate models), but they were not independently related to regional or global disease severity. Neutrophil percentages and total counts were virtually identical in CFA and FASSc in disease of comparable severity, and they increased with increasingly extensive lobar disease and global disease, as judged by CT, p < 0.0005 in all analyses. Neutrophil levels were more closely linked to the extent of disease on CT than to the severity of functional impairment, on univariate and multivariate analysis. The higher BAL eosinophil levels seen in CFA, compared with those seen in FASSc, after adjustment for disease extent, indicate that an eosinophilic influx may be linked to the pathogenesis of Fibrosing Alveolitis. By contrast, BAL neutrophil levels increase with increasingly extensive disease on CT, but they do not differ independently between CFA and FASSc, suggesting that neutrophil degradation products are unlikely to account for the excess mortality in CFA, compared with that in FASSc.

  • lone cryptogenic Fibrosing Alveolitis a functional morphologic correlation based on extent of disease on thin section computed tomography
    American Journal of Respiratory and Critical Care Medicine, 1997
    Co-Authors: Au Wells, R M Du Bois, M B Rubens, Ann D King, Derek Cramer, David M. Hansell
    Abstract:

    In most clinical series of patients with cryptogenic Fibrosing Alveolitis (CFA), disease severity is staged using lung function indices. However, many physiologic indices are measured in routine clinical practice; the choice of variable to evaluate functional severity is contentious. Computed tomography (CT) provides a reproducible means of quantifying the morphologic extent of disease. The aim of this study was to evaluate the functional consequences of smoking-related lung damage in CFA and to identify functional measures best reflecting the extent of Fibrosing Alveolitis on CT. Sixty-eight patients with CFA were studied. Fourteen patients with emphysema on CT were characterized by relative preservation of FVC and TLC (p < 0.005) and relative depression of DLCO (p < 0.05) and KCO (p < 0.00005). On multivariate analysis, the extent of Fibrosing Alveolitis and the presence of emphysema were independent determinants of functional impairment; there was no independent relationship between smoking history and functional abnormalities. In patients without emphysema on CT, percent predicted DLCO (r = -0.68), oxygen desaturation on exercise (r = 0.64), and the physiologic component of the clinical-radiographic-physiologic (CRP) score (r = 0.62) correlated much better with the extent of disease on CT than spirometric and plethysmographic volumes. A composite functional index was generated against the extent of disease on CT, using multivariate analysis; comparison with the CRP score suggested that the relationship between morphologic disease extent and the CRP score would be improved by the inclusion of DLCO and by the use of negative weighting for depression of FEV1. These findings indicate that in CFA, the presence of concurrent emphysema on CT has a more profound influence upon functional measures than the smoking history, and underline the importance of both the measurements of DLCO and exercise testing in the assessment of the severity of CFA.

  • cryptogenic Fibrosing Alveolitis and the Fibrosing Alveolitis of systemic sclerosis morphological differences on computed tomographic scans
    Thorax, 1997
    Co-Authors: T Y K Chan, David M. Hansell, R M Du Bois, M B Rubens, Au Wells
    Abstract:

    BACKGROUND: The purpose of this study was to identify morphological differences on the computed tomographic (CT) scan between cryptogenic Fibrosing Alveolitis (CFA) and the Fibrosing Alveolitis associated with systemic sclerosis (FASSc), and to examine their biological relevance. METHODS: One hundred and seven patients with CFA (n = 55) or FASSc (n = 52) who had undergone thin section CT scanning were included. Multivariate analysis was used to identify morphological differences on the CT scans between lone CFA and FASSc, and to determine whether the pattern and distribution of disease on the CT scans were functionally significant (as judged by the lung transfer factor (TLCO), forced vital capacity (FVC), and arterial oxygen tension (PaO2)) or predictive of survival (independent of the type and extent of Fibrosing Alveolitis, age, sex, and smoking history). RESULTS: Increasingly extensive disease on CT scans was associated with a coarser reticular pattern (increase in reticular score per percentage increase in disease extent = 0.06, 95% confidence interval (CI) 0.03 to 0.09, p < 0.0005) and increasing upper zone involvement (increase in ratio of upper zone to total disease per percentage increase in disease extent = 0.002, 95% CI 0.000 to 0.003, p < 0.04). Patients with CFA were characterised by a higher upper zone ratio (difference = 0.08, 95% CI 0.02 to 0.13, p < 0.004) and a weak trend towards a coarser reticular pattern (p = 0.09), independent of disease extent. Smokers with CFA had more upper zone involvement (difference = 0.11, 95% CI 0.05 to 0.16, p < 0.0005) and a coarser reticular pattern (difference in reticular score = 1.92, 95% CI 0.27 to 3.55, p < 0.02) than smokers with FASSc. The extent of disease on the CT scan was predictive of lung function impairment and survival but the pattern and distribution of disease were not. CONCLUSIONS: Patients with CFA have relatively more upper zone involvement than those with FASSc independent of the extent of disease on the CT scan. This finding may result from smoking related damage but is not functionally significant.

  • functional impairment in Fibrosing Alveolitis relationship to reversible disease on thin section computed tomography
    European Respiratory Journal, 1997
    Co-Authors: Au Wells, R M Du Bois, Michael B. Rubens, David M. Hansell
    Abstract:

    Thin-section computed tomography (CT) provides a reproducible method of quantifying global disease extent and can also discriminate between fibrotic disease, with predominance of reticular abnormalities, and reversible inflammatory cell infiltration, shown as ground-glass attenuation. The aim of this study was to determine whether functional impairment varied according to the presence of ground-glass attenuation on CT, independently of extent of disease on CT, demographic factors, smoking history, therapeutic status, and the type of Fibrosing Alveolitis (lone cryptogenic Fibrosing Alveolitis (CFA) versus Fibrosing Alveolitis associated with systemic sclerosis (FASSc)). Patients with concurrent emphysema on CT (n = 16) and FASSc patients with end-stage pulmonary hypertension (n = 5) were excluded. One hundred and eleven patients were studied (CFA, n = 54; FASSc, n = 57). The severity of functional impairment did not vary independently with the presence of predominant ground-glass attenuation, mixed appearance and predominant reticulation on CT. In 34 treated patients undergoing serial CT scanning, the severity of functional impairment did not differ independently between patients with and without regression of ground-glass attenuation at follow-up. We conclude that the severity of functional impairment does not discriminate between inflammatory and fibrotic disease in Fibrosing Alveolitis, as judged by initial and serial computed tomographic scanning, after adjustment for the morphological extent of disease on computed tomography.

David M. Hansell - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution computed tomography in the evaluation of Fibrosing Alveolitis.
    Clinics in Chest Medicine, 1999
    Co-Authors: David M. Hansell
    Abstract:

    High-resolution computed tomography (HRCT) is now widely used in the investigation of patients with suspected or known diffuse lung disease. This article reviews some of the technical aspects of HRCT and the pathologic considerations that should be appreciated in the context of diagnosing Fibrosing Alveolitis. The precise quantitation of disease extent and characterization of disease pattern on HRCT has been used to provide new insights about the prognosis and pathophysiology of Fibrosing lung disease.

  • Fibrosing Alveolitis in systemic sclerosis indices of lung function in relation to extent of disease on computed tomography
    Arthritis & Rheumatism, 1997
    Co-Authors: Athol U Wells, David M. Hansell, M B Rubens, C M Black, Ann D King, Derek Cramer, R M Du Bois
    Abstract:

    Objective. Thin-section computed tomography (CT) provides a sensitive and reproducible method of quantifying the morphologic extent of disease in the clinical management of Fibrosing Alveolitis associated with systemic sclerosis (FASSc). The aim of this study was to determine which indices of lung function best reflect the extent of disease on CT in FASSc, and to determine the independent influences of smoking history, extent of Fibrosing Alveolitis, demographic features, and concurrent treatment upon functional impairment in FASSc. Methods. Sixty-four patients with FASSc were studied using CT and static and exercise lung function testing. Statistical relationships were determined by multiple regression analyses. Results. Five patients with overt pulmonary hypertension were characterized by severe impairment in 3 indices of lung function: diffusing capacity for carbon monoxide (DLCO), DLCO adjusted for alveolar volume (KCO), and arterial partial pressure of oxygen. On multiple regression analysis, the major determinant of functional impairment was the extent of Fibrosing Alveolitis on CT. A history of smoking was independently associated with preservation of total lung capacity and depression of KCO, but did not otherwise influence functional-morphologic correlations. The percent predicted DLCO correlated better with extent of disease on CT (r = −0.70) than did oxygen desaturation on exercise (r = 0.55), the physiologic component of the clinical-radiographic-physiologic score (CRP index) (r = 0.52), or other indices of lung function. Lung volume measures correlated poorly with disease extent on CT. Conclusion. The percent predicted DLCO best reflects the extent of Fibrosing Alveolitis in FASSc, and therefore should be measured in routine evaluations. Exercise testing may also have a useful role in staging the severity of pulmonary fibrosis, but the CRP index offers no additional advantage over the DLCO and exercise testing.

  • lone cryptogenic Fibrosing Alveolitis a functional morphologic correlation based on extent of disease on thin section computed tomography
    American Journal of Respiratory and Critical Care Medicine, 1997
    Co-Authors: Au Wells, R M Du Bois, M B Rubens, Ann D King, Derek Cramer, David M. Hansell
    Abstract:

    In most clinical series of patients with cryptogenic Fibrosing Alveolitis (CFA), disease severity is staged using lung function indices. However, many physiologic indices are measured in routine clinical practice; the choice of variable to evaluate functional severity is contentious. Computed tomography (CT) provides a reproducible means of quantifying the morphologic extent of disease. The aim of this study was to evaluate the functional consequences of smoking-related lung damage in CFA and to identify functional measures best reflecting the extent of Fibrosing Alveolitis on CT. Sixty-eight patients with CFA were studied. Fourteen patients with emphysema on CT were characterized by relative preservation of FVC and TLC (p < 0.005) and relative depression of DLCO (p < 0.05) and KCO (p < 0.00005). On multivariate analysis, the extent of Fibrosing Alveolitis and the presence of emphysema were independent determinants of functional impairment; there was no independent relationship between smoking history and functional abnormalities. In patients without emphysema on CT, percent predicted DLCO (r = -0.68), oxygen desaturation on exercise (r = 0.64), and the physiologic component of the clinical-radiographic-physiologic (CRP) score (r = 0.62) correlated much better with the extent of disease on CT than spirometric and plethysmographic volumes. A composite functional index was generated against the extent of disease on CT, using multivariate analysis; comparison with the CRP score suggested that the relationship between morphologic disease extent and the CRP score would be improved by the inclusion of DLCO and by the use of negative weighting for depression of FEV1. These findings indicate that in CFA, the presence of concurrent emphysema on CT has a more profound influence upon functional measures than the smoking history, and underline the importance of both the measurements of DLCO and exercise testing in the assessment of the severity of CFA.

  • cryptogenic Fibrosing Alveolitis and the Fibrosing Alveolitis of systemic sclerosis morphological differences on computed tomographic scans
    Thorax, 1997
    Co-Authors: T Y K Chan, David M. Hansell, R M Du Bois, M B Rubens, Au Wells
    Abstract:

    BACKGROUND: The purpose of this study was to identify morphological differences on the computed tomographic (CT) scan between cryptogenic Fibrosing Alveolitis (CFA) and the Fibrosing Alveolitis associated with systemic sclerosis (FASSc), and to examine their biological relevance. METHODS: One hundred and seven patients with CFA (n = 55) or FASSc (n = 52) who had undergone thin section CT scanning were included. Multivariate analysis was used to identify morphological differences on the CT scans between lone CFA and FASSc, and to determine whether the pattern and distribution of disease on the CT scans were functionally significant (as judged by the lung transfer factor (TLCO), forced vital capacity (FVC), and arterial oxygen tension (PaO2)) or predictive of survival (independent of the type and extent of Fibrosing Alveolitis, age, sex, and smoking history). RESULTS: Increasingly extensive disease on CT scans was associated with a coarser reticular pattern (increase in reticular score per percentage increase in disease extent = 0.06, 95% confidence interval (CI) 0.03 to 0.09, p < 0.0005) and increasing upper zone involvement (increase in ratio of upper zone to total disease per percentage increase in disease extent = 0.002, 95% CI 0.000 to 0.003, p < 0.04). Patients with CFA were characterised by a higher upper zone ratio (difference = 0.08, 95% CI 0.02 to 0.13, p < 0.004) and a weak trend towards a coarser reticular pattern (p = 0.09), independent of disease extent. Smokers with CFA had more upper zone involvement (difference = 0.11, 95% CI 0.05 to 0.16, p < 0.0005) and a coarser reticular pattern (difference in reticular score = 1.92, 95% CI 0.27 to 3.55, p < 0.02) than smokers with FASSc. The extent of disease on the CT scan was predictive of lung function impairment and survival but the pattern and distribution of disease were not. CONCLUSIONS: Patients with CFA have relatively more upper zone involvement than those with FASSc independent of the extent of disease on the CT scan. This finding may result from smoking related damage but is not functionally significant.

  • functional impairment in Fibrosing Alveolitis relationship to reversible disease on thin section computed tomography
    European Respiratory Journal, 1997
    Co-Authors: Au Wells, R M Du Bois, Michael B. Rubens, David M. Hansell
    Abstract:

    Thin-section computed tomography (CT) provides a reproducible method of quantifying global disease extent and can also discriminate between fibrotic disease, with predominance of reticular abnormalities, and reversible inflammatory cell infiltration, shown as ground-glass attenuation. The aim of this study was to determine whether functional impairment varied according to the presence of ground-glass attenuation on CT, independently of extent of disease on CT, demographic factors, smoking history, therapeutic status, and the type of Fibrosing Alveolitis (lone cryptogenic Fibrosing Alveolitis (CFA) versus Fibrosing Alveolitis associated with systemic sclerosis (FASSc)). Patients with concurrent emphysema on CT (n = 16) and FASSc patients with end-stage pulmonary hypertension (n = 5) were excluded. One hundred and eleven patients were studied (CFA, n = 54; FASSc, n = 57). The severity of functional impairment did not vary independently with the presence of predominant ground-glass attenuation, mixed appearance and predominant reticulation on CT. In 34 treated patients undergoing serial CT scanning, the severity of functional impairment did not differ independently between patients with and without regression of ground-glass attenuation at follow-up. We conclude that the severity of functional impairment does not discriminate between inflammatory and fibrotic disease in Fibrosing Alveolitis, as judged by initial and serial computed tomographic scanning, after adjustment for the morphological extent of disease on computed tomography.

C M Black - One of the best experts on this subject based on the ideXlab platform.

  • different cytokine profiles in cryptogenic Fibrosing Alveolitis and Fibrosing Alveolitis associated with systemic sclerosis a quantitative study of open lung biopsies
    European Respiratory Journal, 1999
    Co-Authors: S Majumdar, R M Du Bois, C M Black, Panagiotis Pantelidis, T Ansari, Mariusz J Gizycki, Peter K. Jeffery
    Abstract:

    Differences in the inflammatory response and prognosis of cryptogenic Fibrosing Alveolitis (CFA) and that associated with systemic sclerosis (FASSc) are beginning to emerge. It is hypothesized that these differences may be reflected in a distinct pattern of T-helper (Th)-1 and Th-2-type cytokines. Open lung biopsies were obtained from clinically well-documented cases of CFA and FASSc and, as a control, compared with grossly and histologically normal parenchyma obtained from smokers whose lungs were resected for cancer (n=5 in each group). In situ hybridization (ISH) was applied to the samples using anti-sense and sense 35S-labelled riboprobes to detect messenger ribonucleic acid (mRNA) for interleukins (IL)-2, IL-4, IL-5 and interferon (IFN)-gamma. Between 52-91% of cells expressing the cytokines studied were present in the alveolar interstitium rather than in lumenal cells or the alveolar epithelial lining. The highest values for all four cytokines were present in the patients with FASSc, i.e., 22-39 ISH positive cells x mm(-2) alveolar tissue compared with 1-19 cells x mm(-2) and 4-5 cell x mm(-2) in CFA and control subjects, respectively. Whereas the proportions of the four cytokines in FASSc were similar to the control subjects, IL-4 and IL-5 predominated significantly in CFA (p<0.001). For example, the ratio of IL-5 to IFN-gamma was 22:1 in CFA, significantly higher than in the cases with FASSc (2:1) or the control subjects (4:1) (p<0.05). In conclusion, cryptogenic Fibrosing Alveolitis is an inflammatory condition which is characterized, like asthma, by a predominance of gene expression for T-helper-2-type regulatory cytokines, whereas cryptogenic Fibrosing Alveolitis associated with systemic sclerosis appears to have a distinct mixed T-helper-1/T-helper-2 functional phenotype and a greater number of cells expressing each of these pro-inflammatory cytokines.

  • t cell receptor gene usage in patients with Fibrosing Alveolitis and control subjects
    European Journal of Clinical Investigation, 1999
    Co-Authors: P A Lympany, C M Black, A.m. Southcott, K I Welsh, A W Boylston, R M Du Bois
    Abstract:

    BACKGROUND Fibrosing Alveolitis is characterized by inflammation, fibrosis and increased numbers of activated CD4+ T-cells in the lower respiratory tract. The aims of this study were to compare the T-cell antigen receptor repertoire in the lungs of subjects with Fibrosing Alveolitis systemic sclerosis (FASSc) with cryptogenic Fibrosing Alveolitis (CFA) and normal control subjects, to determine whether FASSc is driven by a specific T-cell trigger and is determined by a T-cell driven immune response, and to assess the clonality of CD4+ and CD8+ TcR usage in subjects with FASSc. MATERIALS AND METHODS We used reverse transcription polymerase chain reaction with specific V alpha- and V beta-chain primers to identify the TcR gene usage in biopsy material, bronchoalveolar lavage fluid or peripheral blood from our subjects. RESULTS We found individual-specific restriction of V alpha- and V beta-chain usage in lung biopsies from patients and control subjects. To establish whether this was due to expression bias in the CD4+ or CD8+ T-cells and was restricted to the lung, the alpha beta-T-cell receptor chain usage was assessed in T-cell subsets separated from the lungs of patients with Fibrosing Alveolitis and was compared with that of the peripheral blood. There was no consistent difference in the expression of any variable family chain among the population studied, although there was a significant difference between lung and peripheral blood lymphocyte V beta-families in CD8+ T-cells (P = 0.0007). CONCLUSION We conclude that there is individual TcR V alpha- and V beta-expression bias in subjects with Fibrosing Alveolitis.

  • fibronectin gene polymorphisms associated with Fibrosing Alveolitis in systemic sclerosis
    American Journal of Respiratory Cell and Molecular Biology, 1999
    Co-Authors: J J Avila, C M Black, Panagiotis Pantelidis, P A Lympany, K I Welsh, R M Du Bois
    Abstract:

    Systemic sclerosis (SSc), a multisystem immunologic disease of unknown etiology, is commonly manifested in the lung as Fibrosing Alveolitis (FASSc). There is evidence to support the role of genetic factors in the predisposition to pulmonary fibrosis in SSc (HLA DR3/DR52a). This association is not complete and other candidate genes are likely involved. Of these, fibronectin is a growth factor known to play a crucial role in lung fibrosis. Our study investigated whether polymorphisms of the fibronectin gene are associated with lung fibrosis in SSc. Using the polymerase chain reaction and the restriction enzymes HaeIII, MspI, HindIII, and TaqI, we assessed the restriction fragment length polymorphisms (RFLPs) in 161 patients with SSc and 253 healthy control subjects from the United Kingdom. For each restriction enzyme, three genotypes were possible corresponding to the presence of the cutting site on neither, one, or both chromosomes (HaeIII AA, AB, BB; MspI CC, CD, DD; HindIII EE, EF, FF; TaqI GG, GH, HH). There was a significant decrease of genotype BB (FASSc: 17%, control: 34%; Pcorr = 0.006) with a reciprocal increase of genotype AB (FASSc: 62%, control: 46%; Pcorr = 0.022) in FASSc with the HaeIII RFLP. A significant decrease of genotype DD was observed in FASSc (FASSc: 28%, control: 41%; Pcorr = 0.038) with the MspI RFLP. The coassociation of genotypes AB (HaeIII RFLP) and CD (MspI RFLP) was present in 45% of the FASSc group (P = 0.0059), with an increased relative risk of developing Fibrosing Alveolitis of 1.988. We conclude that genotypes of the fibronectin gene are useful prognostic factors in SSc, helping to predict individuals likely to develop pulmonary fibrosis.

  • Bronchoalveolar lavage cellularity: lone cryptogenic Fibrosing Alveolitis compared with the Fibrosing Alveolitis of systemic sclerosis.
    American journal of respiratory and critical care medicine, 1998
    Co-Authors: Au Wells, M B Rubens, C M Black, Jeremy Cailes, D M Hansell, P L Haslam, R M Du Bois
    Abstract:

    Lone cryptogenic Fibrosing Alveolitis (CFA) is histologically identical to Fibrosing Alveolitis associated with systemic sclerosis (FASSc), but it has a much worse prognosis after matching for disease severity at presentation. The aims of this study were to gain insights into possible pathogenetic mechanisms contributing to this prognostic difference, by comparing bronchoalveolar lavage (BAL) cellularity in the two diseases, and to evaluate the relationships between BAL findings and the regional and global extent of disease, quantified by thin-section computed tomography (CT) and lung function indices. Patients with CFA were distinguished by more extensive Fibrosing Alveolitis on CT (p < 0.02) and by higher counts of neutrophils (total per ml, p < 0.02; percentage p < 0.03) and eosinophils (total per ml, p < 0.002; percentages, p < 0.02) in BAL fluid. After adjustment for functional and morphologic measures of disease extent, eosinophil percentages and total counts were increased in CFA (p < 0.05 in all 12 multivariate models), but they were not independently related to regional or global disease severity. Neutrophil percentages and total counts were virtually identical in CFA and FASSc in disease of comparable severity, and they increased with increasingly extensive lobar disease and global disease, as judged by CT, p < 0.0005 in all analyses. Neutrophil levels were more closely linked to the extent of disease on CT than to the severity of functional impairment, on univariate and multivariate analysis. The higher BAL eosinophil levels seen in CFA, compared with those seen in FASSc, after adjustment for disease extent, indicate that an eosinophilic influx may be linked to the pathogenesis of Fibrosing Alveolitis. By contrast, BAL neutrophil levels increase with increasingly extensive disease on CT, but they do not differ independently between CFA and FASSc, suggesting that neutrophil degradation products are unlikely to account for the excess mortality in CFA, compared with that in FASSc.

  • Fibrosing Alveolitis in systemic sclerosis indices of lung function in relation to extent of disease on computed tomography
    Arthritis & Rheumatism, 1997
    Co-Authors: Athol U Wells, David M. Hansell, M B Rubens, C M Black, Ann D King, Derek Cramer, R M Du Bois
    Abstract:

    Objective. Thin-section computed tomography (CT) provides a sensitive and reproducible method of quantifying the morphologic extent of disease in the clinical management of Fibrosing Alveolitis associated with systemic sclerosis (FASSc). The aim of this study was to determine which indices of lung function best reflect the extent of disease on CT in FASSc, and to determine the independent influences of smoking history, extent of Fibrosing Alveolitis, demographic features, and concurrent treatment upon functional impairment in FASSc. Methods. Sixty-four patients with FASSc were studied using CT and static and exercise lung function testing. Statistical relationships were determined by multiple regression analyses. Results. Five patients with overt pulmonary hypertension were characterized by severe impairment in 3 indices of lung function: diffusing capacity for carbon monoxide (DLCO), DLCO adjusted for alveolar volume (KCO), and arterial partial pressure of oxygen. On multiple regression analysis, the major determinant of functional impairment was the extent of Fibrosing Alveolitis on CT. A history of smoking was independently associated with preservation of total lung capacity and depression of KCO, but did not otherwise influence functional-morphologic correlations. The percent predicted DLCO correlated better with extent of disease on CT (r = −0.70) than did oxygen desaturation on exercise (r = 0.55), the physiologic component of the clinical-radiographic-physiologic score (CRP index) (r = 0.52), or other indices of lung function. Lung volume measures correlated poorly with disease extent on CT. Conclusion. The percent predicted DLCO best reflects the extent of Fibrosing Alveolitis in FASSc, and therefore should be measured in routine evaluations. Exercise testing may also have a useful role in staging the severity of pulmonary fibrosis, but the CRP index offers no additional advantage over the DLCO and exercise testing.

M B Rubens - One of the best experts on this subject based on the ideXlab platform.

  • Bronchoalveolar lavage cellularity: lone cryptogenic Fibrosing Alveolitis compared with the Fibrosing Alveolitis of systemic sclerosis.
    American journal of respiratory and critical care medicine, 1998
    Co-Authors: Au Wells, M B Rubens, C M Black, Jeremy Cailes, D M Hansell, P L Haslam, R M Du Bois
    Abstract:

    Lone cryptogenic Fibrosing Alveolitis (CFA) is histologically identical to Fibrosing Alveolitis associated with systemic sclerosis (FASSc), but it has a much worse prognosis after matching for disease severity at presentation. The aims of this study were to gain insights into possible pathogenetic mechanisms contributing to this prognostic difference, by comparing bronchoalveolar lavage (BAL) cellularity in the two diseases, and to evaluate the relationships between BAL findings and the regional and global extent of disease, quantified by thin-section computed tomography (CT) and lung function indices. Patients with CFA were distinguished by more extensive Fibrosing Alveolitis on CT (p < 0.02) and by higher counts of neutrophils (total per ml, p < 0.02; percentage p < 0.03) and eosinophils (total per ml, p < 0.002; percentages, p < 0.02) in BAL fluid. After adjustment for functional and morphologic measures of disease extent, eosinophil percentages and total counts were increased in CFA (p < 0.05 in all 12 multivariate models), but they were not independently related to regional or global disease severity. Neutrophil percentages and total counts were virtually identical in CFA and FASSc in disease of comparable severity, and they increased with increasingly extensive lobar disease and global disease, as judged by CT, p < 0.0005 in all analyses. Neutrophil levels were more closely linked to the extent of disease on CT than to the severity of functional impairment, on univariate and multivariate analysis. The higher BAL eosinophil levels seen in CFA, compared with those seen in FASSc, after adjustment for disease extent, indicate that an eosinophilic influx may be linked to the pathogenesis of Fibrosing Alveolitis. By contrast, BAL neutrophil levels increase with increasingly extensive disease on CT, but they do not differ independently between CFA and FASSc, suggesting that neutrophil degradation products are unlikely to account for the excess mortality in CFA, compared with that in FASSc.

  • Fibrosing Alveolitis in systemic sclerosis indices of lung function in relation to extent of disease on computed tomography
    Arthritis & Rheumatism, 1997
    Co-Authors: Athol U Wells, David M. Hansell, M B Rubens, C M Black, Ann D King, Derek Cramer, R M Du Bois
    Abstract:

    Objective. Thin-section computed tomography (CT) provides a sensitive and reproducible method of quantifying the morphologic extent of disease in the clinical management of Fibrosing Alveolitis associated with systemic sclerosis (FASSc). The aim of this study was to determine which indices of lung function best reflect the extent of disease on CT in FASSc, and to determine the independent influences of smoking history, extent of Fibrosing Alveolitis, demographic features, and concurrent treatment upon functional impairment in FASSc. Methods. Sixty-four patients with FASSc were studied using CT and static and exercise lung function testing. Statistical relationships were determined by multiple regression analyses. Results. Five patients with overt pulmonary hypertension were characterized by severe impairment in 3 indices of lung function: diffusing capacity for carbon monoxide (DLCO), DLCO adjusted for alveolar volume (KCO), and arterial partial pressure of oxygen. On multiple regression analysis, the major determinant of functional impairment was the extent of Fibrosing Alveolitis on CT. A history of smoking was independently associated with preservation of total lung capacity and depression of KCO, but did not otherwise influence functional-morphologic correlations. The percent predicted DLCO correlated better with extent of disease on CT (r = −0.70) than did oxygen desaturation on exercise (r = 0.55), the physiologic component of the clinical-radiographic-physiologic score (CRP index) (r = 0.52), or other indices of lung function. Lung volume measures correlated poorly with disease extent on CT. Conclusion. The percent predicted DLCO best reflects the extent of Fibrosing Alveolitis in FASSc, and therefore should be measured in routine evaluations. Exercise testing may also have a useful role in staging the severity of pulmonary fibrosis, but the CRP index offers no additional advantage over the DLCO and exercise testing.

  • lone cryptogenic Fibrosing Alveolitis a functional morphologic correlation based on extent of disease on thin section computed tomography
    American Journal of Respiratory and Critical Care Medicine, 1997
    Co-Authors: Au Wells, R M Du Bois, M B Rubens, Ann D King, Derek Cramer, David M. Hansell
    Abstract:

    In most clinical series of patients with cryptogenic Fibrosing Alveolitis (CFA), disease severity is staged using lung function indices. However, many physiologic indices are measured in routine clinical practice; the choice of variable to evaluate functional severity is contentious. Computed tomography (CT) provides a reproducible means of quantifying the morphologic extent of disease. The aim of this study was to evaluate the functional consequences of smoking-related lung damage in CFA and to identify functional measures best reflecting the extent of Fibrosing Alveolitis on CT. Sixty-eight patients with CFA were studied. Fourteen patients with emphysema on CT were characterized by relative preservation of FVC and TLC (p < 0.005) and relative depression of DLCO (p < 0.05) and KCO (p < 0.00005). On multivariate analysis, the extent of Fibrosing Alveolitis and the presence of emphysema were independent determinants of functional impairment; there was no independent relationship between smoking history and functional abnormalities. In patients without emphysema on CT, percent predicted DLCO (r = -0.68), oxygen desaturation on exercise (r = 0.64), and the physiologic component of the clinical-radiographic-physiologic (CRP) score (r = 0.62) correlated much better with the extent of disease on CT than spirometric and plethysmographic volumes. A composite functional index was generated against the extent of disease on CT, using multivariate analysis; comparison with the CRP score suggested that the relationship between morphologic disease extent and the CRP score would be improved by the inclusion of DLCO and by the use of negative weighting for depression of FEV1. These findings indicate that in CFA, the presence of concurrent emphysema on CT has a more profound influence upon functional measures than the smoking history, and underline the importance of both the measurements of DLCO and exercise testing in the assessment of the severity of CFA.

  • cryptogenic Fibrosing Alveolitis and the Fibrosing Alveolitis of systemic sclerosis morphological differences on computed tomographic scans
    Thorax, 1997
    Co-Authors: T Y K Chan, David M. Hansell, R M Du Bois, M B Rubens, Au Wells
    Abstract:

    BACKGROUND: The purpose of this study was to identify morphological differences on the computed tomographic (CT) scan between cryptogenic Fibrosing Alveolitis (CFA) and the Fibrosing Alveolitis associated with systemic sclerosis (FASSc), and to examine their biological relevance. METHODS: One hundred and seven patients with CFA (n = 55) or FASSc (n = 52) who had undergone thin section CT scanning were included. Multivariate analysis was used to identify morphological differences on the CT scans between lone CFA and FASSc, and to determine whether the pattern and distribution of disease on the CT scans were functionally significant (as judged by the lung transfer factor (TLCO), forced vital capacity (FVC), and arterial oxygen tension (PaO2)) or predictive of survival (independent of the type and extent of Fibrosing Alveolitis, age, sex, and smoking history). RESULTS: Increasingly extensive disease on CT scans was associated with a coarser reticular pattern (increase in reticular score per percentage increase in disease extent = 0.06, 95% confidence interval (CI) 0.03 to 0.09, p < 0.0005) and increasing upper zone involvement (increase in ratio of upper zone to total disease per percentage increase in disease extent = 0.002, 95% CI 0.000 to 0.003, p < 0.04). Patients with CFA were characterised by a higher upper zone ratio (difference = 0.08, 95% CI 0.02 to 0.13, p < 0.004) and a weak trend towards a coarser reticular pattern (p = 0.09), independent of disease extent. Smokers with CFA had more upper zone involvement (difference = 0.11, 95% CI 0.05 to 0.16, p < 0.0005) and a coarser reticular pattern (difference in reticular score = 1.92, 95% CI 0.27 to 3.55, p < 0.02) than smokers with FASSc. The extent of disease on the CT scan was predictive of lung function impairment and survival but the pattern and distribution of disease were not. CONCLUSIONS: Patients with CFA have relatively more upper zone involvement than those with FASSc independent of the extent of disease on the CT scan. This finding may result from smoking related damage but is not functionally significant.

  • Fibrosing Alveolitis in systemic sclerosis bronchoalveolar lavage findings in relation to computed tomographic appearance
    American Journal of Respiratory and Critical Care Medicine, 1994
    Co-Authors: Au Wells, David M. Hansell, M B Rubens, P Cullinan, C M Black, P L Haslam, R M Du Bois
    Abstract:

    Fibrosing Alveolitis in systemic sclerosis is histologically identical to lone cryptogenic Fibrosing Alveolitis (CFA) (idiopathic pulmonary fibrosis). The inflammatory cell content of bronchoalveolar lavage (BAL) samples has been used as a guide to prognosis and treatment in CFA. In this study, the relationship was explored between BAL findings and the extent and pattern of disease within the lavaged lobe, as judged by thin-section computed tomography (CT), in systemic sclerosis. Thirty-eight nonsmoking patients were studied; none had been treated with corticosteroids or immunosuppressive agents, and 11 had no evidence of Fibrosing Alveolitis on CT. BAL neutrophils were markedly increased in association with extensive disease on CT compared with less extensive disease (p < 0.001) and normal appearances (p < 0.001); the extent of a reticular pattern on CT (denoting fibrosis) correlated with the neutrophil percentage count (p < 0.005) and total neutrophil count/ml (p < 0.01). BAL eosinophils were increased in less extensive as well as in extensive disease when compared with lobes with a normal CT appearance (p < 0.01); eosinophil percentage counts but not total eosinophil counts/ml correlated with the extent of a ground-glass pattern on CT (through to denote inflammation) (p < 0.05). These findings indicate that in systemic sclerosis a BAL neutrophilia is generally associated with extensive fibrotic disease, whereas a BAL eosinophilia is often seen in less advanced disease, particularly when CT appearances suggest lung inflammation.