[Cyclooxygenase-2 polymorphisms and bronchoalveolar lavage cellularity of sarcoidosis]. / El polimorfismo COX2.8473t>C del gen de la ciclooxigenasa-2 está asociado al cociente CD4/CD8 del lavado broncoalveolar en la sarcoidosis.

OBJECTIVES: Recent studies have found cyclooxygenase-2 (COX-2) and its polymorphisms to be associated with sarcoidosis, being it significantly decreased in alveolar macrophages, with no information on the relationship between these polymorphisms and the rest of cells in bronchoalveolar layage (BAL). The present study aimed to investigate the potential association between COX-2 gene polymorphisms and the BAL cell profile including the CD4/CD8 ratio. MATERIAL AND METHODS: This observational cross-sectional study involved six hospitals in Spain. Patients diagnosed with sarcoidosis with a BAL performed were included. The following variables were recorded: age, gender, initial diagnostic methods, serum angiotensin-converting enzyme levels, pulmonary function tests, radiological stage, and the cellularity and CD4/CD8 ratio from BAL. Genotyping of four COX-2 polymorphisms (COX2.5909T>G, COX2.8473T>C, COX2.926G>C, and COX2.3050G>C) was undertaken on DNA extracted from peripheral blood lymphocytes using fluorescent hybridization probes. The relationship between the polymorphisms and the cellularity was done by means of a multiple linear regression, adjusting for gender. RESULTS: A total of 51 sarcoid patients (23 males, mean age: 45 +/- 15 years) were studied. CD4/CD8 ratio was significantly higher among homozygote allele C carriers of the polymorphism COX2.8473T>C (CC 11.2 +/- 5.5 vs. CT+TT 4.4 +/- 3.5; p = 0.022; beta = 7.43; 95% CI 1.38 - 13.48). Although several differences were observed in other cell groups, they did not reach the statistical significance level. CONCLUSIONS: In patients diagnosed with sarcoidosis, there seems to be a relationship between COX2.8473 polymorphism and CD4/CD8 ratio from BAL.

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

BACKGROUND: The 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. METHODS: We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients. RESULTS: In 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. CONCLUSION: This 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.

[Bronchoalveolar lavage findings in patients with diffuse interstitial lung disease: prospective study of a cohort of 562 patients]. / Hallazgos en el lavado broncoalveolar de pacientes con enfermedad pulmonar intersticial difusa. Estudio de una cohorte prospectiva de 562 pacientes.

OBJECTIVE: Study of the bronchoalveolar lavage (BAL) fluid in some interstitial lung diseases can reveal patterns typical to each disease and that can support the diagnosis. The objective of this study was to perform a descriptive analysis of the cytologic study and of the lymphocyte subpopulations in BAL fluid from patients with interstitial lung disease. MATERIAL AND METHODS: In this prospective, observational study of 562 patients between January 1991 and January 2005, BAL fluid was analyzed to determine the distribution of cell populations and of lymphocyte subsets: CD3, CD4, CD8, CD3(+)CD4(-)CD8(-), and CD56. RESULTS: The mean age was 53.4 years and 53.3% of the patients were women. The following diseases were studied: idiopathic pulmonary fibrosis (n=132), sarcoidosis (n=123), connective tissue diseases (n=133), cryptogenic organizing pneumonia (n=89), and extrinsic allergic alveolitis (n=85). Isolated lymphocytic alveolitis was common in sarcoidosis and extrinsic allergic alveolitis. Mixed alveolitis was the most common pattern in the other interstitial lung diseases. The CD4:CD8 ratio was the most useful parameter. It was high in sarcoidosis (median, 2.3); the ratio was low or inverted in the other interstitial lung diseases, with median values of 1.76 in idiopathic pulmonary fibrosis, 0.45 in extrinsic allergic alveolitis, 0.35 in cryptogenic organizing pneumonia, and 0.33 in the connective tissue diseases. CONCLUSIONS: BAL parameters, in association with clinical and radiologic data, help to discriminate between interstitial lung diseases. BAL should therefore be considered a very useful tool in clinical management, particularly when pulmonary biopsy is not conclusive or is not possible.

[Response to inhaled granulocyte-macrophage colony-stimulating factor in a patient with alveolar proteinosis]. / Proteinosis alveolar. Respuesta al tratamiento con factor estimulante de colonias de granulocitos y macrófagos por vía inhalada.

Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of lipoproteinaceous material derived from alveolar surfactant in the alveoli, with a consequent deterioration in gas exchange. Pathogenesis is related to impaired phagocytic function of alveolar macrophages. In recent years, a new treatment for pulmonary alveolar proteinosis-consisting of subcutaneous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF)-has become available. The commonly accepted treatment, and the one to have shown greatest efficacy in pulmonary alveolar proteinosis, is whole lung lavage. Instead of subcutaneous administration, GM-CSF can also be inhaled as an aerosol. This route of administration of GM-CSF is safe and effective in the treatment of pulmonary alveolar proteinosis and represents an alternative to subcutaneous administration or whole lung lavage. We present a patient with pulmonary alveolar proteinosis who was treated with inhaled GM-CSF and describe her clinical and functional outcome after 1 year of treatment.

Serum levels of soluble mesothelin-related peptides in malignant and nonmalignant asbestos-related pleural disease: relation with past asbestos exposure.

BACKGROUND: Malignant pleural mesothelioma (MPM) results from malignant transformation of mesothelial cells. Past asbestos exposure represents a major risk factor for MPM and other benign pleural disease. Soluble mesothelin-related peptides (SMRP) have been regarded as a promising serum biomarker for MPM. The aim of this study was to investigate serum levels of SMRP in malignant and nonmalignant asbestos-related pleural disease. PATIENTS: Four groups of patients were investigated: group 1 composed of 48 healthy subjects, group 2 composed of 177 patients with previous asbestos exposure and no pleural disease, group 3 composed of 36 patients with MPM, and group 4 composed of 101 patients with previous asbestos exposure and benign pleural disease. Serum SMRP levels were determined by ELISA. RESULTS: Serum SMRP levels were significantly higher among group 3 than the other three groups. There were no differences in SMRP concentrations between groups 2 and 4. Subjects exposed to asbestos had higher SMRP concentrations than normal control subjects regardless of the presence of pleural disease. The area under the receiver operating characteristic curve for SMRP values was 0.75 (95% confidence interval, 0.68-0.83). The SMRP level at 0.55 nmol/L/L was determined as the most optimal cutoff value with resulting sensitivity and specificity of 72% and 72% for the diagnosis of MPM. CONCLUSIONS: These data attest to good diagnostic sensitivity and specificity of SMRP for the diagnosis of malignant mesothelioma. We have also shown that serum SMRP levels might serve as a marker of asbestos exposure.

Cyclooxygenase-2 polymorphisms confer susceptibility to sarcoidosis but are not related to prognosis.

BACKGROUND: The aim of this multicenter study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of the cyclooxygenase-2 (COX2) gene and susceptibility to sarcoidosis, as well as the relation between these SNPs and the evolution of the disease. MATERIAL AND METHODS: This multicenter investigation involved seven hospitals in Spain. We used a case-control design followed by a prospective follow-up study. Sarcoid patients were recruited from the participating institutions during outpatient routine visits. Age- and gender-matched control subjects were recruited mainly from among outpatients attending the participating hospitals. Four SNPs in the COX2 gene (COX2.5909 T > G, COX2.8473 T > C, COX2.926 G > C, and COX2.3050 G > C) were genotyped using fluorescent hybridization probes among 131 patients with sarcoidosis (63 males; mean age: 47 +/- 15 years) and 157 healthy controls (83 males; mean age: 50 +/- 16 years). We employed a binomial multiple logistic regression analysis to test the association between the selected SNPs and disease susceptibility. The clinical, functional and radiological prognosis of the sarcoidosis patients was determined after a mean follow-up of 37.4 +/- 30.4 months. RESULTS: Carriers of the homozygous CC genotype of the COX2.8473 T > C polymorphism had a higher risk of sarcoidosis compared with TT carriers (OR: 3.08; 95% CI: 1.2-7.7; p = 0.035). 84% of patients achieved improvement or complete remission at follow-up. No association between the investigated SNPs and prognosis was seen. CONCLUSIONS: Our data suggest that the homozygous CC genotype of the COX2.8473 T > C polymorphism may be associated with sarcoidosis susceptibility. No significant association with prognosis was detected.

[Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease: data from the Spanish patient registry]. / Neumonía intersticial descamativa y bronquiolitis respiratoria asociada a enfermedad pulmonar intersticial: datos del registro español.

Among the idiopathic interstitial lung diseases, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP) make up a subgroup of rare diseases that are clearly smoking related. Few large case series have been published. We describe 19 cases registered in Spain: 12 patients with DIP and 7 with RB-ILD. Clinical and radiologic features are described along with clinical course, treatments applied, and outcomes. With the exception of 2 patients with DIP, all were smokers or ex-smokers. Cough and dyspnea were the most common symptoms at onset in both diseases. The most frequent radiologic findings were ground-glass opacity in DIP and pulmonary nodules in BR-ILD. Most patients were treated with corticosteroids. Outcomes were good in general; only 1 patient, with DIP, died.

[Hepatopulmonary syndrome in patients with advanced hepatic disease: study of a series of 24 cases]. / Síndrome hepatopulmonar en pacientes con hepatopatía avanzada: estudio de 24 casos.

BACKGROUND AND OBJECTIVE: To describe the characteristics observed in patients diagnosed of hepatopulmonary syndrome (HPS) waiting for orthotopic liver transplantation and those who underwent liver trasplantation. PATIENTS AND METHOD: An observational prospective descriptive study was carried out of patients waiting for liver transplantation in whom data of liver illness and lung function tests were analyzed. RESULTS: 107 patients of 53.69 years average age were studied (7.7 standard deviation). 24 of them (22.4%) had criteria of HPS. Ortodeoxia was present in the 34% of cases. The lung function tests were normal. In the comparative study between patients with HPS and no HPS, differences in diffusion were found (7.1 vs. 8.6 mmol/min/kPa; p = 0.04), as well as in the shunt (8% vs. 5.3%; p = 0.05) and the forced expiratory volume in one second (2,390 vs. 2,743 ml; p = 0.03). Seven patients were transplanted with correction of oxygenation and vascular dilatations in all of them. CONCLUSIONS: HPS is a frequent illness in patients waiting for orthotopic liver transplantation. The main alteration in the blood oxygenation seems owe to shunt, and the diffusion tests is the analysis that could best differentiate patients with HPS. Orthotopic liver transplantation corrects the syndrome in all cases.

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

Incidence of interstitial lung diseases in the south of Spain 1998-2000: the RENIA study.

UNLABELLED: This study aims to describe the distribution of interstitial lung diseases (ILD) in the South of Spain. METHODS: A prospective multicentre population-based registry was established in nine provinces in the south of Spain with a population of 6,848,243 during a 3-year period (1998-2000). The number of participant physicians was 36 among 29 public hospitals. The number of diagnoses recorded was 66, divided in eight categories and coded according to ICD-9. A consensus document was elaborated for the classification of diseases and their diagnostic criteria. The number of cases declared was analysed each 3 months and communicated to each one of the participants. RESULTS: There were 744 cases of them registered with an annual incidence of 3.62 cases/ 100,000. 40.1% of diagnoses were biopsy confirmed. Men had a slightly higher incidence (4.18 cases/ 100,000/year) than women (3.07 cases/100,000/year). The most frequent diseases found were: idiopathic interstitial pneumonias (38.58%), ILD associated to systemic diseases (20.97%), and Sarcoidosis (11.69%). According to province distribution, most of the cases were grouped in an area between the provinces of Seville and Cordoba, which comprised more than 50% of cases. CONCLUSIONS: The study of the incidence of ILD depicts an intermediate situation from previous studies on the incidence and distribution of this group of diseases.

Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis.

Transforming growth factor-beta1 (TGF-beta1) is a cytokine that plays a key role in the development of idiopathic pulmonary fibrosis. There have been reports on the presence of two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located in codons 10 and 25. The objective of this study was to investigate the association between TGF-beta1 gene polymorphisms in codons 10 and 25 and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. Compared with healthy control subjects (n = 140), patients with idiopathic pulmonary fibrosis (n = 128) showed no significant deviations in genotype or allele frequencies. One hundred and ten patients with idiopathic pulmonary fibrosis were followed up for 30.3 +/- 25 months. The presence of a proline allele at codon 10 was independently associated with a significant increase in alveolar arterial oxygen tension difference during follow-up, after controlling for the effect of treatment (coefficient = 0.59; 95% confidence intervals, 0.23 to 0.96; p = 0.002). These findings suggest that (1) TGF-beta1 gene polymorphisms in codons 10 and 25 do not predispose to the development of idiopathic pulmonary fibrosis; and (2) TGF-beta1 gene polymorphisms may affect disease progression in patients with idiopathic pulmonary fibrosis.

Serum neutrophil elastase levels predict initial clinical condition but do not correlate with the progression of interstitial lung disease.

BACKGROUND: Recent publications have suggested that neutrophil elastase (NE) may have a role in evaluating the clinical condition of patients with interstitial lung diseases (ILD). This study aims to evaluate the role of serum NE levels in the follow-up of patients with ILD. MATERIAL/METHODS: A group of 100 consecutive patients diagnosed with various ILDs were prospectively studied on two successive visits. On the first visit, the clinical condition of each patient was assessed, and blood count, pulmonary function tests, chest x-ray and serum NE levels (by latex agglutination assay) were performed on all patients. On the second visit, 8 months later, the patients were classified in two groups: those with unfavorable progression and those who were either in the same clinical status or showed good progression. RESULTS: There was a weak correlation between NE and age (r= -0.383; p < 0.0005). Sex, age, NE and the treatment received were found to be independent predictors of the initial clinical condition. Multivariate analysis including these variables demonstrated that higher levels of serum NE predicted the worst clinical presentation (odds ratio: 4.392; 95% CI: 1.665 - 11.586; p = 0.003). However, none of the variables were found to be significantly different when the progression of the disease was assessed. CONCLUSIONS: Although NE seems to be a good marker for the initial clinical condition in this group of diseases, its role as a prognostic factor could not be proven