A haplotype of cyclooxygenase-2 gene is associated with idiopathic pulmonary fibrosis.

BACKGROUND: Cyclooxygenase-2, a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E2, is downregulated in lung tissue from patients with idiopathic pulmonary fibrosis. OBJECTIVE: To investigate the association between COX2.3050 (G --> C), COX2.8473 (C --> T) and COX2.926 (G --> C) single nucleotide polymorphisms (SNP) and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. DESIGN: Genetic polymorphisms were analyzed in 121 out of 225 available control subjects and in all of 174 patients with idiopathic pulmonary fibrosis by real time polymerase chain reaction. Logistic regression analysis of covariance and chi-squares test were used for statistical analysis. RESULTS: While analysis of disease development did not find any significant association with single SNP genotype, a haplotype analysis revealed a strong association between the disease development and one haplotype [GC] at loci COX2.3050 and COX2.8473, and suggested a recessive genetic effect of this haplotype. Further analysis concluded that subjects having two copies of [GC] haplotype, or equivalently (GG/CC) genotype at the two SNPs, had an increased risk after adjusting for age and sex. Due to the interaction, this elevated risk increased slowly with age, and the estimated odds ratio (OR) decreased with age from OR = 1.4 at age 30 to OR = 1 at age 74 and OR = 0.96 at age SO. The OR was significantly greater than 1 up to age 66, and not significant for age older than 66. Therefore, the recessive effect of [GC] haplotype increased the risk of IPF of subjects younger than 66 years, but its effect diminished for seniors older than 66. One hundred and forty-nine patients with idiopathic pulmonary fibrosis were followed up for 33.7 +/- 2.1 months. Further analysis of disease progressions, defined by the changes in pulmonary function tests, did not reveal any association with either SNP genotypes or haplotypes. CONCLUSIONS: The carriage of double homozygote (GG/CC) at the SNP loci of COX2.3050 and COX2.8473 polymorphisms may increase the susceptibility to idiopathic pulmonary fibrosis, by approximately 1.4 folds at age 30 and by a smaller fold greater than 1 up to age 66 years, but not the progression of the disease. These findings may help to improve our understanding of idiopathic pulmonary fibrosis pathogenesis and may lead to the development of new therapeutic strategies.

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression.

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37+/-0.7 mmHg (0.049+/-0.093 kPa) per month) compared to GA genotype (0.12+/-1 mmHg (0.016+/-0.133 kPa) per month) and GG genotype (0.2+/-0.6 mmHg (0.027+/-0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

Association of the 3050G>C polymorphism in the cyclooxygenase 2 gene with systemic sarcoidosis.

BACKGROUND: We investigated the potential association between cyclooxygenase-2 (COX-2) gene polymorphisms and clinical manifestations of sarcoidosis. METHODS: This observational cross-sectional study involved seven hospitals in Spain. We diagnosed patients with sarcoidosis according to the International Criteria. The following variables were recorded: age, gender, initial diagnostic methods, serum angiotensin-converting enzyme (ACE) levels, pulmonary function tests, radiological stage, and clinical findings at diagnosis. Manifestations of sarcoidosis were classified as systemic vs. nonsystemic. 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 and melting curves. RESULTS: A total of 131 sarcoid patients (63 males, mean age: 47 +/- 15 years) were studied. One hundred twenty-six of these patients had one or more positive biopsies. The results demonstrated that genotype distribution for the COX2.3050G>C polymorphism was significantly different between patients with systemic sarcoidosis and those with nonsystemic forms (p = 0.046). After adjustment for age, gender, and serum ACE levels, a significant association between the carriage of at least one C allele of the COX2.3050G>C polymorphism and systemic sarcoidosis was observed (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.03-5.12, p = 0.031). Other polymorphisms were not associated with either clinical manifestations of the disease or serum ACE levels. CONCLUSIONS: Our results indicate for the first time that the C allele of the COX2.3050G>C polymorphism is associated with systemic sarcoidosis.

[Radiographic staging and bronchoalveolar lavage cell counts in sarcoidosis]. / Estadios radiológicos y lavado broncoalveolar en la sarcoidosis.

OBJECTIVE: Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology that mainly affects the lungs and lymph nodes. Bronchoalveolar lavage (BAL) is known to be useful in diagnosis of the disease but its value as a prognostic marker is unclear. The aim of this study was to assess whether there is a characteristic pattern in BAL cell counts according to radiographic stage and determine whether BAL offers information on disease course. PATIENTS AND METHODS: The study included 34 patients with untreated sarcoidosis. Data were collected on the following variables: age, sex, smoking habit, treatment type, radiographic stage, respiratory function, serological parameters, and BAL cell counts. The patients were classified into 3 groups according to functional and radiographic change at 12-month follow-up. RESULTS: No differences in age, sex, or smoking habit were found according to either radiographic stage or disease course. Although the proportion of lymphocytes in BAL fluid was higher in radiographic stage I than in stages II and III, the differences were not statistically significant. The differences in BAL cell counts between groups based on disease course were not statistically significant. CONCLUSIONS: No differences were found in the characteristics of BAL fluid according to radiographic stage. The differential cell count in BAL fluid does not appear to predict the course of sarcoidosis in the first 12 months.

[Hospital admissions related to lung disease in Andalucia: 1993-1994]. / Ingresos de causa neumológica en hospitales de Andalucía: 1993-1994.

To determine the pneumological causes for hospital admission in Andalucia (Spain) and thereby improve knowledge of respiratory morbidity. From the Combined Minimum Data Base on admissions to Andalusian hospitals for 1993 and 1994, adjusted to the CIE-9-MC coding system, we analyzed main diagnoses registered. Cases with respiratory involvement were obtained, excluding patients under 7 years of age. Admissions for pneumological causes accounted for 6.3% of all admissions, with a total of 314 diagnostic categories, although 98.5% of all admissions were related to only 139 diagnoses. The 53 most frequent diagnostic categories accounted for 93% of patients and 55.2% of admissions were related to only 10 causes and led to 54.16% of all stays for pneumological diseases. Categories 486 and 481 (pneumonias), along with 496, 491.2 and 491.21 (diseases involving chronic air flow obstruction) were the most often used. Respiratory problems account for 6.23% of all hospital admissions in Andalucia, with lung infections and conditions falling under the category of chronic obstructive pulmonary disease being by far the most frequent pneumologically related reasons for hospitalization. The precise interpretation of diagnostic categories needs to be better defined in the coding system.

[Acute interstitial pneumonia (Hamman Rich syndrome)]. / Neumonía intersticial aguda (síndrome de Hamman Rich).

We report the case of a 65-year-old woman with no history of respiratory disease who suffered onset of dyspnea after an episode of pseudoinfluenza. Dyspnea progressed such that within 15 days it was triggered by minimal effort. The patient died 15 hours after admission to our hospital, with a clinical picture of adult respiratory distress. Autopsy allowed us to rule out several diseases and arrive at a diagnosis of acute interstitial pneumonia, consistent with clinical course, anatomical and pathological findings as described in the literature.

[Idiopathic pulmonary fibrosis in a 14-year-old girl]. / Fibrosis pulmonar idiopática en una niña de 14 años.

Pulmonary fibrosis (PF) is a rare disease that develops as the final stage of scarring after a series of episodes of lung injury. PF is idiopathic in most cases (60%), though the exact rate varies from series to series. Childhood PF, which is even rarer than the adult form, is usually diagnosed when the patient is less than five years old. Some cases are familial. We report the case of a 14-year-old girl admitted with a three-year history of dry cough and increasing dyspnea that eventually appeared even with moderate effort. Pulmonary biopsy by mini-thoracotomy showed diffuse fibrosis of unknown cause. She died four years after diagnosis. The patient's age, the rapid course of disease, and the final outcome are all unusual features of this case.

[Metastatic pulmonary calcification: a rare cause of interstitial lung disease]. / Calcificación pulmonar metastásica: una rara causa de enfermedad pulmonar intersticial.

We report the case of a 58-year-old woman with metastatic pulmonary calcinosis who presented with bronchial hyperreactivity. She was receiving calcium and vitamin D supplementation following total bilateral thyroidectomy with parathyroidectomy and had a history of episodes of symptomatic hypercalcemia secondary to exogenous administration. Lung function testing showed slight obstruction that was reversed by bronchodilators. Images showed a bilateral micronodular pattern mainly in the upper fields (x-ray and high resolution computed tomography of the thorax) and abnormal calcium deposition in the lungs (bone scintigraphy). The diagnosis was established by transbronchial biopsy. The clinical course was favorable. Metastatic pulmonary calcinosis is rare and usually asymptomatic and evolution is good. This entity should be taken into account in the differential diagnosis of interstitial lung diseases involving micronodular infiltrates in patients at risk.

[Evaluation of clinical diagnostic guidelines for idiopathic pulmonary fibrosis]. / Evaluación de los criterios diagnósticos clínicos de fibrosis pulmonar idiopática.

OBJECTIVES: To analyze the international consensus statement on diagnostic criteria for idiopathic pulmonary fibrosis. METHODS: All patients diagnosed of any interstitial lung disease by means of open lung biopsy since 1980 were included. The patients' clinical records were examined to determine whether they fulfilled the diagnostic criteria, and their biopsies were reviewed to find those with the usual interstitial pneumonia pattern. We calculated sensitivity, specificity, positive and negative predictive values and likelihood ratios for the diagnostic criteria in the consensus statement. Afterwards, we performed the analyses again using only one of the two conditions for fulfilling the function criterion. RESULTS: Of 39 patients enrolled in the study, 17 had idiopathic pulmonary fibrosis. Specificity and positive predictive value were both 100%, but sensitivity was 41.2% and negative predictive value was 68.7%. The likelihood ratio for a negative result was 0.59. In the second analysis, sensitivity was 64.7% and negative predictive value was 78.5%, while specificity and positive predictive value remained unchanged. The likelihood ratio for a negative result was 0.35. CONCLUSIONS: The criteria are sufficiently specific to allow us to diagnose confidently when the criteria are fulfilled. However, a slight change in the function criterion should be considered in order to increase diagnostic yield.

[Outpatient emergency care in pneumology. A method to alleviate pressure of hospital emergency services]. / Atención urgente extrahospitalaria en neumología. Un método para aliviar la presión asistencial de servicios de urgencias hospitalarios.

We analyze the result of using a pneumological rapid-attention facility for diagnosis and immediate treatment of patients with respiratory symptoms arriving at the emergency room of University Hospital Virgen del Rocío in Seville (Spain). In the first six months the outpatient service saw 321 patients (male/female ratio 2.6), most of whom were between 55 and 75 years of age and had never before seen a pneumologist (83.4%). Dyspnea was the most common respiratory symptom named (by 35% of patients), and acute exacerbation of chronic obstructive pulmonary disease was the most usual diagnosis (in 19.1%). Only 21 (7%) were admitted to the hospital. We that creating the outpatient unit effectively met a societal need for rapid diagnosis and treatment of patients with respiratory complaints in the area served by our hospital emergency service.

[Evaluating the influence of hospital size on respiratory health care efficiency in Andalusia]. / Evaluación de la influencia del tamaño del hospital sobre la eficiencia asistencial neumológica en Andalucía.

OBJECTIVE: To analyze the influence of hospital size on efficient delivery of health care to patients admitted with respiratory problems in Andalusia (Spain). METHOD: From the minimal data base of all public hospital releases from Andalusia for 1994 and 1995, we identified patients whose main diagnosis involved respiratory complaints as shown by diagnosis-related grouper AP-DRG-10.0, excluding patients aged under 15 years. A functional index for each hospital was calculated to estimate hospital efficiency; a case-mix index was used to express the complexity of cases attended. RESULTS: 1) The case-mix indexes of the hospitals studied were not significantly different. Functional indexes were positively related to hospital size. CONCLUSIONS: 1) In Andalusia, case complexity does not increase with the size of public hospital. 2) Larger hospital size led to decreased efficiency in caring for respiratory patients in the population and period under study.

[Antisynthetase syndrome and interstitial lung involvement. Report of 6 cases]. / Síndrome antisintetasa y afección pulmonar intersticial. Descripción de 6 casos.

The cases of 6 patients (4 men, 2 women) with antisynthetase syndrome are reported. The mean age was 60 years and the most frequent symptom was increasing dyspnea (4 patients). One of the remaining 2 patients had hemoptysis and the last was asymptomatic. Systemic symptoms included Raynaud's phenomenon (2 patients), arthritis in hands (3) and muscle impairment (4). Chest films showed linear interstitial infiltrates of varying severity in 5 patients; the patient without such infiltrates also suffered silicosis. Functional assessment showed restrictive impairment in 4 patients; of the remaining 2 patients, 1 had chronic obstructive pulmonary disease and 1 had normal function. The antisynthetase antibody (ASAB) detected was anti-Jo-1 in 4 cases, anti-PL-12 in 1 case, and unidentified in 1 case. The course of disease was satisfactory for 5 patients. ASAB analysis is useful for studying idiopathic interstitial lung disease.

[The effect of continuous positive pressure in the nasal airway on the right ventricular function in obstructive apnea sleep syndrome]. / Efecto de la presión positiva continua en la vía aérea a través de la nariz sobre la función ventricular derecha en el síndrome de apnea obstructiva del sueño.

BACKGROUND: The aim of this study was to evaluate the right ventricular function in the obstructive apnea sleep syndrome (OSAS) and to determine the effect of the continuous use of a continuous positive pressure nasal device on the airway (CPSPn) produces on this aspect of the disease. METHODS: Forty patients were diagnosed of OSAS by study of spontaneous night sleep. A functional respiratory study was performed in all the patients as was a calculation of the index of body mass (IBM) and isotopic ventriculography for the calculation of the right and left ventricular ejection fractions (RVEF and LVEF). Twenty-six patients were followed after 8.4 +/- 3.3 months of home treatment with CPAPn in which these studies were repeated. RESULTS: Twenty-four of the 40 patients (60%) had RVEF lower than 0.45. These 24 patients had paO2 in vigil state (69.9 +/- 13.6 mmHg) than those with a normal RVEF (80.1 +/- 8.7 mmHg) (p < 0.05). After treatment with CPAPn an elevation was observed in the RVEF in the group which was followed. This increase was significant in the subgroup sharing low RVEF (n = 16) prior to starting treatment upon passing from 0.39 (+/- 0.02) to 0.45 (+/- 0.04) (p < 0.001). CONCLUSIONS: Right ventricular dysfunction in frequent in patients with the obstructive apnea sleep syndrome and is more frequent in patients maintaining hypoxemia in vigil. The continual use of continuous positive pressure in the nasal airway produces improvement in right ventricular function particularly in those in whom this was most disturbed.

[A randomized comparative study of 3 days of azithromycin treatment and 10 days of cefuroxime treatment in exacerbations in patients with chronic obstructive pulmonary disease]. / Estudio comparativo, aleatorio entre 3 días de tratamiento con azitromicina y 10 días de tratamiento con cefuroxima en las exacerbaciones de pacientes con enfermedad pulmonar obstructiva crónica.

BACKGROUND: The aim of this study was to prospectively evaluate the clinical and gasometric evolution and the side effects of two treatment schedules in the exacerbations of patients with chronic obstructive pulmonary disease (COPD): 500 mg/24 h of azithromycin (AZM) for three days versus 500 mg/12 h of acetyl cefuroxime (ACF) for 10 days. PATIENTS AND METHODS: Patients were randomized included into each therapeutic schedule. The patients were seen three times (days 1 and 4, and at 15-21 days) to evaluate clinical symptoms scores. Forced spirometry and arterial gasometry were performed the first and the last time the patients were seen. The number of patients requiring admission during follow up and the secondary effects of each antibiotic were quantified. RESULTS: A total de 50 patients were treated with AZM and 51 with ACF. The evolution of the symptoms was similar although with a trend to greater improvement in those treated with AZM. This improvement was significant for the characteristics of expectoration (p < 0.05). Functional and gasometric evolution was similar in the two schedules. Three patients treated with AZM required hospital admission, as did 5 treated with ACF. A greater number of secondary effects were observed in patients treated with ACF (18%) than in those receiving AZM (10%), with gastrointestinal side effects being the most commonly observed. CONCLUSIONS: Treatment with short schedule of AZM may have the same activity as longer schedule of ACF, with fewer secondary effects thereby suggesting that AZM may be an effective alternative in the treatment of exacerbations in patients with COPD.

Estudio en fibroblastos humanos del sistema angiotensina en la fisiopatología de la fibrosis pulmonar idiopática / The study of angiotensin system human fibroblasts in the physiopathology of idiopathic pulmonary fibrosis

En el tejido pulmonar de modelos murinos, la angiotensina II induce la proliferación de fibroblastos, su diferenciación a miofibroblastos y la producción de procolágeno tras su unión al receptor I de la angiotensina. Hemos estudiado el comportamiento de fibroblastos pulmonares humanos procedentes de una línea celular comercial tras la estimulación con TGF-β1. Hemos observado que estos fibroblastos, cuando son estimulados, aumentan la expresión de bFGF, colágeno y α-SMA. Tras el bloqueo del receptor de Angiotensina II con Losartan a una concentración de 10 µM y la estimulación con TGF- β1, se produce una disminución, tanto de los niveles de bFGF como de la concentración de colágeno, sin que llegue a alcanzar la significación estadística con respecto a las células no tratadas. En cuanto a la expresión de α-SMA como marcador de transformación a miofibroblastos, no había diferencias entre las células tratadas con TGF-β1 y TGF-β1 más losartán

In murine model lung tissue, angiotensin II induces the proliferation of fibroblasts, their distinction from myofibroblasts and procollagen production after its binding with the type 1 receptor. We have studied the behavior of human lung fibroblasts from a commercial cell line after stimulation with TGF-β1. We observed that those fibroblasts, when stimulated, increased bFGF, collagen and α-SMA expression. After blocking the angiotensin II receptor with losartan at a concentration of 10 µM and stimulation with TGF- β1, there was a decrease in both bFGF levels and collagen concentration, without reaching statistical significance with regard to untreated cells. With regard to α-SMA expression as an indicator of transformation to myofibroblasts, there were no differences between cells treated with TGF-β1 and TGF-β1 with losartan

Utility of high-resolution computed tomography and BAL in cryptogenic organizing pneumonia.

BACKGROUND: Cryptogenic organizing pneumonia (COP) is a rare disease, and its diagnosis requires histological confirmation. The objective of our study was to describe the findings of the thoracic high-resolution computed tomography (HR-CT) and bronchoalveolar lavage (BAL) in patients with confirmed COP and evaluate the complementary diagnostic use of BAL and thoracic HR-CT. METHODS: Patients recorded in the registry of interstitial pulmonary diseases between 1991 and 2008 were located and the COP patients selected. RESULTS: We identified 21 patients with histological confirmation of COP. The median age was 58.0 ± 15.9 years, and 61.9% of patients were female. The most frequent thoracic HR-CT profile was patchy infiltrate (71.4%), followed by parenchymatous consolidation (42.9%). The most frequent BAL profile was mixed alveolitis (62%) with lymphocyte predominance, a CD4/CD8 index of 0.4 and foamy macrophages. The effectiveness of transbronchial biopsy was 66.6%. The diagnostic utility of Poletti's BAL criteria gives us a specificity of 88.8%, although the sensitivity obtained was low. The specificity of certain HR-CT profiles is 99%. In addition, we observed a complementary use of the HR-CT and the BAL. CONCLUSIONS: The imaging findings and BAL could be useful for patients with appropriate clinical presentation and for those whose transbronchial biopsy is negative or for whom a confirmatory biopsy cannot be performed.