Effects of cyclo-oxygenase inhibition on exhaled eicosanoids in patients with COPD.

BACKGROUND: Leukotriene (LT) B4 concentrations are increased and prostaglandin (PG) E2 concentrations are decreased in exhaled breath condensate (EBC) in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate the short term effects of cyclo-oxygenase (COX) inhibition on exhaled LTB4 and PGE2 concentrations in patients with COPD and to identify the COX isoform responsible for exhaled PGE2 production. METHODS: Two studies were performed. A double blind, crossover, randomised, placebo controlled study with ibuprofen (400 mg qid for 2 days), a non-selective COX inhibitor, was undertaken in 14 patients with stable COPD, and an open label study with oral rofecoxib (25 mg once a day for 5 days), a selective COX-2 inhibitor, was undertaken in a different group of 16 COPD patients. EBC was collected before and after drug treatment. Exhaled LTB4 and PGE2 concentrations were measured with specific immunoassays. RESULTS: All patients complied with treatment as indicated by a reduction in ex vivo serum thromboxane B2 concentrations (ibuprofen) and a reduction in lipopolysaccharide induced increase in ex vivo plasma PGE2 values (rofecoxib) of more than 80%. Exhaled LTB4 was increased after ibuprofen (median 175.5 (interquartile range 128.8-231.5) pg/ml v 84.0 (70.0-98.5) pg/ml, p < 0.001) and exhaled PGE2 was reduced (93.5 (84.0-105-5) pg/ml v 22.0 (15.0-25.5) pg/ml, p < 0.0001). Rofecoxib had no effect on exhaled LTB4 (p = 0.53) or PGE2 (p = 0.23). CONCLUSIONS: Non-selective COX inhibition decreases PGE2 and increases LTB4 in EBC, whereas selective COX-2 inhibition has no effect on these eicosanoids. PGE2 in EBC is primarily derived from COX-1 activity, and COX inhibition may redirect arachidonic acid metabolism towards the 5-lipoxygenase pathway.

Validation of leukotriene B4 measurements in exhaled breath condensate.

OBJECTIVE: To qualitatively validate an enzyme immunoassay to measure leukotriene B4 in exhaled breath condensate. Exhaled breath condensate is a new non-invasive method to monitor airway inflammation. SUBJECTS: Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection. METHODS: Samples were pooled together and purified by reverse-phase high-performance liquid chromatography. The fractions eluted were assayed for leukotriene B4 by enzyme immunoassay. RESULTS: A single peak of leukotriene B4-like immunoreactivity co-eluting with leukotriene B4 standard (retention time: 24 min) was identified by enzyme immunoassay. Reverse phase-high performance liquid chromatography peak of leukotriene B4 was clearly separated from those of 6-trans-leukotriene B4 (retention time: 14 min) and leukotriene B5 (retention time: 18 min) for which the antiserum used in the enzyme immunoassay had the highest cross-reactivity. Leukotriene B4 recovery was 64%. CONCLUSIONS: This study provides evidence for the presence of leukotriene B4 in the exhaled breath condensate and the specificity of the enzyme immunoassay used.

Validation of 8-isoprostane and prostaglandin E(2) measurements in exhaled breath condensate.

OBJECTIVE: To qualitatively validate radioimmunoassays for 8-isoprostane and prostaglandin (PG) E(2) in exhaled breath condensate. SUBJECTS: Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection. METHODS: Samples were pooled together and purified by reverse phase high performance liquid chromatography (RP-HPLC). The eluted fractions were assayed for 8-isoprostane-like immunoreactivity and PGE(2)-like immunoreactivity by radioimmunoassays. In addition, simultaneous measurements of exhaled breath condensate unextracted samples with two anti-8-isoprostane and anti-PGE(2) sera with different cross-reactivity were performed. RESULTS: A single peak of 8-isoprostane-like immunoreactivity and PGE(2)-like immunoreactivity co-eluting with 8-isoprostane (retention time: 13 min) and PGE(2) (retention time: 21 min) standards, respectively, was identified by radioimmunoassays. Testing with two different antisera showed similar results for both 8-isoprostane-like immunoreactivity (limits of agreement = 4.5 pg/ml and - 4.1 pg/ml, n = 12) and PGE(2)-like immunoreactivity (limits of agreement = 6.1 pg/ ml and - 6.1 pg/ml, n = 12). CONCLUSION: This study provides evidence for the specificity of the radioimmunoassays for 8-isoprostane and PGE(2) in exhaled breath condensate. This is critical for proposing these markers as a non-invasive way for monitoring airway inflammation.

Correlates of osteoporosis in chronic obstructive pulmonary disease.

The aim of this study was to analyse the correlates of reduced bone mineral density in patients with chronic obstructive pulmonary disease (COPD), with special regard to a possible protective role of hypercapnia. One hundred and four consecutive COPD inpatients in stabilized respiratory conditions underwent a comprehensive assessment of their health status. Bone mineral density was measured by X-ray absorptiometry at the lumbar site and at the femoral neck site. Differences in health-related variables between patients with (group O, n=62) and without (group N, n=42) lumbar and/or femoral neck osteoporosis were assessed first by univariate analysis and then by logistic regression analysis aimed to identify independent correlates of osteoporosis. Group O was characterized by worse nutritional status, as reflected by indices exploring either lean or fat mass, and by a trend towards lower forced expiratory volume in 1 sec/forced vital capacity ratio. Arterial tension of carbon dioxide lacked any correlation with bone mineral density. According to the logistic regression analysis, body mass index < or = 22 kg m(-2) qualified as the only and positive independent correlate of osteoporosis (odds ratio=4.18; 95% confidence intervals=1.19-14.71). In conclusion, malnutrition characterizes COPD patients with osteoporosis, while mild to moderate hypercapnia lacks either a positive or negative effect on bone mineral density. Longitudinal studies are needed to identify predictors rather than correlates of bone mineral density.

Respiratory function impairment in pulmonary tuberculosis.

Main alterations of respiratory function in pulmonary tuberculosis are analyzed. Due to the wide range of clinical manifestations, all possible patterns of dysfunctions are described with particular reference to the impact on gas exchange. Possible sequelae of pulmonary tuberculosis are also reported.

Slow compartment features and gas exchange impairment in mild asthma: effects of beta agonist inhalation.

Static and dynamic lung volumes, arterial blood gases, alveolar ventilation and ventilation-perfusion (VA/Q) relationships were studied in 14 mild asthmatic patients and in 7 normal subjects (as controls) before and after fenoterol inhalation. Multiple nitrogen washout curves were analyzed by a bicompartmental distribution model, in order to assess the distribution of ventilation and VA/Q mismatch. At baseline, asthmatics showed mild airway obstruction and gas exchange impairment [forced expiratory volume in 1 s (FEV1) = 79% pred; PaO2 = 87.4; alveolar-arterial oxygen tension gradient (AaPO2) = 22.9 mm Hg]. By analysing nitrogen washout curves, an alveolar slow space representing 45.1% of total lung volume (vs. 36.8% in normals; p = 0.044) was identified; its alveolar ventilation per minute per unit lung volume (VA2/L2) was lower than in normals (p = 0.01). beta-Agonist inhalation by the asthmatics, which reversed airway obstruction (FEV1 = 98% pred.; p < 0.001) and improved gas exchange (PaO2 = 92.6 mm Hg, p < 0.001; AaPO2 = 16.8 mm Hg, p = 0.003), led to a highly significant increase in VA2/L2 (p = 0.001). The improvement in PaO2 was associated with the increase in VA2/L2 (r2 = 0.39; p = 0.017), but not with the increase in FEV1. Lastly, the changes in FEV1 and VA2/L2 were not correlated with each other. We conclude that even in mild stable asthma there is substantial unevenness of ventilation, detectable by bicompartmental analysis of nitrogen washout curves, which is responsible for gas exchange impairment and is not related to common spirometric parameters. In addition, the improvement in gas exchange is probably due to the effect of fenoterol on the tributary airways of the alveolar slow compartment. This effect can be assessed by this simple method, which can be used in clinical pharmacology studies and in the follow-up of asthmatic patients.

Airway disease: anatomopathologic patterns and functional correlations.

Airways represent a serial and parallel branched system, through which the alveoli are connected with the external air. They participate in the mechanical and immune defense against noxious agents, regional flow regulation to optimize the perfusion/ventilation ratio and provide lung mechanical support. Functional exploration of central airways is based on resistance measurement, flow-volume curve or spirometry, while peripheral airways influence parameters as the upstream resistance, the slope of phase III nitrogen washout and the residual volume. Bronchodynamic tests supply important information on airway reversibility and nonspecific reactivity. Anatomopathologic alterations of obstructive chronic bronchitis, pulmonary emphysema and bronchial asthma account for their specific functional and bronchodynamic alterations. There is a growing interest for bronchiolitis in the clinical, radiologic and functional field. This type of lesion, always present in COPD, asthma and interstitial disease, becomes relevant when isolated or predominant. The most useful anatomofunctional classification separates the "constrictive" forms, the cause of obstruction and hyperinflation, from "proliferative" forms where an intraluminal proliferation more or less extended to alveolar air spaces as in BOOP (bronchiolitis obliterans organizing pneumonia) results in restrictive dysfunction. Constrictive bronchiolitis obliterans represents a severe and frequent complication of lung and bone marrow transplantation. Idiopathic BOOP may occur with cough or flue-like symptoms. In other cases, constrictive and proliferative forms may have a toxic (gases or drugs), postinfective or immune etiology (rheumatoid arthritis, LES, etc). Respiratory bronchiolitis or smokers' bronchiolitis, an often asymptomatic lesion, rarely associated to an interstitial lung disease, should be considered separately. The relationships between respiratory bronchiolitis, COPD and initial centriacinar emphysema is still to be elucidated. The diagnostic combination of the more sensitive functional tests with HRCT will allow a better understanding of the natural history of the various forms of bronchiolitis.

Deaths from asthma in Italy (1974-1988): is there a relationship with changing pharmacological approaches?

In this article we consider the relationship between asthma mortality rates, obtained from the Italian National Institute of Statistics (ISTAT), and the doses of all antiasthmatic drugs except systemic steroids sold in Italy in the years 1974-1988. The total asthma mortality rate showed three different trends: it decreased slowly until 1978 (period A); increased 10-fold from 1979 to 1985, rising from 0.30 to 4.17/100,000 (period B); and remained stable until 1988 (period C). More than half of the deaths in 1988 occurred in people 75 years of age or more. Men died more in the older age groups, while the mortality of women prevailed in the 35- to 54-year age group. In the 5- to 34-year age group the rate rose from 0.01 in 1978 to 0.21 /100,000 in 1986. Coding changes due to the 9th revision of the International Classification of Disease, adopted in Italy in 1979, probably increased the number of deaths being attributed to asthma in case of contemporary mention of bronchitis, a common diagnosis in older men, which showed the greatest increase in mortality. Increased prevalence and awareness of asthma may also have played a role. Although international comparisons strongly suggest undertreatment of asthma in Italy, the doses of anti-asthma drugs sold in Italy grew from 276 to 1,080 million from 1974 to 1985. During period B xanthine sales rose sevenfold and grew from 6.5 to 23.3% of the total doses, along with a twofold increase in beta 2-agonist and cromolyn sales. Period C was characterized by stable total doses (1155 million in 1988), with increases only in antiinflammatory and preventive drug sales. The increase in asthma deaths in Italy has been striking despite the contemporary rise in sales of all antiasthma drugs, particularly of beta 2-agonist metered aerosols and xanthine tablets. The increase in antiinflammatory and preventive drug sales may have contributed to the stabilization of asthma deaths during period C.

Lung function in children and adolescents with occasional exposure to environmental tobacco smoke.

We investigated the effects of occasional exposure to environmental tobacco smoke (ETS) on lung function in children. A total of 317 healthy 12- to 15-yr-old nonsmoking children and adolescents, living in households in which none of the adults were active smokers, were selected for the present analysis. The urinary cotinine:creatinine ratio (CCR) was taken as the biologic indicator of exposure, and children were classified according to CCR quartiles. The ratio between FEV1 and FVC (FEV1/FVC) and both early (peak expiratory flow [PEF]) and midexpiratory flow rates (FEF25-75) were lower in children with higher CCR values. In percent terms, the decrease in adjusted lung function for children belonging to the second, third, and fourth quartiles in comparison with those in the first quartile was -1.37, -2.12, and -1.94 for FEV1/FVC (p for trend = 0.012); 0.98, -3.31, and -4.54 for PEF (p for trend = 0.024); and -0.05, -4.85, and -6.13 for FEF25-75 (p for trend = 0.022), respectively. The effects remained significant when possible confounding by father's education and urinary creatinine level had been taken into account, and when children whose parents' smoking status may have been misclassified were excluded. This study suggests an adverse effect on lung function from even low-level exposure to ETS among nonsmoking children living with reportedly nonsmoking parents.

Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease.

PURPOSE: To identify factors affecting the short-term prognosis of patients with acutely exacerbated chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: The 590 patients having COPD as primary disease who were hospitalized in the pneumology unit of a university hospital from 1981 to 1990 were studied. A standardized protocol for the treatment of acutely exacerbated COPD was adopted for all the patients. The patient records were retrospectively analyzed by two observers, and 23 clinical and laboratory variables defining the patient status on admission were collected. Age and arterial gas data were also taken into account, and the outcome mortality was recorded. Interobserver reproducibility was tested by computing the kappa coefficient and Spearman's rho for dichotomous and continuous variables, respectively. The relationship of clinical and laboratory factors to the outcome was assessed first by univariate analysis and then by a logistic regression analysis assessing the independent predictive role of variables previously shown to be univariately correlated with mortality. RESULTS: The mortality rate was 14.4%. The logistic regression analysis identified four independent predictors of death: age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.04 to 1.11), alveolar-arterial oxygen gradient greater than 41 mm Hg (OR 2.33; 95% CI 1.39 to 3.90), ventricular arrhythmias (OR 1.91; 95% CI 1.10 to 3.31), and atrial fibrillation (OR 2.27; 95% CI 1.14 to 4.51). CONCLUSIONS: Patients with acutely exacerbated COPD having a high risk of death can be identified at the time of admission. Variables reflecting heart dysfunction are important determinants of this risk. Among pulmonary function data, only alveolar-arterial oxygen gradient contributes to the predictive model.

Evaluation of the efficacy of pidotimod in the exacerbations in patients affected with chronic bronchitis.

The efficacy and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new oral synthetic immunostimulating agent, were investigated in a multicentre study, performed in 10 university and hospital centres of pneumophthisiology and respiratory physiopathology, according to a double-blind vs. placebo experimental design. Primary objective of the investigation was to verify the efficacy of pidotimod against infectious exacerbations in patients affected with chronic bronchitis. 181 inpatients or outpatients (117 male, 64 female; mean age: 62.5 years), affected with chronic bronchitis, were enrolled in the study. Pidotimod 800 mg/die or placebo sachets were administered by oral route for 60 consecutive days, followed by a 60-day follow-up period. Clinical observations were performed at baseline (D 0), after 30 (D 30) and 60 (D 60) days of treatment, as well as at the end of the follow-up (D 120). Time and frequency of infectious relapses were considered as the target variable for the evaluation of the efficacy of the drug. Clinical picture, expectoration characteristics, spirometric parameters and laboratory tests were monitored to evaluate patients' conditions. The results indicate that pidotimod is significantly more effective than placebo against infectious relapses in patients suffering from chronic bronchitis. During the first month, 9% of patients treated with pidotimod were affected with an infectious relapse vs. 39.5% of patients treated with placebo (chi 2, p < 0.001). In the second month, infectious episodes were reported by 1.2% of patients treated with the drug vs. 46.1% of patients treated with placebo (chi 2, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial responsiveness in children living in areas with different air pollution levels.

This study evaluated the prevalence of increased bronchial responsiveness (BR) in children living in two areas with different air pollution levels. A total of 1,215 methacholine challenge tests were performed among a random sample of primary schoolchildren in an industrial town polluted by oil-fired thermoelectric power plants and in a rural area chosen as a control. The two groups showed similar lung function data (forced vital capacity [FVC] and forced expiratory volume in 1 s [FEV1.0]) and prevalence of positive prick tests to common aeroallergens. All children responding with a 20% drop in FEV1.0 to a methacholine concentration < or = 64 mg/ml, "all responders" (PC20FEV1.0 < or = 64 mg/ml), and the subgroup of "strong responders" (PC20FEV1.0 < or = 4 mg/ml) were compared separately with "nonresponders" (PC20FEV1.0 > 64 mg/ml), calculating odds ratios (ORs). There were more "all responders" (57.2% versus 41.4%) and "strong responders" (20.0% versus 14.8%) among subjects living in the industrial area; the excess remained when several potential confounders were taken into account ("all responders": OR = 2.0, 95% confidence interval [95% CI] = 1.5-2.6; "strong responders": OR = 1.9, 95% CI = 1.3-2.8), and it was even more pronounced among girls. When the effect of clinical predictors of increased airways responsiveness (history of asthma, allergic rhinitis, baseline airways caliber, skin reactivity, recent respiratory infection) was considered through multiple logistic regression, the odds ratios associated with living in the industrial area were still significantly increased in girls. The cross-sectional approach and the lack of individual exposure data limit the interpretation of the findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Passive smoking as a determinant of bronchial responsiveness in children.

The effect of passive smoking on the degree of nonspecific bronchial responsiveness (BR) in children was evaluated. In a cross-sectional survey of primary school children (7 to 11 yr) in Latium (Italy), a total of 1,215 methacholine challenge tests was performed. The children were divided into nonresponders (PC20 FEV1 > 64 mg/ml) and responders (PC20 FEV1 < or = 64 mg/ml), the latter including a subgroup of strong responders (PC20 FEV1 < or = 4.0 mg/ml). The role of passive smoking exposure was analyzed through logistic regression models. Higher odds ratios were found among girls (for strong responders: maternal smoking, OR 2.92; paternal smoking, OR 2.59); moreover, among girls there was a dose-response relationship with the number of cigarettes smoked by the mother. An effect modification was also detected for father's education and household crowding: maternal and paternal smoking were strong predictors of bronchial hyperresponsiveness in families in which the head was less educated and in overcrowded houses. The results were confirmed using a continuous index of BR (slope) and after adjustment for baseline airway caliber. We suggest that the effect of parental smoking on children's bronchial responsiveness is detectable when the conditions for a higher exposure level at home are met; females seem to be more susceptible.

Bronchial asthma: still an inadequately assessed and improperly treated disease.

In this paper we present data on the assessment and treatment of asthma in a large sample (13,899 subjects) representative of the population of young males living in four districts of the Tuscany region (Italy). In this group, 404 asthmatics (2.9%) were identified and 365 of the eligible patients were included in the study. A total of 323 asthmatics (88.5%) reported respiratory symptoms during the preceding year. A total of 162 asthmatics (44%) had previously had lung function tests to assess asthma, whereas in 89% of the patients the atopic component of asthma had been previously evaluated by prick tests. Fifty-seven percent of the patients in whom bronchial obstruction was observed and 38% of the asthmatics with severe bronchial hyperresponsiveness (BH) were receiving either no medication or treatment with only one drug. The drugs prescribed most frequently during the preceding year were beta agonists (56%) as opposed to sodium cromoglycate (22%) and inhaled steroids (17%); the latter two drugs were included in the therapy of 143 asthmatics (39%) and represented the treatment of choice in 16% of the subjects with bronchial obstruction and in 38% of the subjects with severe BH. We conclude that in our sample of young asthmatics the pulmonary function tests and the inhaled anti-inflammatory drugs were insufficiently utilized.

The relationship between sporting activity and smoking habits in young adults.

The authors investigated the relationship between sporting activity and smoking habits in young Italian men. One thousand, one hundred fifty-three men, age 20 years, completed a self-administered questionnaire on their smoking habits and sporting activity patterns. Five hundred sixty subjects (53%) were found to be smokers, with a high prevalence of heavy smokers (33.6%). Four hundred sixty-four (44%) of the examined subjects were sportsmen. In the group of young men not engaged in sports, the rate of smokers was significantly higher. Non-sportsmen started smoking earlier than sportsmen, and the prevalence of heavy smokers was significantly higher in the non-sportsmen group than in the sportsmen group. Finally, the young men not engaged in sports were more likely to be habitual smoke inhalers than sportsmen. These results suggest that sporting activity may indirectly influence smoking habits.

Effects of environment on atopic status and respiratory disorders in children.

BACKGROUND: We investigated whether living in areas with higher air pollution levels increases the prevalence of positive skin reactivity in children and the possible synergic effect of air pollution exposure and atopy on respiratory disorders. METHODS: This cross-sectional study was conducted in an urban area, in an industrialized area, and in a rural control area in the Latium region of Italy. A total of 2226 subjects, aged 7 to 11 years, were studied. RESULTS: The prevalence of children with positive skin test results did not vary significantly over the areas (urban area = 21.0%, industrialized area = 22.0%, rural area = 20.2%). Children living in polluted areas experienced significantly more cough and phlegm (odds ratio [OR] = 1.5), rhinitis (OR = 1.7), pneumonia (OR = 1.7), and early respiratory infections (OR = 1.4) than control subjects. The pattern of the odds ratios for atopy and air pollution suggested that the two factors were probably additive in affecting asthma and early respiratory infections (synergy index [SI] = 1.04 and 1.27, respectively), whereas they seemed to act synergically in regard to cough and phlegm (SI = 1.59), rhinitis (SI = 3.01), and pneumonia (SI = 2.75). CONCLUSION: Environmental air pollution seems not to increase the prevalence of atopic status; it seems, however, to enhance the development of clinical symptoms among already sensitized subjects.

An uncommon case of brainstem tumor with selective involvement of the respiratory centers.

We report a clinical case of a young man with a brainstem tumor with a stable alveolar hypoventilation syndrome as the only symptom of the disease. The ventilatory response to CO2 was almost absent and the ventilatory pattern during tidal breathing was very irregular. The diagnosis was made by magnetic resonance imaging of the brain and confirmed by a stereotactic brain biopsy specimen.

[The nonspecific bronchial stimulation test with methacholine and an ultrasonic mist of distilled water: which is to be preferred in the military sphere?]. / Test di broncostimolazione aspecifica con metacolina e con nebbia ultrasonica di acqua distillata: quale preferire in ambito militare?

The authors compare the methacholine (Mch) and the nebulized ultrasonic distilled water (NUDW) bronchial challenge as regard sensitivity and time required to perform them. For military service fitness, were studied 24 asthmatic patients. Each subject performed random a bronchial challenge by Mch (Yan method) and by NUDW (Allegra method) in two different days; for each bronchial challenge has been measured the time required to perform it. The atopic status has been evaluated by skin-prick test. All the subjects have shown a positive response to Mch test (PD 20 FEV1 mean: 352 mcg, range 80-850) whereas 13 subjects (54%) have shown a positive response to NUDW. The time required to evaluate all the subjects by Mch test has been 199.5 minutes whereas the total time required to evaluate all the subjects by NUDW test (127 minutes) and to evaluate by Mch test the non responders to NUDW (100 minutes) has been 227 minutes. The most of subjects were skin reactors. No difference was found as regard onset of disease, basal lung function and atopic status between responders and non responders to NUDW test. We conclude that NUDW test has shown a lack of sensitivity in this sample (50% of asthmatic patients could be misdiagnosed) and that the Mch test is preferable to determine a rapid method for measurement of bronchial responsiveness.