Effects of omalizumab in severe asthmatics across ages: A real life Italian experience.

BACKGROUND: This retrospective study aimed at evaluating long-term effects of Omalizumab in elderly asthmatics in a real-life setting. METHODS: 105 consecutive severe asthmatics (GINA step 4-5; mean FEV1% predicted:66 ± 15.7) treated with Omalizumab for at least 1 year (treatment mean duration 35.1 ± 21.7 months) were divided into 3 groups according to their age at Omalizumab treatment onset: 18-39, 40-64 and ≥ 65 years. RESULTS: Comorbidities, number of overweight/obese subjects and patients with late-onset asthma were more frequent among older people. A similar reduction of inhaled corticosteroids dosage and SABA on-demand therapy was observed in all groups during Omalizumab treatment; a similar FEV1 increased was also observed. Asthma Control Test (ACT) improved significantly (p < 0.001) in the three groups, increasing from 15 [IQR:12-18] to 24 [IQR:22-25] in younger subjects, from 14 [IQR:10-16] to 21 [IQR:20-23] in the 40-64-year-group and from 15 [IQR:12-16] to 20 [IQR:18-22] in elderly patients where improvement was lower (p = 0.039) compared to younger people. Asthma exacerbations decreased significantly after Omalizumab but the percentage of exacerbation-free patients was higher in younger people (76.9%) compared to middle aged patients (49.2%) and the elderly (29%) (p = 0.049). After Omalizumab treatment, the risk for exacerbations was lower in subjects aged 40-64 (OR = 0.284 [CI95% = 0.098-0.826], p = 0.021) and 18-39 (OR = 0.133 [CI95% = 0.026-0.678], p = 0.015), compared to elderly asthmatics. Also, a significantly reduced ACT improvement (ß = -1.070; p = 0.046) passing from each age class was observed. CONCLUSION: Omalizumab improves all asthma outcomes independently of age, although the magnitude of the effects observed in the elderly seems to be lower than in the other age groups.

Effects of nicotine replacement therapy on markers of oxidative stress in cigarette smokers enrolled in a smoking cessation program.

Twenty healthy, asymptomatic long-term cigarette smokers (8 males, 12 females; mean age: 43 +/- 9 years) were selected at random from a larger series receiving nicotine replacement therapy (NRT) for 12 weeks to study the effects of NRT on plasma markers of oxidative stress. Plasma aliquots, obtained at baseline (T0) and after 12 weeks (T12) of NRT, were used to measure malondialdeyde (MDA) and total Trolox-equivalent antioxidant capacity (TEAC). In subjects who completely quit smoking ('quitters', n = 10), MDA was higher at T0 (1.08 mumol/l, interquartile range 0.85-1.16) than at T12 (0.71 mumol/l, range 0.32-0.92; p < 0.01), and TEAC was lower at T0 (1.20 mM, range 1.11-1.31) than at T12 (1.43 mM, range 1.31-1.49; p < 0.05). In subjects who had only reduced the number of cigarettes smoked per day ('reducers', n = 10), differences between the T0 and T12 levels of MDA (0.81 [0.75-0.96] vs. 0.76 [0.58-0.84] mumol/l) and TEAC (1.28 [1.05-1.50] vs. 1.25 [1.09-1.42] mM) were not significant. At T0, MDA and cotinine levels correlated in reducers (r = 0.79, p < 0.05) and, though not significantly, in quitters (r = 0.50, p = 0.12). At T12 this relationship between MDA and cotinine was still present in the reducers (r = 0.70, p < 0.05), while the scatter of points in quitters was completely dispersed (r = (0.09). These results show that smoking cessation but not smoking reduction is associated with decreased markers of oxidative stress in the plasma of active cigarette smokers.

Serum antibodies to benzo(a)pyrene diol epoxide-DNA adducts in the general population: effects of air pollution, tobacco smoking, and family history of lung diseases.

Polycyclic aromatic hydrocarbons (PAHs) are almost ubiquitous pollutants that may interact with metabolic systems in human tissues and eventually cause cancer. PAH-adducted DNA becomes antigenic and antibodies anti-benzo(a)pyrene diol epoxide (BPDE)-DNA may be found in serum of PAH-exposed subjects. The presence of serum antibodies anti-BPDE-DNA adduct was investigated in 1345 individuals from family clusters of the general population of a small area in central Italy in whom information about smoking habits, site of residence, and personal and family history of lung diseases, including cancer, were obtained. Anti-BPDE-DNA antibodies in the sera were detected with a direct ELISA and the association of anti-BPDE-DNA antibodies with subjects' data from a standardized respiratory questionnaire including age, occupation, tobacco smoking habits, respiratory symptoms, and family history of respiratory diseases was subsequently tested by multivariate logistic regression analysis. The overall prevalence of subjects with anti-BPDE-DNA antibodies was 21.0% (n=283), with no differences between males and females. Anti-BPDE-DNA positivity was associated with living in the urban area [odds ratio (OR), 1.49; 95% confidence interval (CI), 1.16-1.92], with active tobacco smoking (OR, 1.25; 95% CI, 1.06-1.48), and with family history of lung cancer (OR, 1.30; 95% CI, 0.90-1.88), and positivity increased with the number of members in the family cluster positive to anti-BPDE-DNA antibodies (OR, 1.30; 95% CI, 1.03-1.65). This study on a large general population sample indicates that serum anti-BPDE-DNA antibodies may be considered as biomarkers of exposure to environmental carcinogens and of DNA damage. The genetic and familial components of their association with tobacco smoking lend further support to the argument about the familial predisposition to lung cancer.

Plasma 3-nitrotyrosine in cigarette smokers.

Peroxynitrite has been associated with increased oxidative reactions and DNA damage in inflamed tissues as it may cause a reduction of plasma antioxidants as well. Nitration of tyrosine residues of proteins leads to the production of 3-nitrotyrosine (NTYR), which may be considered as a marker of NO.-dependent oxidative damage. We developed a highly sensitive method to detect NTYR in human plasma and tested it in cigarette smokers and in healthy control subjects. Peripheral venous blood (10 ml) was obtained in 20 healthy, asymptomatic cigarette smokers (13 males, 7 females; age: 49 +/- 11 yr) and in 18 healthy nonsmokers (10 males and 8 females; age: 36 +/- 6 yr). In smokers, plasma nicotine, cotinine, and expired CO levels were measured. NTYR was determined with a sequential HPLC/gas chromatography-thermal energy analysis (GC-TEA) technique. The total plasma Trolox-equivalent antioxidant capacity (TEAC) was also measured using metmyoglobin as peroxidase and a phenothiazine as a radical donor. NTYR was detectable (detection limit: 0.02 ng/injection) in 11 smokers (mean +/- SD: 1.60 +/- 1.24 ng/mg protein) and in two nonsmokers (1.10 and 1.20 ng/mg protein, respectively). NTYR was not associated with nicotine and cotinine levels or expired CO in smokers. Plasma TEAC in smokers was significantly lower (0.43 +/- 0.38 mM) than in nonsmokers (1.42 +/- 0.3 mM; p < 0.001) and showed a biphasic, negative relationship with NTYR (r = 0.96, p < 0.001). This highly sensitive HPLC/GC-TEA method for detection and quantitation of plasma NTYR may be used for monitoring oxidative reactions associated with tobacco smoking. This assay might be incorporated into molecular epidemiologic studies for lung chronic inflammatory and neoplastic disorders in which exposure to oxidants may be an important risk factor.

Presence and persistence of serum anti-benzo[a]pyrene diolepoxide-DNA adduct antibodies in smokers: effects of smoking reduction and cessation.

Among biomarkers of tobacco smoke (TS)-induced genotoxic damage, benzo[a]pyrene diolepoxide-DNA adducts (BPDE-DNA) are extensively studied. Adducted DNA becomes antigenic and antibodies anti-BPDE-DNA (BPDE-DNA-Abs) may be found in serum of exposed subjects. Little is known about the persistence of BPDE-DNA, and no study has been performed to evaluate the persistence of BPDE-DNA-Abs after cessation of exposure. Fifty heavy smokers, enrolled in a smoking cessation program with nicotine patch substitution therapy, were evaluated for the presence of BPDE-DNA-Abs before (w0) and 1, 3, 6 and 12 weeks (w1-12) after the start of the program. Nicotine or placebo patches were randomly assigned to the subjects. BPDE-DNA-Abs were determined in serum by non-competitive ELISA. After the start of the cessation program, 28 subjects quit smoking (group Q) and the other 22 reduced by about 75% the number of cigarettes smoked per day (group R). At the start of the program (w0) 8% of subjects were positive. At w1 the prevalence of positivity had increased both in subjects who quit smoking (Q: 21%) and in subjects who had reduced the number of cigarettes per day (R: 27%). Positivity remained stable up to w12 (21%) for group Q, whereas it increased to 41% in group R. Serum BPDE-DNA-Abs can be detected in smokers, and their persistence for months after smoking cessation suggests their usefulness for relatively long-term surveys. The low percentage of positivity in actual heavy smokers and the increase in antibody positivity with smoking cessation or reduction must be taken into account when interpreting serum BPDE-DNA-Ab measurement in exposed individuals.

The earliest histopathological response to hypobaric hypoxia in rabbits in the Rifugio Torino (3370 M) on Monte Bianco.

Twelve Dutch rabbits were kept on Monte Bianco at an altitude of 3370 m. Half of the animals were killed after 3 months, the remainder after 6 months, and a further six animals maintained at sea-level acted as controls. The carotid bodies of all the rabbits were processed for light and electron microscopy and examined qualitatively and quantitatively. The lungs were processed for light microscopical assessment of small pulmonary arterial vessels; the thickness of the pulmonary trunks and aortas were measured; and the hearts were dissected to obtain ratios of the ventricular weight. There was a slight increase in the right ventricular weight in the hypoxic rabbits but no change in the thickness of the pulmonary trunk compared with that of the aorta. In particular, there was no hypoxic remodelling of the pulmonary vasculature such as muscularization of pulmonary arterioles or intimal longitudinal muscle in pulmonary arteries. The earliest histopathological response to hypoxia occurred in the carotid bodies in the form of an increase in the count of the dark variant of chief cell after 3 months which returned to normal after 6 months. It is concluded that the carotid body of the rabbit responds with a change in its population of dark chief cells to a level of hypoxia which is insufficient to affect the pulmonary arterioles. Changes in the cardiopulmonary system can no longer be considered to be the earliest histopathological response to hypobaric hypoxia.

The carotid bodies in bronchial asthma.

A histological study was made of right-sided carotid bodies resected therapeutically from 50 patients with bronchial asthma. Also studied as controls were 10 right-sided carotid bodies from subjects coming to necropsy. Hypoxaemia was considered a contra-indication to glomectomy and only patients with a resting arterial oxygen tension exceeding 65 mm Hg were submitted to operation. It was found that in patients with a short history of bronchial asthma the carotid bodies were not enlarged, but there was hyperplasia of sustentacular cells. In cases with asthma for 5 years or more the sustentacular cell hyperplasia was more pronounced and was associated with many nerve fibrils and slight enlargement of the carotid bodies. The functional significance of the proliferation of sustentacular cells and the abundance of nerve axons is obscure. In the asthma cases there was prominence of the dark variant of chief cells, thought to be related to episodes of hypoxaemia.

Monodisperse labeled aerosol to visualize airflow redistribution in the lung after a mucokinetic drug.

A technique based on inhalation of nebulized albumin minimicrospheres labeled with 99mTc (HAMM) was applied to visualize the redistribution of convective ventilation in the lung after a mucokinetic drug treatment. A randomized double-blind study comparing the effect of 7 days treatment with 800 mg daily oral sobrerol versus placebo in two groups of 10 patients each, affected by chronic bronchitis, was performed. Routine pulmonary function tests (PFT) and alveolar-arterial (Aa) gradients of oxygen and carbon dioxide were performed. Both PFT and Aa gradients did not show significant modification, but the inhomogeneity of HAMM deposition resulted significantly reduced after sobrerol treatment. By means of HAMM technique it was possible to show objectively the reduction of bronchial obstruction secondary to sobrerol treatment.

Vagal reflexes and asthma.

Although vagal reflexes are well documented in animal models of airway hyperresponsiveness, their importance in asthmatic attacks in man is less documented. Indeed most of the stimuli that can trigger bronchoconstriction act only partially through a cholinergic reflex. However, inflammatory mediators released in airways during asthma attacks may stimulate different sites of cholinergic pathways, i.e. in the sensory receptors, afferent, efferent, ganglionic or postganglionic sites. Further studies are required to assess the real influence of chemical mediators on vagal activity in asthmatic subjects during spontaneous or induced bronchoconstriction.

Muscarinic cholinergic receptors in lung of developing rats.

The muscarin-specific radioligand 1-quinuclidinyl-[phenyl-4-3H]-benzilate was used to determine the development of muscarinic receptors in particulate membranes of rat lung. Postnatal development is associated with a decrease in the number of binding sites (Bmax). Bmax was 65.61 +/- 11.33 fmol/mg protein in 21-day-old rat fetuses and it decreased to 36.64 +/- 10.18 at postnatal day 1, 32.37 +/- 4.99 at day 7 and 16.15 +/- 4.13 fmol/mg protein at 2 months. Bmax at 2 months was significantly different from all the others (Dunnett's test). The dissociation constant Kd was 0.25 nM in 2-month-old animals and it did not undergo significant changes during development.

Atropine does not inhibit late asthmatic responses induced by toluene-diisocyanate in sensitized subjects.

To determine whether early and/or late asthmatic responses induced by toluene diisocyanate (TDI) are caused by a reflex mechanism involving stimulation of muscarinic receptors, we studied the effect of the muscarinic antagonist atropine on early and late airway response induced by TDI. A preliminary study was conducted in asthmatics to assess whether the selected dose of atropine provided adequate muscarinic blockade. On different days we measured the provocation dose (in milligrams) of carbachol causing a 15% decrease in FEV1 (PD15FEV1) without and with atropine premedication (0.008 or 0.012 mg/kg subcutaneous atropine 30 or 90 min before carbachol challenge test). We found that 0.008 to 0.012 mg/kg subcutaneous atropine increased the PD15FEV1 carbachol by 6- to 10-fold, inducing a consistent and prolonged decrease in nonspecific bronchial hyperresponsiveness to cholinergic agent. Then we examined 10 subjects with a history of sensitization to TDI in 2 sets of experiments. In the first set of experiments, we studied the subjects before and after exposure to TDI (0.04 ppm; 30 min) after no treatment. In the second set of experiments, carried out 1 to 2 wk later, we repeated the same procedure after treatment with atropine (0.008 to 0.012 mg/kg atropine sulfate administered subcutaneously 30 min before TDI challenge, and then at 90-min intervals after TDI exposure); all patients showed symptoms of atropine effect (dryness of mouth, cycloplegia, increased heart rate).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional aspects of reversible airway obstruction.

The determination of the prevailing site of bronchial constriction in asthma is of noteworthy interest as regards knowledge of the pathophysiological mechanisms of this disease, and of practical importance because the intrapulmonary distribution of inhaled drugs depends chiefly on airway caliber. To visualize the alteration of convective ventilation caused by the alterations of airway caliber, we developed a technique based on inhalation of a monodispersed aerosol of human albumin minimicrospheres (mean aerodynamic diameter 0.75 micron, geometric SD 1.19) labeled with 99mTc(Hamm). Intrapulmonary HAMM deposition is revealed externally by means of a gamma camera in 4 projections, soon after inhalation and 4 h later, when the mucociliary activity has removed the fraction of HAMM deposited in larger airways. In normal subjects, about 16% of the inhaled HAMM deposited in airways, mostly (90% of total deposited fraction) by sedimentation in airways peripheral to the 16th generation. We obtained 58 determinations of the HAMM deposition pattern in 38 patients (17 males and 21 females, mean age 35.2 +/- 16.8 years) with symptomatic or asymptomatic asthma, none under acute attack. At the same time we obtained the determination of bronchoconstriction degree by measuring the forced expiratory volume in 1 s (FEV1) and the airway resistance (Raw) by plethysmographic technique. In 10 asymptomatic patients with normal bronchoconstriction indexes, we revealed the pattern of HAMM deposition before and after a reduction of about 30% in FEV1 in induced by bronchial challenge with carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)