Piersante Sestini

Inhaler mishandling remains common in real life and is associated with reduced disease control.

Proper inhaler technique is crucial for effective management of asthma and COPD. This multicentre, cross-sectional, observational study investigates the prevalence of inhaler mishandling in a large population of experienced patients referring to chest clinics; to analyze the variables associated with misuse and the relationship between inhaler handling and health-care resources use and disease control. We enrolled 1664 adult subjects (mean age 62 years) affected mostly by COPD (52%) and asthma (42%). Respectively, 843 and 1113 patients were using MDIs and DPIs at home; of the latter, the users of Aerolizer®, Diskus®, HandiHaler® and Turbuhaler® were 82, 467, 505 and 361. We have a total of 2288 records of inhaler technique. Critical mistakes were widely distributed among users of all the inhalers, ranging from 12% for MDIs, 35% for Diskus® and HandiHaler® and 44% for Turbuhaler®. Independently of the inhaler, we found the strongest association between inhaler misuse and older age (p = 0.008), lower schooling (p = 0.001) and lack of instruction received for inhaler technique by health caregivers (p < 0.001). Inhaler misuse was associated with increased risk of hospitalization (p = 0.001), emergency room visits (p < 0.001), courses of oral steroids (p < 0.001) and antimicrobials (p < 0.001) and poor disease control evaluated as an ACT score for the asthmatics (p < 0.0001) and the whole population (p < 0.0001). We conclude that inhaler mishandling continues to be common in experienced outpatients referring to chest clinics and associated with increased unscheduled health-care resource use and poor clinical control. Instruction by health caregivers is the only modifiable factor useful for reducing inhaler mishandling.

Road traffic and adverse respiratory effects in children. SIDRIA Collaborative Group.

OBJECTIVES: To investigate the relation between traffic indicators in the area of residence and the occurrence of chronic respiratory disorders in children. METHODS: A population based survey was conducted in 10 areas of northern and central Italy (autumn 1994 to winter 1995) in two age groups (6-7 and 13-14 years). Information on several respiratory disorders and on traffic near residences was collected with a questionnaire given to children and to their parents. The sample analysed included 39,275 subjects (response rate 94.4%). Outcomes were: (a) early (first 2 years of life) respiratory diseases, and (b) current respiratory disorders (asthma, wheeze, cough, or phlegm in the past year). Odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusted for several potential confounders, were estimated from logistic regression models. Main results were stratified by level of urbanisation (metropolitan areas, other centres). RESULTS: In the metropolitan areas, high frequency of lorry traffic in the street of residence was associated with significantly increased risks for many adverse respiratory outcomes. Among early respiratory diseases, the strongest associations were found for recurrent bronchitis (OR 1.69, 95% CI 1.24 to 2.30), bronchiolitis (1.74, 1.09 to 2.77) and pneumonia (1.84, 1.27 to 2.65), although no association was detected for episodes of wheezing bronchitis. All the current respiratory disorders were positively and consistently associated with frequency of lorry traffic, particularly the most severe bronchitic and wheezing symptoms: persistent phelgm for > 2 months (1.68; 1.14 to 2.48), and severe wheeze limiting speech (1.86; 1.26 to 2.73). No or weaker associations with heavy vehicular traffic were detected in urban and rural areas and no increased risks were found in the whole sample with the reported traffic density in the zone of residence. After extensive evaluations, the potential of reporting bias seems unlikely. CONCLUSION: Exposure to exhausts from heavy vehicular traffic may have several adverse effects on respiratory health of children living in metropolitan areas, increasing the occurrence of lower respiratory tract infections early in life and of wheezing and bronchitic symptoms at school age.

Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions.

The movement of ions and water across the membranes of bronchial cells is part of the control of the bronchial obstructive response to physical stimuli. In a double-blind, randomized, crossover study, we compared the effect of an aerosol of the loop diuretic furosemide with that of a placebo on the early (within 60 minutes) and late (4 to 12 hours) asthmatic responses to a specific inhaled allergen. We studied 11 subjects with mild allergic asthma, who had both early and late asthmatic responses to a specific inhaled allergen in a preliminary challenge. After placebo administration, the maximal changes (mean +/- SE) from base line in the forced expiratory volume in one second (FEV1) and specific airway resistance were, respectively, a decrease of 35 +/- 4 percent and an increase of 288 +/- 56 percent between 0 and 60 minutes after inhalation of the allergen (early response) and a decrease of 35 +/- 5 percent and an increase of 301 +/- 40 percent between 4 and 12 hours (late response). After furosemide administration (4 ml; 10 mg per milliliter), the early response to inhaled allergen was markedly attenuated in all the subjects, and the late response in all but one. The maximal changes in the FEV1 and specific airway resistance were, respectively, a decrease of 11 +/- 2 percent and an increase of 61 +/- 2 percent between 0 and 60 minutes and a decrease of 20 +/- 4 percent and an increase of 178 +/- 25 percent between 4 and 12 hours (P less than 0.05 for all comparisons). No significant differences were seen in the bronchoconstrictor response to inhaled methacholine after furosemide or placebo administration. We conclude that a furosemide-sensitive mechanism in the airways is involved in the pathogenesis of the reactions of patients with allergic asthma. Whether inhaled furosemide might be useful in the treatment of allergic asthma is uncertain and will require further study.

Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children

BACKGROUND A beneficial effect of fresh fruit consumption on lung function has been observed in several studies. The epidemiological evidence of the effect on respiratory symptoms and asthma is limited. The consumption of fruit rich in vitamin C was examined in relation to wheezing and other respiratory symptoms in cross sectional and follow up studies of Italian children. METHODS Standardised respiratory questionnaires were filled in by parents of 18 737 children aged 6–7 years living in eight areas of Northern and Central Italy. The winter intake of citrus fruit and kiwi fruit by the children was categorised as less than once per week, 1–2 per week, 3–4 per week, and 5–7 per week. A subset of 4104 children from two areas was reinvestigated after one year using a second parental questionnaire to record the occurrence of wheezing symptoms over the intervening period. RESULTS In the cross sectional analysis, after controlling for several confounders (sex, study area, paternal education, household density, maternal smoking, paternal smoking, dampness or mould in the childs bedroom, parental asthma), intake of citrus fruit or kiwi fruit was a highly significant protective factor for wheeze in the last 12 months (odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.55 to 0.78, for those eating fruit 5–7 times per week compared with less than once per week), shortness of breath with wheeze (OR = 0.68, 95% CI 0.56 to 0.84), severe wheeze (OR = 0.59, 95% CI 0.40 to 0.85), nocturnal cough (OR = 0.73, 95% CI 0.65 to 0.83), chronic cough (OR = 0.75, 95% CI 0.65 to 0.88), and non-coryzal rhinitis (OR = 0.72, 95% CI 0.63 to 0.83). In the follow up study fruit intake recorded at baseline was a strong and independent predictor of all symptoms investigated except non-coryzal rhinitis. In most cases the protective effect was evident even among children whose intake of fruit was only 1–2 times per week and no clear dose-response relationship was found. The effect was stronger (although not significantly so (p = 0.13)) in subjects with a history of asthma; those eating fresh fruit at least once a week experienced a lower one year occurrence of wheeze (29.3%) than those eating fruit less than once per week (47.1%) (OR = 0.46, 95% CI 0.27 to 0.81). CONCLUSIONS Although the effect of other dietary components cannot be excluded, it is concluded that the consumption of fruit rich in vitamin C, even at a low level of intake, may reduce wheezing symptoms in childhood, especially among already susceptible individuals.

Changes in Prevalence of Asthma and Allergies Among Children and Adolescents in Italy: 1994–2002

BACKGROUND. Several studies conducted during the 1990s indicated an increase in the prevalence of symptoms of asthma; more recent investigations suggest that the trend is stabilizing or may even be reversing. OBJECTIVE. We compared 2 cross-sectional surveys conducted in 1994 and 2002 in 8 areas in northern and central Italy, to evaluate prevalence changes for asthma, allergic rhinitis, and eczema. METHODS. The International Study of Asthma and Allergies in Childhood methods and questionnaires were used to investigate 6- to 7-year-old children (16115 and 11287 questionnaires completed by parents in 1994–1995 and 2002, respectively) and 13- to 14-year-old adolescents (19723 and 10267 questionnaires completed by adolescents in 1994–1995 and 2002, respectively). In each phase, the overall response rate was >90%. Prevalence changes were calculated as the absolute difference between the prevalence recorded on the 2 occasions. RESULTS. The prevalence of wheeze (past 12 months) increased slightly among children (change: 0.8%; 95% confidence interval [CI]: 0.0% to 1.6%) and was rather stable among adolescents. Symptoms of allergic rhinitis (children: change: 5.2%; 95% CI: 4.0% to 6.4%; adolescents: change: 4.1%; 95% CI: 1.9% to 6.3%) and symptoms of atopic eczema (children: change: 4.4%; 95% CI: 3.6% to 5.2%; adolescents: change: 2.1%; 95% CI: 1.2% to 3.0%) increased clearly in both age groups. There was some heterogeneity across the centers among adolescents, especially for allergic rhinitis, with larger increases seen in the 3 metropolitan areas. The changes observed paralleled profound family changes, ie, better parental education, higher rates of maternal employment, and lower rates of exposure to parental smoke. These factors, however, do not explain all of the observed changes in prevalence. CONCLUSIONS. The results indicate that the epidemiologic features of asthma and allergies in Italy are changing rapidly, although the causes are still uncertain.

Gene expression profiling reveals novel TGFβ targets in adult lung fibroblasts

BackgroundTransforming growth factor beta (TGFβ), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFβ on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown.MethodsWe used Affymetrix oligonucleotide microarrays U95v2, containing approximately 12,000 human genes, to study the transcriptional profile in response to a four hour treatment with TGFβ in control lung fibroblasts and in fibroblasts from patients with idiopathic and scleroderma-associated pulmonary fibrosis. A combination of the Affymetrix change algorithm (Microarray Suite 5) and of analysis of variance models was used to identify TGFβ-regulated genes. Additional criteria were an average up- or down- regulation of at least two fold.ResultsExposure of fibroblasts to TGFβ had a profound impact on gene expression, resulting in regulation of 129 transcripts. We focused on genes not previously found to be regulated by TGFβ in lung fibroblasts or other cell types, including nuclear co-repressor 2, SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), bone morphogenetic protein 4, and angiotensin II receptor type 1 (AGTR1), and confirmed the microarray results by real time-PCR. Western Blotting confirmed induction at the protein level of AGTR1, the most highly induced gene in both control and fibrotic lung fibroblasts among genes encoding for signal transduction molecules.Upregulation of AGTR1 occurred through the MKK1/MKK2 signalling pathway. Immunohistochemical staining showed AGTR1 expression by lung fibroblasts in fibroblastic foci within biopsies of idiopathic pulmonary fibrosis.ConclusionsThis study identifies several novel TGFβ targets in lung fibroblasts, and confirms with independent methods the induction of angiotensin II receptor type 1, underlining a potential role for angiotensin II receptor 1 antagonism in the treatment of lung fibrosis.

Commensal bacteria as vectors for mucosal vaccines against sexually transmitted diseases: vaginal colonization with recombinant streptococci induces local and systemic antibodies in mice

There is a need to develop vaccines to control the spread of sexually transmitted diseases (STDs). Novel immunization strategies that elicit a mucosal immune response in the genital tract, may show improved protection by preventing or at least limiting entry of the pathogenic micro-organism. However, it has proven difficult to obtain a local immune response in the vaginal mucosa. Our approach is based on the use of recombinant bacteria capable of colonizing mucosal surfaces as live vaccine vectors. The human commensal Streptococcus gordonii, engineered to express the E7 protein of human papillomavirus type 16, was used for intravaginal immunization of mice. A single inoculum of recombinant bacteria was sufficient to establish colonization of the murine vagina and therefore induce papillomavirus-specific vaginal IgA and serum IgG. Evidence that mucosal colonization with recombinant commensal bacteria can induce a local immune response in the female genital tract represents a significant step toward the development of new vaccines against STDs.

The impact of parental smoking on asthma and wheezing. SIDRIA Collaborative Group. Studi Italiani sui Disturbi Respiratori nell'Infanzia e l'Ambiente.

To evaluate the impact of parental smoking on childhood asthma and wheezing, we studied two random samples of subjects ages 6–7 and 13–14 years in ten areas of northern and central Italy. Standardized questionnaires were completed by parents of 18,737 children and 21,068 adolescents (response rates, 92.8% and 96.3%, respectively) about their smoking habits and the respiratory health of their children. Adolescents were asked about their respiratory health and personal smoking. We compared two groups of cases with healthy subjects: “current asthma” (children, 5.2%; adolescents, 6.2%) and “current wheezing” not labeled as asthma (children = 4.5%, adolescents = 8.5%). Exposure to smoke of at least one parent increased the relative risk of current asthma among children [odds ratio (OR) =.34; 95% confidence interval (CI) = 1.11–1.62] and of current wheezing among adolescents OR = 1.24; 95% CI = 1.07–1.44). Maternal smoking had a stronger effect than paternal smoking. Maternal smoking during pregnancy was associated with current asthma (OR = 1.62; 95% CI = 1.34–1.96) and current wheezing in children (OR = 1.31; 95% CI = 1.06–1.62); the effects were lower among adolescents. Among subjects with a negative history of parental asthma, maternal smoking was associated with current wheezing in both age groups, whereas among those with a positive history of parental asthma it was associated with current asthma in children, but not in adolescents. We estimated that 15% (95% CI = 12–19) of the current asthma cases among children and 11% (95% CI = 8.3–14) of the current wheezing cases among adolescents are attributable to parental smoking in Italy. (Epidemiology 1999;10:692–698)

Efficacy and Tolerability of Nimesulide in Asthmatic Patients Intolerant to Aspirin

SummaryInflammation of the airways accompanied by eosinophil infiltration appears to play a fundamental role in the pathogenesis of bronchial asthma. Therefore, anti-inflammatory agents (at present corticosteroids, cromoglycate and nedocromil) are the first-line treatment for this condition. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and indomethacin, however, have never been used in this setting, mainly for fear of adverse effects (e.g. severe obstructive reactions); these can occur, in a consistent number of patients as a consequence (according to the most widely accepted theory) of inhibition of prostaglandin synthesis. In a double-blind crossover placebo-controlled study involving 20 aspirin-sensitive patients with asthma, we found that oral nimesulide 100mg was well tolerated both clinically and functionally (no significant changes in forced expiratory volume in 1 second and specific airway resistance after drug intake). In a more recent study, we observed a mild obstructive reaction (easily controlled with inhaled bronchodilators) after oral administration of nimesulide 400mg to 3 patients who had previously tolerated a 100mg dose. On the basis of clinical experience, nimesulide (unlike most other NSAIDs) in the recommended doses appears to be well tolerated in aspirin-sensitive asthmatic patients. Furthermore, this distinctive anti-inflammatory agent might provide a novel approach to the treatment of bronchial asthma.

Respiratory symptoms in children living near busy roads and their relationship to vehicular traffic: results of an Italian multicenter study (SIDRIA 2).

BackgroundEpidemiological studies have provided evidence that exposure to vehicular traffic increases the prevalence of respiratory symptoms and may exacerbate pre-existing asthma in children. Self-reported exposure to road traffic has been questioned as a reliable measurement of exposure to air pollutants. The aim of this study was to investigate whether there were specific effects of cars and trucks traffic on current asthma symptoms (i.e. wheezing) and cough or phlegm, and to examine the validity of self-reported traffic exposure.MethodsThe survey was conducted in 2002 in 12 centers in Northern, Center and Southern Italy, different in size, climate, latitude and level of urbanization. Standardized questionnaires filled in by parents were used to collect information on health outcomes and exposure to traffic among 33,632 6–7 and 13–14 years old children and adolescents. Three questions on traffic exposure were asked: the traffic in the zone of residence, the frequency of truck and of car traffic in the street of residence. The presence of a possible response bias for the self-reported traffic was evaluated using external validation (comparison with measurements of traffic flow in the city of Turin) and internal validations (matching by census block, in the cities of Turin, Milan and Rome).ResultsOverall traffic density was weakly associated with asthma symptoms but there was a stronger association with cough or phlegm (high traffic density OR = 1.24; 95% CI: 1.04, 1.49). Car and truck traffic were independently associated with cough or phlegm. The results of the external validation did not support the existence of a reporting bias for the observed associations, for all the self-reported traffic indicators examined. The internal validations showed that the observed association between traffic density in the zone of residence and respiratory symptoms did not appear to be explained by an over reporting of traffic by parents of symptomatic subjects.ConclusionChildren living in zones with intense traffic are at higher risk for respiratory effects. Since population characteristics are specific, the results of validation of studies on self-reported traffic exposure can not be generalized.