Allergic sensitization to laboratory animals is more associated with asthma, rhinitis, and skin symptoms than sensitization to common allergens.

BACKGROUND: Workers exposed to laboratory animals have a high risk of developing laboratory animal allergy (LAA). Atopy seems to be the main risk factor for LAA. We hypothesized that occupational sensitization is a better predictor for the development of asthma, rhinitis, and bronchial hyperresponsiveness (BHR) than common sensitization. OBJECTIVE: To investigate the association between occupational sensitization to laboratory animals and clinical outcomes. METHODS: This was a cross-sectional study performed at two universities on students and employees dealing with small rodents. The subjects were allocated in groups: non-sensitized, common sensitization, or occupational sensitization, according to the results of the skin prick test (SPT). All subjects answered a questionnaire about animal exposures, symptoms, allergic diseases, and underwent spirometry and bronchial challenge test with mannitol. Multivariate analysis was performed using Poisson regression to estimate the prevalence ratio (PR). RESULTS: Data from 453 volunteers were analysed. Non-sensitized group comprised 237 subjects; common sensitization group, 142 subjects; and occupational sensitization group, 74 subjects. Occupational sensitization was associated with greater risk for all outcomes studied. When the common sensitization group was reference, skin symptoms had PR of 1.36, 95% confidence interval (CI): 1.01-1.85; wheezing had PR of 1.75, CI 95%: 1.21-2.53; rhinitis had PR of 1.25, 95%: 1.11-1.40; nocturnal dyspnoea had PR of 2.40, 95% CI: 1.31-4.40; bronchial hyperresponsiveness (BHR) had PR of 2.47, 95% CI: 1.50-4.09; and confirmed asthma had PR of 2.65, 95% CI: 1.45-4.85. In addition, the overlap of asthma, rhinitis, and skin symptoms in a same subject was significantly more prevalent in the occupational sensitization group, 16.2% versus 4.9% in the common sensitization group. CONCLUSION AND CLINICAL RELEVANCE: Occupational sensitization is associated with allergic symptoms and respiratory diseases. SPT with occupational allergens along with other parameters may contribute to detection of risk for allergic and respiratory diseases associated with exposure to laboratory animals.

Effects of ipratropium on exercise-induced bronchospasm.

Exercise-induced bronchospasm (EIB) is the transient narrowing of the airways that follows vigorous exercise. Ipratropium bromide may be used to prevent EIB, but its effect varies among individuals. We hypothesized that time of administration of ipratropium interferes with its action. This was a prospective, double-blind, cross-over study carried out to evaluate the bronchoprotective and bronchodilatory effect of ipratropium at different times of day. The study consisted of 4 exercise challenge tests (2 at 7 am and 2 at 6 pm). In the morning, one of the tests was performed after placebo administration and the other one after ipratropium (80 microg) and the two tests (placebo and ipratropium) were repeated in the evening. Twenty-one patients with severe or moderate asthma and previous confirmation of EIB were enrolled in this prospective trial. The bronchodilatory effect of ipratropium was 0.25+/-0.21 L or 13.11+/-10.99% (p=0.001 compared to baseline values) in the morning, and 0.14+/-0.25 L or 7.25+/-11.37% (p>0.05) in the evening. In the morning, EIB was 0.58+/-0.29 L on the placebo day and 0.38+/-0.22 L on the treatment day (p=0.01). In the evening, EIB was 0.62+/-0.28 L on the placebo day and 0.51+/-0.35 L on the treatment day (p>0.05). We suggest that the use of ipratropium for the treatment of asthma and EIB should take into consideration the time of administration.

Biomass smoke COPD has less tomographic abnormalities but worse hypoxemia compared with tobacco COPD.

Special attention has emerged towards biomass smoke-induced chronic obstructive pulmonary disease (COPD), providing new knowledge for prevention and therapeutic approach of non-smoker COPD patients. However, the understanding of biomass smoke COPD is still limited and somewhat controversial. The aim of the present study was to compare COPD exclusively caused by tobacco smoking with COPD exclusively caused by environmental or occupational exposures. For this cross-sectional study, COPD patients were recruited from outpatient clinics and formed two groups: non-smoker COPD group (n=16) with exposure to biomass smoke who did not smoke cigarette and tobacco smoker COPD group (n=15) with people who did not report biomass smoke exposure. Subjects underwent pulmonary function tests, thoracic high-resolution computed tomography, 6-min walk test, and sputum induction. The non-smoker COPD group had biomass smoke exposure of 133.3±86 hour-years. The tobacco COPD group smoked 48.5±27.4 pack-years. Women were 62.5 and 66.7%, respectively, of non-smokers and smokers. The non-smoker COPD group showed higher prevalence of dyspnea, lower arterial oxygen tension (PaO2), and lower arterial oxygen saturation (SaO2%) with similar spirometry results, lung volumes, and diffusion capacity. Regarding inflammatory biomarkers, differences were detected in sputum number of lymphomononuclear cells and in sputum concentrations of interleukin (IL)-6 and IL-8 with higher values in the smoker group. Emphysema was more prevalent in the tobacco smoker group, which also showed higher relative bronchial wall thickness and lower lung density by quantitative analysis. Biomass smoke induced more hypoxemia compared to tobacco in COPD patients with similar severity.

Impact of specific sensitization on asthma and rhinitis in young Brazilian and Chilean adults.

BACKGROUND: The pattern of associations and the attributable fractions (AF) of atopic conditions due to specific sensitizations vary between countries. OBJECTIVE: To assess the level of associations and AF between sensitization to five allergens and atopic conditions in two settings. METHODS: We studied 2063 Brazilians and 1231 Chileans of both sexes using representative samples selected at birth in the 1970s. Information on asthma and rhinitis was based on the European Community Respiratory Health Survey questionnaire. We assessed bronchial hyperresponsiveness (BHR) to methacholine and sensitization to Dermatophagoides pteronyssinus, cat, dog, grass blend and Alternaria alternata. RESULTS: The prevalence of sensitization to one or more allergens was 50% in Brazilians and 22% in Chileans. The level of associations varied according to the outcome used. Strong associations between sensitization and asthma, defined as wheeze or awakening with breathlessness at night and positive BHR, were found for each of the five allergens in Chileans [varying from odds ratio (OR) 3.24, 95% confidence interval (CI) 1.47, 7.15 for D. pteronyssinus to 8.44, 95% CI 3.82, 18.66 for cat], whereas the level of associations was restricted to D. pteronyssinus, cat and dog in Brazilians and was somewhat weaker (highest OR 3.90, 95% CI 2.80-5.44). The AF of sensitization on asthma was 54% in Brazil and 44% in Chile. D. pteronyssinus and cat made an independent contribution to asthma in the two samples. The patterns of associations between sensitization and rhino-conjunctivitis were similar to those for asthma. CONCLUSION: The associations between sensitization, and asthma and rhinitis were high in Chile and moderately high in Brazil, but the AF were higher in Brazil, reflecting a higher prevalence of sensitization. In Brazil, dust mite had the greatest impact on atopic conditions while in Chile several allergens had an impact. Sensitization is as serious a problem in Chile and Brazil as in developed countries.

Cat ownership is associated with increased asthma prevalence and dog ownership with decreased spirometry values.

The association between pet ownership and the development of allergic and respiratory diseases has been the aim of several studies, however, the effects of exposure in adults remain uncertain. The aims of the present study were to investigate the prevalence of asthma and lung function status among dog and cat owners. This cross-sectional study was performed at two universities with students and workers who were allocated into 3 groups according to pet ownership in the previous year: cat owners, dog owners, and no pets (control group). Subjects underwent spirometry, bronchial challenge test with mannitol, skin prick tests, and questionnaires about animal exposures and respiratory symptoms. Control group comprised 125 subjects; cat owner group, 51 subjects; and dog owner group, 140 subjects. Cat owners had increased asthma prevalence (defined by symptoms and positive bronchial challenge test), but no changes in lung function compared to the control group. The dog owner group had lower spirometry values (forced expiratory volume in one second and lower forced vital capacity), but similar asthma prevalence, compared to the control group. In the cat owner group, excess of asthma may have an immunological basis, since we found an association with atopy. Although we did not have endotoxin data from volunteers' households, we postulated that low values of lung function were associated to exposure to endotoxins present in environments exposed to dogs.

Prevalence and risk factors for work related asthma in young adults.

OBJECTIVES: To investigate the prevalence and predictors of work related asthma in young adults from the general population. METHODS: A total of 1922 subjects randomly selected from a birth cohort 1978/79 in Brazil, aged 23-25 years, completed a respiratory symptoms questionnaire based on the European Community Respiratory Health Survey, and underwent spirometry, bronchial challenge test with methacholine, and skin prick test. For subjects presenting with bronchial hyperresponsiveness, workplace exposure and its relationship with symptoms were assessed by a specific questionnaire and individualised job description to define cases of work related asthma. RESULTS: The prevalence of work related asthma was 4.2% (81 cases): 1.5% (29 cases) were classified as aggravated asthma and 2.7% (52 cases) as occupational asthma. Work related asthma was associated with atopy and education. Lower educational level (1-8 years of schooling) was associated with work related asthma (odds ratio 7.06, 95% CI 3.25 to 15.33). There was no association between work related asthma and smoking, gender, or symptoms of rhinitis. CONCLUSION: The prevalence of work related asthma was high (4.2%), and was associated with low schooling, probably because of low socioeconomic level. The disease may therefore be a consequence of poverty.

Comparison of morning and afternoon exercise training for asthmatic children.

Fitness improvement was used to compare morning with afternoon exercise periods for asthmatic children. Children with persistent moderate asthma (according to GINA criteria), 8 to 11 years old, were divided into 3 groups: morning training group (N = 23), afternoon training group (N = 23), and non-training group (N = 23). The program was based on twice a week 90-min sessions for 4 months. We measured the 9-min running distance, resting heart rate and abdominal muscle strength (sit-up number) before and after the training. All children took budesonide, 400 microg/day, and an on demand inhaled ss-agonist. The distance covered in 9 min increased (mean +/- SEM) from 1344 +/- 30 m by 248 +/- 30 m for the morning group, from 1327 +/- 30 m by 162 +/- 20 m for the afternoon group, and from 1310 +/- 20 m by 2 +/- 20 m for the control group (P < 0.05 for the comparison of morning and afternoon groups with the control group by ANOVA and P > 0.05 for morning with afternoon comparison). The reduction of resting heart rate from 83 +/- 1, 85 +/- 2 and 86 +/- 1 bpm was 5.1 +/- 0.8 bpm in the morning group, 4.4 +/- 0.8 bpm in the afternoon group, and -0.2 +/- 0.7 bpm in the control group (P > 0.05 for morning with afternoon comparison and P < 0.05 versus control). The number of sit-ups in the morning, afternoon and control groups increased from 22.0 +/- 1.7, 24.3 +/- 1.4 and 23 +/- 1.1 sit-ups by 9.8 +/- 0.9, 7.7 +/- 1.4, and 1.9 +/- 0.7 sit-ups, respectively (P > 0.05 for morning with afternoon comparison and P < 0.05 versus control). No statistically significant differences were detected between the morning and afternoon groups in terms of physical training of asthmatic children.

Do steroids interfere in dyspnoea sensation?

Dyspnoea remains a remarkable clinical problem and a therapeutic challenge, mainly in chronic respiratory conditions. This study investigated the potential effects of steroids on dyspnoea sensation regardless of their pulmonary anti-inflammatory actions. Sixteen healthy men (mean age +/- SD = 22.5 +/- 1.6 years) developed uncomfortable breathing by the use of inspiratory resistors (loads of 0, 7, 14 and 21 cm H2O/l/s) and breathholding 6 h after taking 40 mg of prednisone (Pred) or placebo (Plac). Respiratory discomfort during breathing with loads was evaluated with a 100 mm visual analog scale. The maximum voluntary apnoea time did not differ between the prednisone and placebo days (Plac = 96 +/- 11.8 s x Pred = 105 +/- 12.2 s) and prednisone did not influence the dyspnoea sensation induced by different inspiratory loads (0 cm H2O/l/s: Pred = 2.8 mm x Plac = 1.9 mm; 7 cm H2O/l/s: Pred = 18.3 mm x Plac = 18.6 mm; 14 cm H2O/l/s; Pred = 33.0 mm x Plac = 34.1 mm; 21 cm H2O/l/s: Pred = 48.1 mm x Plac = 49.6 mm). Prednisone intake was associated with a significant increase in minute ventilation during breathing with no inspiratory loads (Pred = 11.91 +/- 1.28 l/min- x Plac = 9.95 +/- 0.86 l/min). Although steroids certainly may improve respiratory conditions due to anti-inflammatory actions, available evidence does not support any specific beneficial effect of these drugs on these perception of dyspnoea itself.

Dyspnea scales in the assessment of illiterate patients with chronic obstructive pulmonary disease.

BACKGROUND: Multiple physiological, psychological, social and environmental factors may affect the perception of dyspnea. Although different scales have been used to record the severity of dyspnea in subjects with chronic obstructive pulmonary disease (COPD), none has reported evaluating the properties of such tools in illiterate patients. The objective of this study was to evaluate the reliability and features of concurrent validity of 4 dyspnea scales in illiterate (IL) subjects with COPD. METHODS: One hundred COPD patients submitted to spirometry and were asked to score their breathlessness using a visual analogue scale (VAS), a numerical rating scale (NRS), the Borg scale (BS), and the basal dyspnea index (BDI). Each scale was presented to the patients before and after they had performed spirometry and measurement of residual volume. The obtained scores were analyzed according to the literacy status of the patients. RESULTS: Thirty-three patients were classified as IL and 67 as literate (L). Both groups showed similar respiratory impairment and median scores of dyspnea (VAS, L = 45.0, IL = 49.0; NRS, L = 5.0, IL = 5.0; BS, L = 3.0, IL = 3.0; BDI, L = 5.0, IL = 4.0). No significant differences were found between the dyspnea scores obtained before and after spirometry for all scales in both groups. The degree of correlation between forced expiratory volume in 1 second (FEV1) and usual dyspnea evaluated by BDI did not show a statistical difference between the two groups (L, r = 0.37; IL, r = 0.51). CONCLUSION: The employed dyspnea scales showed comparable reliability in both L and IL COPD subjects.

Pulmonary function, cholinergic bronchomotor tone, and cardiac autonomic abnormalities in type 2 diabetic patients.

This prospective study analyzed the involvement of the autonomic nervous system in pulmonary and cardiac function by evaluating cardiovascular reflex and its correlation with pulmonary function abnormalities of type 2 diabetic patients. Diabetic patients (N = 17) and healthy subjects (N = 17) were evaluated by 1) pulmonary function tests including spirometry, He-dilution method, N2 washout test, and specific airway conductance (SGaw) determined by plethysmography before and after aerosol administration of atropine sulfate, and 2) autonomic cardiovascular activity by the passive tilting test and the magnitude of respiratory sinus arrhythmia (RSA). Basal heart rate was higher in the diabetic group (87.8 +/- 11.2 bpm; mean +/- SD) than in the control group (72.9 +/- 7.8 bpm, P<0.05). The increase of heart rate at 5 s of tilting was 11.8 +/- 6.5 bpm in diabetic patients and 17.6 +/- 6.2 bpm in the control group (P<0.05). Systemic arterial pressure and RSA analysis did not reveal significant differences between groups. Diabetes intragroup analysis revealed two behaviors: 10 patients with close to normal findings and 7 with significant abnormalities in terms of RSA, with the latter subgroup presenting one or more abnormalities in other tests and clear evidence of cardiovascular autonomic dysfunction. End-expiratory flows were significantly lower in diabetic patients than in the control group (P<0.05). Pulmonary function tests before and after atropine administration demonstrated comparable responses by both groups. Type 2 diabetic patients have cardiac autonomic dysfunction that is not associated with bronchomotor tone alterations, probably reflecting a less severe impairment than that of type 1 diabetes mellitus. Yet, a reduction of end-expiratory flow was detected.

Biomass smoke COPD has less tomographic abnormalities but worse hypoxemia compared with tobacco COPD

Special attention has emerged towards biomass smoke-induced chronic obstructive pulmonary disease (COPD), providing new knowledge for prevention and therapeutic approach of non-smoker COPD patients. However, the understanding of biomass smoke COPD is still limited and somewhat controversial. The aim of the present study was to compare COPD exclusively caused by tobacco smoking with COPD exclusively caused by environmental or occupational exposures. For this cross-sectional study, COPD patients were recruited from outpatient clinics and formed two groups: non-smoker COPD group (n=16) with exposure to biomass smoke who did not smoke cigarette and tobacco smoker COPD group (n=15) with people who did not report biomass smoke exposure. Subjects underwent pulmonary function tests, thoracic high-resolution computed tomography, 6-min walk test, and sputum induction. The non-smoker COPD group had biomass smoke exposure of 133.3±86 hour-years. The tobacco COPD group smoked 48.5±27.4 pack-years. Women were 62.5 and 66.7%, respectively, of non-smokers and smokers. The non-smoker COPD group showed higher prevalence of dyspnea, lower arterial oxygen tension (PaO2), and lower arterial oxygen saturation (SaO2%) with similar spirometry results, lung volumes, and diffusion capacity. Regarding inflammatory biomarkers, differences were detected in sputum number of lymphomononuclear cells and in sputum concentrations of interleukin (IL)-6 and IL-8 with higher values in the smoker group. Emphysema was more prevalent in the tobacco smoker group, which also showed higher relative bronchial wall thickness and lower lung density by quantitative analysis. Biomass smoke induced more hypoxemia compared to tobacco in COPD patients with similar severity.

Cat ownership is associated with increased asthma prevalence and dog ownership with decreased spirometry values

The association between pet ownership and the development of allergic and respiratory diseases has been the aim of several studies, however, the effects of exposure in adults remain uncertain. The aims of the present study were to investigate the prevalence of asthma and lung function status among dog and cat owners. This cross-sectional study was performed at two universities with students and workers who were allocated into 3 groups according to pet ownership in the previous year: cat owners, dog owners, and no pets (control group). Subjects underwent spirometry, bronchial challenge test with mannitol, skin prick tests, and questionnaires about animal exposures and respiratory symptoms. Control group comprised 125 subjects; cat owner group, 51 subjects; and dog owner group, 140 subjects. Cat owners had increased asthma prevalence (defined by symptoms and positive bronchial challenge test), but no changes in lung function compared to the control group. The dog owner group had lower spirometry values (forced expiratory volume in one second and lower forced vital capacity), but similar asthma prevalence, compared to the control group. In the cat owner group, excess of asthma may have an immunological basis, since we found an association with atopy. Although we did not have endotoxin data from volunteers' households, we postulated that low values of lung function were associated to exposure to endotoxins present in environments exposed to dogs.

Fluticasone/formoterol dry powder versus budesonide/formoterol in adults and adolescents with uncontrolled or partly controlled asthma.

UNLABELLED: This 12-week study compared the efficacy and safety of a fixed combination of fluticasone propionate plus formoterol (FL/F) 250/12 µg b.i.d. administered via a dry powder inhaler (DPI) (Libbs Farmacêutica, Brazil) to a combination of budesonide plus formoterol (BD/F) 400/12 µg b.i.d. After a 2-week run-in period (in which all patients were treated exclusively with budesonide plus formoterol), patients aged 12-65 years of age (N = 196) with uncontrolled asthma were randomized into an actively-controlled, open-labeled, parallel-group, multicentre, phase III study. The primary objective was to demonstrate non-inferiority, measured by morning peak expiratory flow (mPEF). The non-inferiority was demonstrated. A statistically significant improvement from baseline was observed in both groups in terms of lung function, asthma control, and the use of rescue medication. FL/F demonstrated a statistical superiority to BD/F in terms of lung function (FEV(1)) (p = 0.01) and for asthma control (p = 0.02). Non-significant between-group differences were observed with regards to exacerbation rates and adverse events. In uncontrolled or partly controlled asthma patients, the use of a combination of fluticasone propionate plus formoterol via DPI for 12-weeks was non-inferior and showed improvements in FEV(1) and asthma control when compared to a combination of budesonide plus formoterol. ( CLINICAL TRIAL NUMBER: ISRCTN60408425).

Protective effect of bronchial challenge with hypertonic saline on nocturnal asthma.

Inhalation of hypertonic saline (HS) causes bronchoconstriction in asthmatic subjects. Repeated inhalation of HS leads to substantially reduced bronchoconstriction, known as the refractory period. Refractoriness due to different stimuli has also been described (cross-refractoriness). Nocturnal asthma is defined as an increase in symptoms, need for medication, airway responsiveness, and/or worsening of lung function that usually occurs from 4 to 6 am. Our objective was to determine the effect of refractoriness on nocturnal asthma. The challenge test consisted of inhalations of 4.5% saline with increasing durations until a reduction of 20% in forced expiratory volume in 1 s (FEV1) (PD20HS) or total time of 15.5 min. Twelve subjects with nocturnal asthma were challenged with HS at 16:00 and 18:00 h and FEV1 was measured at 4:00 h. One to 2 weeks later, FEV1 was determined at 16:00 and 4:00 h. LogPD20HS at 18:00 h was significantly greater than logPD20HS at 16:00 h, 0.51 +/- 0.50 and 0.69 +/- 0.60 mg, respectively (P = 0.0033). When subjects underwent two HS challenges in the afternoon, mean (+/- SD) FEV1 reduction was 206 +/- 414 mL or 9.81 +/- 17.42%. On the control day (without challenge in the afternoon) FEV1 reduction was 523 +/- 308 mL or 22.75 +/- 15.40% (P = 0.021). Baseline FEV1 values did not differ significantly between the control and study days, 2.48 +/- 0.62 and 2.36 +/- 0.46 L, respectively. The refractory period following HS challenges reduces the nocturnal worsening of asthma. This new concept may provide beneficial applications to asthmatic patients.

Asthma definitions, relative validity and impact on known risk factors in young Brazilians.

BACKGROUND: An asthma score was proposed in the European Community Respiratory Health Survey (ECRHS) framework, as dichotomous definitions could be less appropriate in the study of chronic diseases. The aims of this study were to assess the value of this asthma score in comparison with other definitions of asthma in another population setting, using as criteria bronchial hyperresponsiveness (BHR) to methacholine and diagnosed asthma, and the association of these definitions to known risk factors of asthma. METHODS: We used the ECRHS questionnaire on 2063 Brazilians, aged 23-25 years, and measured their BHR. We assessed the positive and negative likelihood ratios (PLR and NLR) of the asthma score (0-8), a three question score (ECRHS definition) and single asthma symptoms in relation to BHR and diagnosed asthma. RESULTS: The PLR were relatively low for all asthma definitions with odd ratios varying from 1.47 for asthma score to 5.50 for wheeze and waking with breathlessness without a cold. The NLR were near 1. The PLR were lower for assessments using the score than for dichotomous assessments or the ECRHS definition. The PLR increased with asthma scores, but the prevalence with higher scores was too low for useful analysis. The asthma score was slightly better for identifying associations from a set of known risk factors than the other two approaches. CONCLUSION: Our study provided little support for a greater validity of this asthma score over other asthma definitions, and only marginal advantage for identifying risk factors.

Eotaxin-2 in sputum cell culture to evaluate asthma inflammation.

The aim of the present study was to elucidate whether the culture of cells recovered from induced sputum may represent a suitable model to evaluate cytokine and chemokine production by airway inflammatory cells. Sputum induction was performed in 21 normal subjects and 30 asthmatic patients. A total of 21 out of the 30 asthmatic patients were taking inhaled corticosteroids, while the remaining nine were steroid-naive asthmatics. The steroid-naive group was evaluated before and after a 14-day treatment with oral prednisone (40 mg.day(-1)). The supernatant of lysed and centrifuged sputum and the supernatant of sputum cell culture were analysed. Tumour necrosis factor-alpha, interleukin (IL)-8 (CXCL8), IL-1beta, IL-13 and eotaxin-2 (CCL24) concentrations were determined by specific ELISA. Eotaxin-2 production by cell culture was higher in the asthma group (131+/-108 pg.mL(-1)) than in the control group (36+/-41 pg.mL(-1)) and treatment with oral corticosteroids eliminated this difference. In addition, reduction of eotaxin-2 levels by corticosteroid treatment was greater in cell culture (81.3% reduction) than in sputum (26.4%). There was correlation between the decrease in eotaxin-2 production and the decrease in blood eosinophil number and between eotaxin-2 and eosinophils in sputum. Eotaxin-2 may play an important role in asthma and the response to corticosteroid treatment suggests that analysis of sputum cell culture is relevant as an inflammatory parameter.

Allergen-induced airway inflammation in rats. Role of insulin.

Clinical asthma appears to be less severe when diabetes mellitus is superimposed. To examine whether insulin influences the development of allergic reactions in the airway mucosa antigen challenge, normal and diabetic rats sensitized against ovalbumin (OA) were used. Compared with controls, animals rendered diabetic by the injection of alloxan presented markedly decreased cell yields from bronchoalveolar lavage after OA challenge. The impaired response was not related to antibody production because enhanced IgE antibody titers of the same magnitude were found in both control and diabetic animals. Similarly, the mechanism underlying the inhibited responses could not be ascribed to hyperglycemia or intracellular glucopenia, first, because correction of blood glucose levels through fasting did not restore the decreased response, and second, because administration of 2-deoxyglucose, which blocks glucose utilization, did not affect the bronchoalveolar reaction to OA challenge in normal animals. Reversal of the impaired responses was attained by treatment of diabetic animals with insulin. There is evidence that insulin exerts proinflammatory effects. We conclude that insulin might modulate the inflammatory component of asthmatic responses.

Recent innovations in asthma therapy.

Guidelines for the diagnosis and management of asthma have been published since 1990 and already new versions are being published. The recommendations for the treatment of asthma were organized around four components of effective asthma management: i) use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy, ii) environmental control measures to avoid or eliminate factors that precipitate asthma symptoms or exacerbations, iii) comprehensive pharmacologic therapy for long-term management designed to reverse and prevent the airway inflammation characteristic of asthma as well as pharmacologic therapy to manage asthma exacerbations, and iv) patient education that fosters a partnership among the patient, family and clinicians. Newly released medications include anti-leukotriene (LTs) agents which function either by blocking the interaction of LTs with receptors (receptor antagonists) or by inhibiting leukotriene synthesis (synthesis inhibitors). Representatives of the antagonists discussed here are zafirlukast, pranlukast and montelukast. Zafirlukast (20 mg twice daily) improves pulmonary function indices and days without symptoms and decreases the asthma exacerbation frequency. Pranlukast, the first leukotriene receptor antagonist to be marketed, improves lung function and symptoms when 450 mg twice daily is used. A study with montelukast demonstrated similar positive results irrespective of the use of concomitant inhaled corticosteroid. This indicates that leukotriene receptor antagonists may have additive effects to steroid therapy. They may also be a potential alternative to inhaled steroids, although more studies need to be performed before defining the role of receptor antagonists in the treatment of asthma. Zileuton, a leukotriene synthesis inhibitor, has been shown to improve lung function, reduce symptoms and reduce use of beta-agonists and asthma exacerbations. These positive effects are dose-dependent and liver function abnormalities seem to be a relevant issue during zileuton use in some patients. Other compounds that inhibit LTs synthesis are in development and, like zileuton, need more tests. Phosphodiesterases (PDE), enzymes that break down cAMP and cGMP, have been a target for new compounds developed to treat asthma. Inhibition of PDE enzymes increases intracellular cAMP or cGMP which then produces bronchodilation. Recent studies have also shown antiinflammatory effects by suppressing some PDE isoenzymes, including PDE III and PDE IV. These effects were detected by studies in vitro and in animal models. Clinical trials are necessary to determine which PDE inhibitors can be useful for the treatment of asthma.

Bronchodilators and corticosteroids in the treatment of asthma.

Despite advancements in treatment, the incidence of asthma, asthma-related deaths and hospitalizations for asthma have increased significantly during the past decade. Although asthma mortality may now be decreasing, reasons for the worsening of morbidity and mortality in asthma remain unclear. These unexpected changes in asthma severity have sparked renewed interest in research into the pathogenesis and treatment of the condition. Beta(2)-Adrenergic agonists are the most commonly used class of drugs for the treatment of asthma. Recent concerns about safety issues for beta-agonists caused reevaluation of prescribing practices, and using them on an as-needed basis is now more frequently accepted and recommended. In acute asthma, a beta(2)-adrenergic agonist is still the medication of choice. Long-acting salmeterol and formoterol, administered only twice daily, can decrease symptoms of asthma during day and nighttime. On the other hand, the role of tolerance to their bronchodilator and bronchoprotective effects is still to be determined in the treatment of asthma. Theophylline, whose use has been limited by the potential for serious toxicity, may regain an important position in asthma treatment with the development of the knowledge about its antiinflammatory actions. Dosing theophylline on a time- related basis also improves the risk/benefit ratio and makes it a useful drug for nocturnal asthma. Ipratropium bromide, an anticholinergic drug, still awaits a defined role in the treatment of asthma. Studies on its use for acute asthma have not achieved consensus and, for nocturnal asthma, the short duration of effect limits the benefits. Corticosteroids, including inhaled steroids, have measurable effects on symptoms, lung function, bronchial responsiveness and inflammation associated with asthma. Side effects of chronic use limit systemic, but not inhaled administration. Newer preparations, like budesonide, flunisolide and fluticasone, decrease the incidence of possible side effects related to inhaled steroids by having better ratio of topical to systemic potency. Daily doses up to 1600 micro g of beclomethasone (or equivalent) are considered safe and higher doses should be reserved for patients with moderate to severe asthma. Although future trials are necessary to clarify many issues related to dosing of inhaled steroids, chronotherapy studies have shown that single administration between 3 and 5:30 p.m. may be as effective as 4 times a day dosing.

The effects of upper respiratory infection on T-cell proliferation and steroid sensitivity of asthmatics.

BACKGROUND: The common cold is a potent trigger for asthma symptoms. Although the mechanisms are not completely understood, inflammatory events may play an important role. OBJECTIVE: We tested the hypothesis that changes in steroid responsiveness are implicated in the relationship between asthma and the common cold. METHODS: We investigated the steroid sensitivity of T cells from 10 patients with asthma (not taking steroids) and 10 control subjects, during upper respiratory infection and at recovery (6 weeks later). We stimulated peripheral blood mononuclear cells with phytohemagglutinin to measure T-cell proliferation, sensitivity to the inhibitory effects of steroids, and cytokine production. RESULTS: During infection compared with recovery, the asthma group exhibited lower responsiveness to dexamethasone at 10(-10) and 10(-9)mol/L and to 10(-10)mol/L hydrocortisone (P <.05) and both groups had decreased T-cell proliferation (P <.05). During recovery, patients with asthma had greater T-cell proliferation than control subjects (P <.02); the values expressed as uptake of [3H]-thymidine were 60119+/-3944 cpm (asthma) and 39078+/-6459 cpm (control subjects). The asthma group had higher TNF-alpha and IFN-gamma production during infection (P <.05); changes in IL-8 and IL-10 levels were not significant, and IL-4 was not detected. CONCLUSION: During infection, asthmatic subjects exhibit decreased T-cell responsiveness to steroids. The T-cell proliferative response to phytohemagglutinin, higher in asthma, is decreased with a common cold. These findings are associated with changes in the cytokine profile. Thus viral-induced upper respiratory infections can produce an inflammatory milieu with altered steroid function and selective increases in cytokines.