Heberto Ghezzo

Specific serum antibodies against isocyanates: association with occupational asthma.

Although increased levels of specific IgE and/or IgG antibodies have been documented in individual cases of occupational asthma caused by common types of isocyanates (hexamethylene diisocyanate [HDI] and diphenylmethane diisocyanate [MDI]), the frequency among workers with occupational asthma is still unknown. The sera of 62/65 workers referred for specific inhalation challenges with isocyanates were analyzed for the presence of specific antibodies to the relevant isocyanate. Most workers (39, 63%) were exposed to HDI, some to MDI (17, 27%), and a few to toluene diisocyanate (six, 10%). Specific inhalation challenges were positive in 29 subjects, eliciting either immediate (seven), early late (two), late (13), or dual (seven) reactions. Specific inhalation challenges were more often positive in those subjects with increased nonspecific bronchial responsiveness. Twenty-nine subjects demonstrated increased levels of specific IgE and/or IgG antibodies to isocyanates in the absence of antibodies against human serum albumin (increased IgE only, no subject; IgG only, 20; both IgE and IgG, nine subjects). Although there was a loose association between the results of specific inhalation challenges and levels of specific IgE, the association was much better with the level of specific IgG. Indeed, 21 of the 29 subjects (72%) with positive challenges had increased levels of specific IgG, whereas 25 of the 33 subjects (76%) with negative challenges had normal levels of antibodies. The association was significant with both HDI and MDI. The levels of antibodies were not significantly associated with the type of temporal reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction

BACKGROUND The patterns of airway remodeling and the biomarkers that distinguish different subtypes of severe asthma are unknown. OBJECTIVES We sought to characterize subjects with severe asthma with and without chronic persistent airflow obstruction with respect to airway wall remodeling (histopathologic and radiologic) and specific sputum biomarkers. METHODS Subjects with severe asthma with chronic persistent (n = 16) or intermittent (n = 18) obstruction were studied. Endobronchial biopsy specimens were analyzed for airway smooth muscle area, epithelial detachment, basement membrane thickness, and submucosal fibrosis. Levels of eosinophil cationic protein, myeloperoxidase, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 1 (ELISA), and 27 cytokines (multiplex assay) and differential cell counts were measured in induced sputum. Airway thickness was measured by means of high-resolution computed tomographic scanning. RESULTS Chronic persistent obstruction was associated with earlier age of onset, longer disease duration, more inflammatory cells in the sputum, and greater smooth muscle area (15.65% +/- 2.69% [n = 10] vs 8.96% +/- 1.99% [n = 14], P = .0325). No differences between groups were found for any of the biomarker molecules measured in sputum individually. However, principal component analysis revealed that the dominant variables in the chronic persistent obstruction group were IL-12, IL-13, and IFN-gamma, whereas IL-9, IL-17, monocyte chemotactic protein 1, and RANTES were dominant in the other group. Airway imaging revealed no differences between groups. CONCLUSION Subjects with severe asthma with chronic persistent obstruction have increased airway smooth muscle with ongoing T(H)1 and T(H)2 inflammatory responses. Neither airway measurements on high-resolution computed tomographic scans nor sputum analysis seem able to identify such patients.

Natural history of occupational asthma: Relevance of type of agent and other factors in the rate of development of symptoms in affected subjects

It is unknown whether factors such as the nature of the agent, gender, age, atopy, smoking habits, continuous or noncontinuous exposure, and pattern of asthmatic reaction can influence the rate of development of symptoms in subjects with occupational asthma. We compared several clinical and functional parameters among three groups of subjects with occupational asthma caused by Western red cedar (group 1, n = 433), isocyanates (group 2, n = 107), and high molecular weight agents acting through an IgE-mediated mechanism (group 3, n = 121). Survival analysis showed that the three curves relating years of exposure before onset of symptoms to the proportion of subjects without symptoms were significantly different in two respects: (1) almost 40% of subjects in groups 1 and 2 as compared with 20% of subjects in group 3 became symptomatic within 1 year of exposure; (2) after 5 years of exposure, the rate of sensitization was slower for subjects in groups 2 and 3 as compared with those in group 1. Having a nonimmediate reaction at the time of specific inhalation challenges, being continuously exposed and being younger slightly increased the risk at each time point on the curve of developing symptoms in subjects with occupational asthma. These data suggest that the natural history for onset of occupational asthma is different depending on the sensitizing agent. Factors such as age, type of exposure, and pattern of reaction on exposure to the agent also modulate the rate of development of this condition.

Long-Term Outcomes of Acute Irritant-induced Asthma

RATIONALE The long-term outcomes of acute irritant-induced asthma (IIA) are mostly unknown. OBJECTIVES To study the long-term outcomes of IIA. METHODS We reassessed 35 subjects who experienced IIA at a mean interval of 13.6 +/- 5.2 years. MEASUREMENTS AND MAIN RESULTS The causal agent was chlorine in 20 cases (57%). At diagnosis, the mean +/- SD FEV(1) was 74.5 +/- 19.5% predicted, and all subjects showed bronchial hyperresponsiveness. At reassessment, all subjects reported respiratory symptoms, and 24 (68%) were on inhaled steroids. There were no significant improvements in FEV(1) and FEV(1)/FVC values. Twenty-three subjects had a methacholine test, and only six subjects had normal levels of responsiveness. Of the remaining 12 subjects, six had improvement in FEV(1) after bronchodilator >or=10%. In samples of induced sputum obtained from 27 subjects, six had eosinophils >or=2%. Levels of inflammatory and remodeling mediators were higher than in control subjects but were no different from subjects with occupational asthma due to sensitization. Quality of life score was 4.4 +/- 1.5 on a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal depression score. CONCLUSIONS This study provides the first evidence of significant long-term impact of acute IIA on various outcomes.

Skin bruising in asthmatic subjects treated with high doses of inhaled steroids: frequency and association with adrenal function

High doses of inhaled corticosteroids (ICS) (budesonide and beclo-methasone > or = 800 micrograms.day-1) are commonly used in the treatment of asthma. Some investigators have presented evidence for cutaneous effects (bruising), which suggests systemic absorption. This study aimed to assess the prevalence of skin bruising, relate the occurrence of skin bruising to adrenocortical function, and determine the risk factors for skin bruising. One hundred adult asthmatic subjects taking high doses (800-2,000 micrograms.day-1) of ICS for 3 months or more were recruited in an asthma clinic, and 100 control subjects paired for sex and age were recruited from an ophthalmology out-patient clinic. A detailed questionnaire on asthma, general habits and cutaneous lesions was administered. A cutaneous examination was performed. Urine cortisol levels were assessed on two consecutive days. Blood cortisol level and the response to Cortrosyn injection (60 min test) were evaluated. One hundred adult asthmatics (66 females and 34 males), 73 on beclomethasone and 27 on budesonide, were included. The prevalence of skin bruising was 71% based on the questionnaire (32% in controls) and 48% (39 out of 81 subjects) based on direct examination of the skin. We found a satisfactory association between the response to questionnaire and examination of the skin. Adrenocortical function testing showed that a minority of subjects (14 with at least one abnormal test) had lower urinary or blood cortisol levels. These low cortisol levels occurred in subjects who reported skin bruising. By multiple logistic regression, being a female (odds ratio (OR) = 20; 95% confidence interval (95% CI) = 13-33) and taking ICS for asthma (OR = 12; 95% CI = 8-18) were significantly (t = 5.4) related to the likelihood of developing skin bruising. In addition, among the asthmatic subjects, being older (OR = 1.6; 95% CI = 1.1-2.4/10 yrs interval) (t = 2.3) and being a female (OR = 22; 95% CI = 7-75) (t = 5.0) influenced the occurrence of skin bruising as documented by questionnaire. In asthmatic subjects, taking high doses of ICS is associated with: 1) increased occurrence of skin bruising by comparison with controls, particularly in older subjects; and 2) a generally normal adrenocortical function, although this function is significantly lower in subjects reporting skin bruising.

Salmeterol, a new inhaled beta2-adrenergic agonist, has a longer blocking effect than albuterol on hyperventilation-induced bronchoconstriction☆

The duration of the blocking effect of salmeterol (50 micrograms), albuterol (200 micrograms), and a placebo were compared in a double-blind study in 12 adult subjects with asthma who underwent hyperventilation tests with cold dry air (-20 degrees C) on 4 study days. On the first day, the hyperventilation test was performed at various time intervals (baseline, 1, 4, 6, 8, 12, and 24 hours) with spontaneous functional recovery between each test to determine the within-day within-subject variability of the response. The response was assessed by interpolating the dose of cold dry air causing a 20% fall in FEV1. On the 3 remaining days, separated by an interval of at least 5 days, the active or placebo medication was administered after spontaneous recovery from the first hyperventilation test. Spirometry was assessed 15 minutes and 1 hour later. The hyperventilation test was then performed and repeated 4 hours after administration of the drug. The test was repeated 6, 8, 12, and 24 hours later to detect any significant blocking effect. The improvement in FEV1 15 minutes and 1 hour after the drug was administered was 19.8% and 20.4%, as compared to baseline for albuterol, and 16.3% and 16.8% for salmeterol (not significant). The mean duration of the blocking effect was 0.25 hour for the placebo, 3.5 hours for albuterol, and 15.9 hours for salmeterol (F = 24.5; p less than 0.001; Newman-Keuls test was significant for every contrast). Eight of the 12 subjects still demonstrated some blocking effect 8 hours after taking salmeterol; this was true for only one subject receiving albuterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of occupational asthma and immunologic sensitization to guar gum among employees at a carpet-manufacturing plant

Guar gum is a high-molecular-weight agent that can cause occupational rhinitis and asthma. We surveyed the employees at a carpet-manufacturing plant in which guar gum is used to adhere the dye to the fiber; 162/177 of the employees (92%) participated in the first part of the survey that included a questionnaire and skin prick tests with common allergens and guar gum (1 mg/ml). IgE and IgG antibodies to guar gum were also measured in those subjects (133/162 or 82%) who agreed to blood tests. Thirty-seven subjects (23%) had a history suggestive of occupational asthma and 59 (36%), of occupational rhinitis. Eight subjects (5%) demonstrated immediate skin reactivity to guar gum. Eleven subjects (8.3%) had serum IgE antibodies to guar gum. All subjects, except one subject who had a history suggestive of occupational asthma (n = 37) or positive skin tests (n = 4), participated in the second part of the study. A methacholine-inhalation test was performed during a workshift or in the 3 to 4 hours after the workshift. Five subjects had a concentration of methacholine causing a 20% fall in FEV1 of less than 16 mg/ml (significant bronchial hyperresponsiveness) and positive skin reactions to guar gum. Four of these subjects underwent specific inhalation challenges. The remaining subject had a history of severe bronchospastic reaction on exposure to guar gum, and his FEV1 of 1.6 L made specific challenges impossible. Two subjects had typical isolated immediate reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Host determinants for the development of allergy in apprentices exposed to laboratory animals

The aim of this study was to evaluate whether determinants of work-related symptoms, skin sensitization and diseases differ between atopic and nonatopic subjects starting a career with exposure to laboratory animals (LA). A cohort of 417 apprentices in animal-health technology was prospectively followed during 32 or 44 months. The effect on the study outcomes of variables derived from questionnaire, skin reactivity, and lung function assessments at baseline were compared in atopic (n=212) and nonatopic (n=183) subjects. Eighty-five incident cases of sensitization to a LA-derived allergen were identified, 67 among atopic and 18 among nonatopic subjects. Baseline rhinitis symptoms in contact with pets and skin sensitization to pets were associated with the development of work-related rhinoconjunctivitis (RC) symptoms in atopic subjects, whereas perannual rhinitis symptoms and having a PC20 (provocative concentration causing a 20% fall in forced expiratory volume in one second) ≤32 mg·mL−1 were associated in nonatopic subjects. Baseline rhinitis symptoms on contact with pets and a PC20 value ≤32 mg·mL−1 were significant determinants for developing sensitization to a specific allergen in atopic subjects only. Finally, baseline rhinitis symptoms in contact with pets and perannual rhinitis symptoms were associated with the development of occupational RC in atopic subjects, whereas in nonatopic subjects this was associated with having a PC20 value ≤32 mg·mL−1. In conclusion, the determinants for the development of specific skin sensitization, symptoms and disease are different between atopic and nonatopic apprentices starting occupational exposure to laboratory-animal-derived allergens.

Exposure to domestic animals and risk of immunologic sensitization in subjects with asthma

BACKGROUND The objective of the study was to determine whether exposure to domestic animals plays a significant role, beyond atopy, in the development of immediate sensitization to animal-derived antigens. METHODS To test this hypothesis, 200 subjects with asthma (85 male subjects and 115 female subjects; mean age, 37 +/- 16 years) seen consecutively in an asthma clinic were enrolled in a cross-sectional survey. Each subject answered a questionnaire about allergy symptoms and past and current exposure to domestic animals. Skin prick testing with extracts of common inhalant allergens including antigens from eight species of animal (cat, dog, horse, rabbit, rat, mouse, guinea pig, and hamster) were also carried out. RESULTS Seventy-nine percent of subjects were atopic, and 91% had kept animals at home at some point (figures were 80% for dogs, 68% for cats, 23% for rabbits, and 20% for rodents). Using two-by-two tables, we showed that skin reactivity to at least one animal antigen was strongly linked to atopy (86% of atopic subjects had skin reactions as compared with 34% of nonatopic subjects: p < 0.001) but not to previous and current exposure to domestic animals (78% of both exposed and never exposed subjects). However, with the use of logistic regression, the determinants of skin reactivity to animals were atopy (p < 0.001), followed by cumulative duration of exposure to domestic animals (p < 0.01). The number of animals times the number of species times the duration of exposure was also a significant determinant of skin reactivity (p = 0.05). CONCLUSIONS We conclude that beyond the predominant role of atopy, cumulative duration of exposure to domestic animals is a significant determinant for immediate sensitization to animal-derived antigens in subjects with asthma.

Late asthmatic reactions to occupational sensitizing agents: Frequency of changes in nonspecific bronchial responsiveness and of response to inhaled β2-adrenergic agent

Late asthmatic reactions have been demonstrated, generally, to increase bronchial responsiveness and are believed to respond poorly to inhaled bronchodilator. To assess the frequency of changes in bronchial responsiveness, we reviewed the records of 101 subjects with late asthmatic reactions and of 63 subjects with isolated immediate reactions after specific inhalation challenges to various occupational agents. These subjects had undergone nonspecific inhalation challenges to histamine or methacholine on a control day and after the late reaction when FEV1 had returned to +/- 10% baseline. We also reviewed 99 cases of subjects with late reactions who were administered an inhaled beta 2-agent (albuterol, 200 micrograms) during the late reaction. Fifty-seven/101 (56%) subjects with late reactions and 24/63 (38%) subjects with isolated immediate reactions demonstrated a twofold or greater change in provocative concentration of histamine or methacholine causing a 20% change in FEV1 (PC20) from baseline (p = 0.02; odds for the presence of significant changes in PC20 in subjects with late reactions, 56%; odds for the absence of significant changes in PC20 in subjects with immediate reactions, 62%). Changes in FEV1 greater than 20% after administering albuterol at the time of the late reactions occurred in 78% of the subjects tested; in 66%, FEV1 returned to greater than 90% baseline. This retrospective study demonstrates that changes in bronchial responsiveness after late reactions are not constant and do not appear to distinguish satisfactorily late from immediate reactions. Furthermore, late reactions respond well to beta 2-agonist.(ABSTRACT TRUNCATED AT 250 WORDS)