Sputum Inflammatory Patterns are Associated with Distinct Clinical Characteristics in Subjects with Occupational Asthma Independently from the Causal Agent.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity in sensitizer-induced occupational asthma (OA) and its relationship to airway inflammatory profiles remain poorly elucidated. To further characterize the interactions between induced sputum inflammatory patterns, asthma-related outcomes and the high- or low-molecular-weight category of causal agents in a large cohort of subjects with OA. METHODS: This multicenter, retrospective, cross-sectional study was conducted among 296 subjects with OA ascertained by a positive specific inhalation challenge who completed induced sputum assessment before and 24 hours after challenge exposure. RESULTS: Multivariate logistic regression analysis revealed that sputum eosinophilia ≥3% was significantly associated with a high dose of inhaled corticosteroid (odds ratio [95% confidence interval], 1.31 [1.11-1.55] for each 250-µg increment in daily dose), short-acting b2-agonist use less than once a day (3.54 [1.82-7.00]), and the level of baseline nonspecific bronchial hyperresponsiveness (mild: 2.48 [1.21-5.08]); moderate/severe: 3.40 [1.44-8.29]). Sputum neutrophilia ≥76% was associated with age (1.06 [1.01-1.11]), male gender (3.34 [1.29-9.99]), absence of corticosteroid use (5.47 [2.09-15.16]), short-acting b2-agonist use once or more a day (4.09 [1.71-10.01]), ≥2 severe exacerbations during the last 12 months at work (4.22 [1.14-14.99]), and isolated early reactions during the SIC (4.45 [1.85-11.59]). CONCLUSIONS: The findings indicate that sputum inflammatory patterns in subjects with OA are associated with distinct phenotypic characteristics and further highlight the differential effects of neutrophils and eosinophils on asthma-related outcomes. These associations between inflammatory patterns and clinical characteristics share broad similarities with what has been reported in nonoccupational asthma and are not related to the type of causal agent.

Cutaneous sensitization to aziridine preceding the onset of occupational asthma.

We describe a 47-year-old non-atopic woman, working as a spray painter in a tannery for 23 years, with a 16-year history of cutaneous symptoms and a subsequent 2-year history of asthmatic symptoms after exposure to aerosol and vapour of polyfunctional aziridine (PFA) at work. To confirm the occupational origin of the dermatitis and asthma we performed a skin prick test with PFA and a specific inhalation challenge (SIC) with PFA. Prick test with PFA elicited an immediate positive skin reaction. She developed an immediate asthmatic reaction upon SIC with PFA. The onset of occupational dermatitis before asthma is consistent with the hypothesis that the sensitization to PFA was triggered in the skin. The observation that the reactions elicited in skin and airways upon exposure to PFA exhibited the same time course, suggests a similar mechanism at both sites. Thus, the avoidance of both skin and airway exposure to PFA should be recommended in workplace hygiene practice.

Exhaled nitric oxide dynamics in asthmatic reactions induced by diisocyanates.

BACKGROUND: Isocyanate-induced asthmatic reactions are associated with delayed increase in fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (FeNO50), a biomarker of airway inflammation. The time course of FeNO increase is compatible with the activation of NO synthase, but the origin of NO production in the lung is undetermined. OBJECTIVE: The aim of this study was to define the dynamics of airway and alveolar NO during specific inhalation challenge (SIC) with isocyanates and the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase. METHODS: Spirometry, exhaled NO parameters (FeNO50, bronchial wall NO concentration, NO airway diffusing capacity, NO flux to luminal space, alveolar NO) and ADMA levels in exhaled breath condensate were measured before and at intervals up to 24 h after exposure to isocyanates. The results were compared between 17 SIC-positive and eight SIC-negative subjects. RESULTS: A significant FeNO50 increase in SIC-positive subjects was detected 24 h after exposure and was associated with the augmented NO flux from airway wall to the lumen, whereas airway NO diffusion and alveolar NO were not affected. The changes in NO dynamics were specific for the subjects who developed an asthmatic reaction, but were independent from the pattern and magnitude of bronchoconstriction. There was no evidence that exhaled NO is modulated by the changes in ADMA concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Because isocyanate-induced increase in FeNO50 was almost exclusively determined by the increase in NO flux, the use of FeNO50 appears adequate to monitor the exhaled NO dynamics during SIC. FeNO50 measurement may provide additional information to spirometry, because bronchoconstriction and airway inflammatory responses are dissociated.

The role of non-invasive biomarkers in detecting acute respiratory effects of traffic-related air pollution.

The role of non-invasive methods in the investigation of acute effects of traffic-related air pollution is not clearly established. We evaluated the usefulness of non-invasive biomarkers in detecting acute air pollution effects according to the age of participants, the disease status, their sensitivity compared with lung function tests and their specificity for a type of pollutant. Search terms lead to 535 titles, among them 128 had potentially relevant abstracts. Sixtynine full papers were reviewed, while 59 articles were excluded as they did not meet the selection criteria. Methods used to assess short-term effects of air pollution included analysis of nasal lavage (NAL) for the upper airways, and induced sputum (IS), exhaled breath condensate (EBC) and exhaled nitric oxide (FeNO) for central and lower airways. There is strong evidence that FeNO evaluation is useful independently from subject age, while IS analysis is suitable almost for adults. Biomarker changes are generally observed upon pollutant exposure irrespective of the disease status of the participants. None of the biomarkers identified are specific for a type of pollutant exposure. Based on experimental exposure studies, there is moderate evidence that IS analysis is more sensitive than lung function tests, whereas this is not the case for biomarkers obtained by NAL or EBC. Cells and some cytokines (IL-6, IL-8 and myeloperoxidase) have been measured both in the upper respiratory tract (NAL) and in the lower airways (IS). Overall, the response to traffic exposure seems different in the two compartments. In conclusion, this survey of current literature displays the complexity of this research field, highlights the significance of short-term studies on traffic pollution and gives important tips when planning studies to detect acute respiratory effects of air pollution in a non-invasive way.

OCCUPATION study (OCCUPationl asthma: a naTIONal based study): a survey on occupational asthma awareness among Italian allergists.

Occupational asthma (OA) is the most common work-related respiratory disease. Case identification still remains underperformed. The present survey aimed at investigating the awareness about OA among Italian allergists. 538 Italian Allergists completed a web anonymous questionnaire concerning: patient profile, occupational history, disease features, diagnostic work-up, causal agents, management after diagnosis. 80 cases were registered by 14 members (2.4%). Patients were mostly between 30 and 62 years old; noteworthy, 19% were between 18 and 30. All the patients had a concomitant rhinitis, usually preceding asthma onset. Bakers, hairdressers and healthcare workers were more frequently involved. Diagnostic process included: skin prick test (85%), stop/resume test (57%), specific IgE dosage for occupational allergens (52.5%), peak expiratory flow monitoring (32.5%). Noteworthy, only 27,5% of patients underwent specific challenge. After the diagnosis 50% of patients did not change job. One third of the subjects were not referred to the national Workers Compensation Authority. Our data show that OA is quite neglected by Italian allergists, despite they have a pivotal role both in early identification and in primary prevention of OA. Thus, it is worth increasing awareness concerning OA and creating an easy-access network involving allergists and referral centers for Occupational respiratory diseases.

Guidelines for the management of work-related asthma.

Work-related asthma, which includes occupational asthma and work-aggravated asthma, has become one of the most prevalent occupational lung diseases. These guidelines aim to upgrade occupational health standards, contribute importantly to transnational legal harmonisation and reduce the high socio-economic burden caused by this disorder. A systematic literature search related to five key questions was performed: diagnostics; risk factors; outcome of management options; medical screening and surveillance; controlling exposure for primary prevention. Each of the 1,329 retrieved papers was reviewed by two experts, followed by Scottish Intercollegiate Guidelines Network grading, and formulation of statements graded according to the Royal College of General Practitioners' three-star system. Recommendations were made on the basis of the evidence-based statements, which comprise the following major evidence-based strategic points. 1) A comprehensive diagnostic approach considering the individual specific aspects is recommended. 2) Early recognition and diagnosis is necessary for timely and appropriate preventative measures. 3) A stratified medical screening strategy and surveillance programme should be applied to at-risk workers. 4) Whenever possible, removing exposure to the causative agent should be achieved, as it leads to the best health outcome. If this is not possible, reduction is the second best option, whereas respirators are of limited value. 5) Exposure elimination should be the preferred primary prevention approach.

EAACI consensus statement for investigation of work-related asthma in non-specialized centres.

Work-related asthma (WRA) is a relevant problem in several countries, is cause of disability and socioeconomic consequences for both the patient and the society and is probably still underdiagnosed. A correct diagnosis is extremely important to reduce or limit the consequences of the disease. This consensus document was prepared by a EAACI Task Force consisting of an expert panel of allergologists, pneumologists and occupational physicians from different European countries. This document is not intended to address in detail the full diagnostic work-up of WRA, nor to be a formal evidence-based guideline. It is written to provide an operative protocol to allergologists and physicians dealing with asthma useful for identifying the subjects suspected of having WRA to address them to in-depth investigations in a specialized centre. No evidence-based system could be used because of the low grade of evidence of published studies in this area, and instead, 'key messages' or 'suggestions' are provided based on consensus of the expert panel members.

Management of occupational asthma: cessation or reduction of exposure? A systematic review of available evidence.

Reduction of exposure to sensitising agents causing occupational asthma has been proposed as an alternative to total avoidance in order to minimise the adverse socio-economic impact of the condition. The aim of this systematic review was to compare the effects of these two management options on asthma and socio-economic outcomes. A bibliographic search was conducted to identify studies examining the outcome of workers with occupational asthma after reduction or cessation of exposure to the causal agent. The changes in asthma symptoms and nonspecific bronchial hyperresponsiveness after reduction or cessation of exposure were described in nine and five studies, respectively. The meta-analysis of pooled data showed that a reduction of exposure was associated with a lower likelihood of improvement (OR 0.16, 95% CI 0.03-0.91) and recovery (OR 0.30, 95% CI 0.11-0.84) of asthma symptoms and a higher risk of worsening of the symptoms (OR 10.23, 95% CI 2.97-35.28) and nonspecific bronchial hyperresponsiveness (OR 5.65, 95% CI 1.11-28.82), compared with complete avoidance of exposure. This systematic review indicates that reduction of exposure cannot be routinely recommended as an alternative to cessation of exposure in the management of occupational asthma. However, further investigations are required before drawing evidence-based conclusions on the cost-effectiveness of this approach.

Noneosinophilic asthma in children: relation with airway remodelling.

Noneosinophilic asthma is increasingly recognised as an important clinical-pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling - basement membrane thickening, epithelial loss and angiogenesis - and immune activation - inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-ß, TGF-ß receptor type II - were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-ß receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life.

Personal exposure to particulate matter is associated with worse health perception in adult asthma.

BACKGROUND: Epidemiological studies have shown positive associations between particulate matter (PM) air pollution and short-term mortality and morbidity for asthma. The hypothesis that lung inflammation is responsible for these effects has been tested in panel and controlled exposure studies in asthmatic adults, with inconsistent results. OBJECTIVES: We investigated whether personal exposure to PM10 and PM2.5 were related to changes in the clinical course of asthma and to lung inflammatory responses in adult asthmatics. METHODS: A cohort of 32 asthmatic patients was followed for 2 years. Asthma control test (ACT) and St George's Respiratory Questionnaire (SGRQ) scores, forced expired volume in the first second (FEV1), exhaled nitric oxide (Fe(NO)), and pH of exhaled breath condensate (EBC) were determined on 6 occasions during different seasons. Personal exposure to PM was measured for 24 hours prior to clinical assessments. RESULTS: A 10 microg/m3 increase in PM10 personal exposure was associated with an increase in SGRQ scores (regression coefficient beta = 0.22; 95% confidence interval [CI], -0.005 to 4.451; P =.055) and with a decrease in ACT scores (beta = -0.022; 95% CI, -0.045 to 0.001; P = .060), whereas no associations were found between PM10 and FEV1, Fe(NO), or EBC pH. A positive association was detected between Fe(NO) and outdoor O3 (P = .042) and SO2 (P = .042) concentrations in the subgroup of nonsmoking asthmatics. CONCLUSIONS: We concluded that increments in personal exposure to PM10 are associated with a decrease in asthma control and health-related quality of life. However, this study does not provide evidence that 24-hour exposures to PM are associated with short-term changes in lung function or inflammatory responses of the lung.

[Features of occupational asthma in migrant workers living in northern Italy: observational study from 1987 to 2011]. / Caratteristiche dell'asma professionale nei lavoratori migranti nell'Italia settentrionale: studio osservazionale nel periodo 1987-2011.

In the period 1987-2011, 387 cases of occupational asthma (OA) in local workers (LL) and 32 in migrants (LM) were diagnosed in the 36 level Center of Occupational Medicine at University of Padova. Total number of OA decreased from early nineties to 2011. However the proportion of OA in migrants increased from 0.7% to 36.4% along the study period. Severity and causing agents were similar in the two groups. The most frequent cause were isocyanates (68.7% LM vs 52.7% LL). Most of OA in migrants was observed in painters (46.9%), whereas the jobs in asthmatic LL were more widely distributed.

Carbon monoxide pollution is associated with decreased lung function in asthmatic adults.

The aim of the present study was to test the effects of exposure to air pollutants on lung function. A panel of 19 adult asthmatics living in Padua (Italy) was followed for five 30-day periods during 2 yrs consecutively (1,492 morning and 1,434 evening measures analysed). Peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV(1)) were measured using a pocket electronic meter. Daily levels of air pollutants and meteorological variables were collected at outdoor city monitoring sites. Significant inverse associations were observed between morning and evening PEF and carbon monoxide level (p = 0.01-0.03), without clear differences between lags (0-3 days). An increment of 1 mg.m(-3) CO was associated with a PEF variation ranging -2.6- -2.8%. All effect estimates on PEF for CO remained significant and even increased after controlling for particles with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)), nitrogen dioxide and sulphur dioxide in single and multi-pollutant models. A similar trend was observed for FEV(1), but the associations were nonsignificant. A nonsignificant inverse relationship between evening PEF and SO(2) was also detected. PEF and FEV(1) were not related to PM(10) and NO(2) concentrations. The present results indicate that, in this panel of adult asthmatics, the worsening of lung function is associated with exposure to gaseous pollutants and occurs at levels of CO and SO(2) lower than current European standards.

Developments in the field of allergy in 2009 through the eyes of Clinical and Experimental Allergy.

In 2009 the journal published in the region of 200 papers including reviews, editorials, opinion pieces and original papers that ran the full gamut of allergic disease. It is instructive to take stock of this output to determine patterns of interest and where the cutting edge lies. We have surveyed the field of allergic disease as seen through the pages of Clinical and Experimental Allergy (CEA) highlighting trends, emphasizing notable observations and placing discoveries in the context of other key papers published during the year. The review is divided into similar sections as the journal. In the field of Asthma and Rhinitis CEA has contributed significantly to the debate about asthma phenotypes and expressed opinions about the cause of intrinsic asthma. It has also added its halfpennyworth to the hunt for meaningful biomarkers. In Mechanisms the considerable interest in T cell subsets including Th17 and T regulatory cells continues apace and the discipline of Epidemiology continues to invoke a steady stream of papers on risk factors for asthma with investigators still trying to explain the post-second world war epidemic of allergic disease. Experimental Models continue to make important contributions to our understanding of pathogenesis of allergic disease and in the Clinical Allergy section various angles on immunotherapy are explored. New allergens continue to be described in the allergens section to make those allergen chips even more complicated. A rich and vibrant year helpfully summarized by some of our associate editors.

Noninvasive methods for assessment of airway inflammation in occupational settings.

The present document is a consensus statement reached by a panel of experts on noninvasive methods for assessment of airway inflammation in the investigation of occupational respiratory diseases, such as occupational rhinitis, occupational asthma, and nonasthmatic eosinophilic bronchitis. Both the upper and the lower airway inflammation have been reviewed and appraised reinforcing the concept of 'united airway disease' in the occupational settings. The most widely used noninvasive methods to assess bronchial inflammation are covered: induced sputum, fractional exhaled nitric oxide (FeNO) concentration, and exhaled breath condensate. Nasal inflammation may be assessed by noninvasive approaches such as nasal cytology and nasal lavage, which provide information on different aspects of inflammatory processes (cellular vs mediators). Key messages and suggestions on the use of noninvasive methods for assessment of airway inflammation in the investigation and diagnosis of occupational airway diseases are issued.

[New methods for evaluation of the effects of urban pollutants]. / Nuovi metodi per valutare gli effetti degli inquinanti urbani.

Air pollution represents a health risk for inhabitants of cities and workers operating in urban environment. Short-term effects of pollutants are mainly observed in individuals with preexisting pulmonary and cardiovascular diseases. The present paper reviews the methods for studying short-term effects of pollutants on respiratory tract. The design of such studies is problematic since pollution is present indoor and outdoor making it difficult the examination of non-exposed individuals. Moreover, the causing agent(s) cannot be easily identified due to the multiplicity of pollution components. Whether an inflammatory mechanism plays a role, it is still controversial. Non invasive methods to study pulmonary inflammation have been introduced, that are suitable to study elevated number of subjects, particularly if they are healthy. The methods better standardized are induced sputum, exhaled nitric oxide and exhaled breath condensate.

[Diagnosis of occupational chronic pulmonary diseases]. / Diagnosi delle broncopneumopatie croniche da lavoro.

Occupational risk factors may induce chronic nonmalignant respiratory diseases such as pneumoconiosis, hypersensitivity pneumonitis, chronic obstructive pulmonary disease (COPD), asthma or bronchiolitis obliterans syndrome. Diagnosis is well codified by international guidelines for most of these occupational diseases except for COPD. The study of occupational COPD is complicated by several issues. In fact, COPD is a multifactorial disease and has a long latency between exposure to causative agents and the occurrence of disease. The main confounding factor is smoking. The quantitative estimation of cigarette smoked is easier and more accurate than that of occupational exposure. The diagnosis of COPD is based on the presence of chronic airflow limitation at spirometry; moreover, an accelerated decline in respiratory function may be observed in the longitudinal evaluation of workers. The retrospective assignment of occupational aetiology of COPD remains difficult in individual cases, especially with a significant history of smoking.

Soluble human leucocyte antigen-G and interleukin-10 levels in isocyanate-induced asthma.

BACKGROUND: We previously reported that in moderate-to-severe asthma there is a deficit of IL-10 secretion that could prevent the production of soluble HLA-G (sHLA-G), a non-classical human leucocyte antigen class I molecule with tissue-protective properties in inflammatory responses. OBJECTIVE: Our objective was to investigate the production of sHLA-G and the secretion of IL-10 by peripheral blood mononuclear cells (PBMCs) in asthma induced by isocyanates and to compare the results with those obtained in non-occupational allergic asthma. METHOD: sHLA-G and IL-10 were measured by ELISA in the culture supernatants of unstimulated or lipopolysaccharide (LPS)-stimulated PBMCs obtained from 20 subjects with isocyanate asthma, 16 asymptomatic subjects exposed to isocyanates, 18 subjects with non-occupational allergic asthma, and 26 healthy control subjects. RESULTS: Occupational exposure to isocyanates was associated with high baseline levels of secretion of IL-10 by PBMCs, whether or not the exposed subjects had asthmatic symptoms. However, spontaneous production of sHLA-G by PBMC was significantly higher in subjects with isocyanate asthma compared with asymptomatic-exposed controls. In contrast, PBMCs from subjects with non-occupational allergic asthma produced sHLA-G only after LPS stimulation. CONCLUSIONS: sHLA-G production and IL-10 secretion are influenced by workplace exposure to isocyanates and by development of asthma. The different behaviour of both sHLA-G and IL-10 in asthma induced by isocyanates compared with non-occupational allergic asthma suggests a heterogeneous biological role for HLA-G molecules and for IL-10, a key cytokine of immune and inflammatory responses.

Increased activation of p38 MAPK in COPD.

Inflammation, oxidative stress and apoptosis, which are involved in chronic obstructive pulmonary disease (COPD) pathogenesis, may activate the p38 subgroup of mitogen-activated protein kinases (MAPKs). Therefore, the aim of the present study was to evaluate the expression of the phosphorylated, active form of p38 MAPK (phospho-p38) in the lungs of COPD patients. Surgical specimens were obtained from 18 smokers with COPD at different stages of disease severity, plus nine smoking and eight nonsmoking subjects with normal lung function. Phospho-p38+ cells were quantified by immunohistochemistry in both alveolar spaces and alveolar walls. Moreover, a Western blot analysis of phospho-p38 and total p38alpha isoform expressed by alveolar macrophages was performed. Phospho-p38+ alveolar macrophages and phospho-p38+ cells in alveolar walls were increased in patients with severe and mild/moderate COPD, compared with smoking and nonsmoking controls. Moreover, they were inversely correlated to values of forced expiratory volume in one second (FEV(1)) and FEV(1)/forced vital capacity. Western blot analysis showed that phosphorylated p38, but not the total p38alpha isoform, was specifically increased in alveolar macrophages from COPD patients. Activation of the p38 mitogen-activated protein kinase pathway appears to be involved in the pathogenesis of chronic obstructive pulmonary disease. The present findings suggest that this protein may be a suitable pharmacological target for therapeutic intervention.