Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation.

BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2.

Inhalation challenges with occupational agents: threshold duration of exposure.

OBJECTIVES: The aim of this study was to characterize the threshold duration of exposure needed to elicit an asthmatic reaction during specific inhalation challenges (SIC) with various occupational agents and to determine the duration of exposure that should be completed before the test can be considered negative. METHODS: This retrospective study analysed the cumulative duration of challenge exposure that was required to elicit a ≥20% fall in forced expiratory volume in one second in 335 consecutive subjects with a positive SIC. RESULTS: The threshold duration of challenge exposure required to induce an asthmatic reaction was ≤60 min in 179 (53%) subjects, between 61 and 120 min in 74 (22%) subjects, and longer than 120 min in 82 (25%) subjects. The multivariate linear regression analysis showed that a longer duration of exposure was associated with exposure to low-molecular-weight agents (p < 0.001), a higher level of baseline non-specific bronchial hyperresponsiveness to histamine (p = 0.015), increasing age (p = 0.011), and a shorter duration of asthma symptoms at work (p = 0.060). CONCLUSIONS: This study demonstrates that the sensitivity of SICs for diagnosing OA is highly dependent upon the duration of the challenge exposure. These data may provide useful guidance for improving the reliability of SICs performed with realistic methods of exposure.

Incidence of severe asthmatic reactions after challenge exposure to occupational agents.

BACKGROUND: Specific inhalation challenges (SICs) with occupational agents are used to establish the diagnosis and etiology of occupational asthma. The aim of this study was to assess the frequency and determinants of severe asthmatic reactions induced by various occupational agents during SICs performed using realistic methods of exposure. METHODS: The SIC records of 335 consecutive subjects with a positive SIC (ie, ≥ 20% fall in FEV1) due to various occupational agents were reviewed. Asthmatic reactions were graded as moderate when requiring repeated administration of an inhaled short-acting ß2-agonist (SABA) and severe when requiring repeated SABA and systemic corticosteroids. RESULTS: Overall, 68 of the 335 subjects (20%) required an inhaled SABA during the SICs. The multivariate logistic regression analysis showed that the need for an inhaled SABA increased when the SIC involved a low-molecular-weight agent (LMW) (OR, 2.47; 95% CI, 1.43-4.28) and marginally so when the subjects required regular treatment with an inhaled corticosteroid (OR, 1.62; 95% CI, 0.93-2.80). The severity of asthmatic reactions was graded as moderate in 12% and severe in 3% of the subjects. Of the 10 severe reactions, five developed after exposures ≤ 5 min. Multivariate logistic regression analysis showed that challenging subjects with a LMW agent was the only significant determinant for the development of moderate/severe reactions (OR, 3.05; 95% CI, 1.62-5.73). CONCLUSIONS: Challenges with LMW agents are associated with a higher risk of an asthmatic reaction requiring pharmacologic treatment. This study may provide useful guidelines for further improving the safety of SICs.

Asthma related to cleaning agents: a clinical insight.

OBJECTIVE: To determine the agents causing asthmatic reactions during specific inhalation challenges (SICs) in workers with cleaning-related asthma symptoms and to assess the pattern of bronchial responses in order to identify the mechanisms involved in cleaning-related asthma. DESIGN: A retrospective case series analysis. SETTING: The study included all participants who completed an SIC procedure with the cleaning/disinfection products suspected of causing work-related asthma over the period 1992-2011 in a tertiary centre, which is the single specialised centre of the French-speaking part of Belgium where all participants with work-related asthma are referred to for SIC. RESULTS: The review identified 44 participants who completed an SIC with cleaning/disinfection agents. Challenge exposure to the suspected cleaning agents elicited a ≥20% fall in forced expiratory volume in 1 s (FEV1) in 17 (39%) participants. The cleaning products that induced a positive SIC contained quaternary ammonium compounds (n=10), glutaraldehyde (n=3), both of these agents (n=1) and ethanolamines (n=2). Positive SICs were associated with a significant decrease in the median (IQR) value of the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) from 1.4 (0.2-4.2) mg/mL at baseline to 0.5 (0.4-3.0) mg/mL after the challenge and a significant increase in sputum eosinophils from 1.8 (0.8-7.2)% at baseline to 10.0 (4.1-15.9)% 7 h after the challenge exposure while these parameters did not significantly change in participants with a negative SIC. Overall, 11 of 17 participants with positive SICs showed greater than threefold decrease in postchallenge histamine PC20 value, a >2% increase in sputum eosinophils, or both of these outcomes. CONCLUSIONS: These data indicate that a substantial proportion of workers who experience asthma symptoms related to cleaning materials show a pattern of bronchial reaction consistent with sensitiser-induced occupational asthma. The results also suggest that quaternary ammonium compounds are the principal cause of sensitiser-induced occupational asthma among cleaners.

Occupational asthma caused by natural rubber latex: outcome according to cessation or reduction of exposure.

BACKGROUND: The long-term effects of reducing exposure to latex in subjects with latex-induced asthma remain unknown. OBJECTIVE: The purpose of this study was to compare the health and socioeconomic outcomes of subjects with latex-induced asthma before and after reduction or cessation of exposure to latex. METHODS: Thirty-six subjects with latex-induced asthma as ascertained by specific inhalation challenges were investigated after a median follow-up of 56 months (range, 12 to 92 months). Initial and follow-up visits included use of a detailed questionnaire and measurement of the concentration of histamine causing a 20% fall in FEV(1) (PC(20)). At follow-up, information on employment, financial status, and quality of life was collected. RESULTS: At follow-up, 16 subjects were no longer exposed to latex, whereas 20 subjects had reduced exposure. In the subjects who avoided exposure, asthma severity decreased from a median score of 8.5 to 3.5 (P =.001) and the median histamine PC(20) value increased from 0.4 mg/mL to 2.3 mg/mL (P =.002). In the subjects who reduced their exposure, asthma-severity score improved from 6.5 to 2.5 (P <.001) and PC(20) values rose from 0.5 mg/mL to 2.4 mg/mL (P <.001). Cessation of exposure to latex was associated with asthma-related work disability (69%) and loss of income (62%) more frequently than was reduction of exposure (35% and 30%, respectively). CONCLUSION: Reduction of exposure to latex should be considered a reasonably safe alternative that is associated with fewer socioeconomic consequences than removal from exposure.