Chlorine Inhalation Challenge in Humans: Development of a New Closed-Circuit Methodology / Prueba de provocación bronquial con cloro en humanos: desarrollo de una nueva metodología con circuito-cerrado

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A kit to facilitate and standardize the processing of sputum for measurement of airway inflammation.

BACKGROUND: The use of inflammometry has been shown to be effective for managing asthma. However, sputum processing can be time consuming. Furthermore, methods of sputum processing can vary among facilities. To help with standardization and to simplify the procedure for laboratory staff, a novel, commercially available processing device (Accufilter, Cellometrics Inc, Canada) has been developed. OBJECTIVE: To assess the validity of the Accufilter device and kit for recovery of treated specimens, and for quantitative sputum inflammatory cell counts by comparing intrasample measurements with those using the same procedure without the Accufilter device and kit. METHODS: The present study was a wet laboratory comparison of induced sputum cell counts obtained from sputum processed with versus without the device and kit. Comparisons of each sputum specimen were performed by the same technologist in random order. RESULTS: A total of 39 samples were processed using both the standard method and the Accufilter device. The intraclass correlation coefficients were high for the weight of the filtrate, and for eosinophil and neutrophil differential counts. CONCLUSION: A good degree of agreement of results was apparent when the two methods were compared. The differences noted between both methods were minimal and did not modify clinical interpretation. The use of the Accufilter device and kit can be used in place of the standard method for sputum quantitative analysis, especially in centres with large sample loads.

Work-exacerbated asthma and occupational asthma: do they really differ?

BACKGROUND: Although work-exacerbated asthma (WEA) is a prevalent condition likely to have an important societal burden, there are limited data on this condition. OBJECTIVES: The aims of this study were (1) to compare the clinical, functional, and inflammatory characteristics of workers with WEA and occupational asthma (OA) and (2) compare health care use and related costs between workers with WEA and OA, as well as between workers with work-related asthma (WRA; ie, WEA plus OA) and those with non-work-related asthma (NWRA) in a prospective study. METHODS: We performed a prospective observational study of workers with and without WRA with a 2-year follow-up. The diagnosis of OA and WEA was based on the positivity and negativity of results on specific inhalation challenges, respectively. RESULTS: One hundred fifty-four subjects were enrolled: 53 with WEA, 68 with OA, and 33 control asthmatic subjects (NWRA). WEA was associated with more frequent prescriptions of inhaled corticosteroids (odds ratio [OR], 4.4; 95% CI, 1.4-13.6; P = .009), a noneosinophilic phenotype (OR, 0.3; 95% CI, 0.1-0.9; P = .04), a trend toward a lower FEV1 (OR, 0.9; 95% CI, 0.9-1.0; P = .06), and a higher proportion of smokers (OR, 2.5; 95% CI, 0.96-9.7; P = .06) than the diagnosis of OA. The health care use of WRA and related costs were 10-fold higher than those of NWRA. CONCLUSION: Workers with WEA appeared to have features of greater asthma severity than workers with OA. In contrast with OA, WEA was associated with a noneosinophilic phenotype. Both OA and WEA were associated with greater health care use and 10-fold higher direct costs than NWRA.

Airway inflammatory responses following exposure to occupational agents.

BACKGROUND: Airway inflammatory responses to specific inhalation challenges (SICs) with low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have not been studied thoroughly. We assessed the changes in airway inflammatory cells following SIC in sensitized workers, and looked at the influence of various factors on the pattern of inflammatory responses to SIC. METHODS: Induced sputum analysis was performed in workers sensitized to LMW (n = 41) or HMW agents (n = 41) after a control day and after a positive SIC. Cell counts were compared with lung function and various clinical parameters. RESULTS: In the LMW group, eosinophils were increased following late asthmatic responses (median [interquartile range], 0.02 [0.04] × 10(6) cells/g vs 0.30 [0.80] × 10(6) cells/g and 1.0% [3.5] vs 8.9% [8.0], P < .05), as were neutrophil numbers (0.8 [1.3] × 10(6) cells/g vs 2.3 [5.4] × 10(6) cells/g, P = .04). In the HMW group, eosinophil percentages increased both after early (1.0% [2.2] vs 5.5% [14.5], P = .003) and dual asthmatic responses (4.5% [3.7] vs 15.0% [13.7], P = .02). In the LMW group, the increases in neutrophils were higher in current smokers than in ex-smokers or nonsmokers. The length of exposure to the agent, tobacco use, and baseline percentage of eosinophils were independent predictors of the change in eosinophils, whereas age and baseline neutrophil percentage were predictors of the change in neutrophils. CONCLUSIONS: This study confirms that eosinophils and neutrophils are increased after SIC, whatever the causal agent. The type of agent is not predictive of the inflammatory response to SIC. Smoking is associated with a more neutrophilic response after SIC with an LMW agent.

Effects of a short course of inhaled corticosteroids in noneosinophilic asthmatic subjects.

BACKGROUND: Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS). OBJECTIVE: To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS. METHODS: A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 mcg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count of 2% or less. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 mcg/salmeterol 50 mcg, twice daily for all subjects. RESULTS: After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n = 6) (decrease of 1.0 ± 0.5) compared with the placebo group (n = 6) (decrease of 0.09 ± 0.4) (P = 0.008). Forced expiratory volume in 1 s declined in the placebo group (-0.2 ± 0.2 L) and did not change in the ICS group (0.04 ± 0.1 L) after four weeks of treatment (P = 0.02). The open-label treatment with fluticasone propionate 250 mcg/salmeterol 50 mcg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone. CONCLUSION: A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.

Protocol: influence of budesonide and budesonide/formoterol on asthma control in smoking asthmatic adults.

RATIONALE: A reduced response to inhaled corticosteroids (ICS) has been reported in smoking asthmatic patients but the effects of other medications remain to be evaluated in this population. SUBJECTS AND METHODS: We evaluated the effects of a combined therapy of budesonide 200 microg twice daily and formoterol 6 microg twice daily compared with budesonide 200 microg twice daily alone on asthma control questionnaire (ACQ), asthma quality of life questionnaire (AQLQ- Juniper), pulmonary function and airway inflammation, in a cross-over randomized double-blind study with treatment periods of two months separated by a one-month wash-out period. Seventeen smoking and 22 non-smoking patients not using inhaled corticosteroids with slightly uncontrolled mild asthma completed the study. RESULTS: ACQ and AQLQ scores were similar in both groups at baseline and improved similarly after treatments. beta2-agonist use was higher in smokers, regardless of the treatment received (p=0.03), as it was on baseline (p=0.003). Smokers treated with budesonide/formoterol showed an increase in the number of asthma episodes (intercurrent asthma symptoms, p=0.016) while non-smoking subjects had a significant decrease in these episodes (p=0.009). No difference was found between smokers and non-smokers in regard to post-treatment airway inflammatory parameters. CONCLUSIONS: No significant differences were found between smoking and non-smoking subjects with mild asthma in regard to clinical changes in asthma control, pulmonary function and airway inflammation following a 2-month treatment period with budesonide or the association of budesonide and formoterol for a period of 2 months. This should be further explored in larger groups of subjects.

Outcome of occupational asthma after removal from exposure: A follow-up study.

BACKGROUND: Despite being removed from their workplace, the majority of workers with occupational asthma (OA) remain afflicted with asthma. OBJECTIVES: To assess the time course of clinical, functional and inflammatory parameters in subjects with OA over a four-year period, and whether the airway inflammation observed at the time of the diagnosis predicts the outcome of OA. METHODS: The present study was a four-year, prospective, longitudinal investigation of workers with OA. Spirometry, methacholine challenge and sputum induction were performed at two weeks, and followed up at six months, and one, two, three and four years after the performance of specific inhalation challenges. RESULTS: A total of 24 subjects were enrolled. Overall, clinical and functional characteristics remained stable during the four-year follow-up period. Sputum eosinophil (Eos) counts  decreased within two weeks after exposure. Two groups of subjects were identified according to low (less than 2%, Eos-) or high (2% or greater, Eos+) Eos counts after exposure to the offending agent. The Eos+ group decreased their dose of inhaled corticosteroids, had a trend toward an improvement of airway responsiveness as well as a stable forced expiratory volume in 1 s (FEV1), whereas the Eos- group showed a decrease in FEV1, without any improvement in their functional parameters. The Eos- group also had an increase in sputum neutrophils after exposure to the occupational agents as well as during the follow-up period. CONCLUSION: There was a rapid decrease in eosinophilic inflammation after removal from exposure. Subjects with a noneosinophilic asthmatic reaction during specific inhalation challenge seemed to have a poorer prognosis than subjects with eosinophilic airway  inflammation.

Investigation of occupational asthma: sputum cell counts or exhaled nitric oxide?

BACKGROUND: The measure of sputum eosinophil counts is a useful tool in the investigation of occupational asthma (OA), but processing sputum is time consuming. Measuring the fractional concentration of exhaled nitric oxide (FENO) may be an alternative in clinical practice. The aim of this study was to assess the respective changes of sputum eosinophil counts and FENO following exposure to occupational agents in the routine practice of two tertiary centers in North America and Europe. METHODS: Workers undergoing specific inhalation challenges (SICs) for possible OA in tertiary clinics in both Canada and Belgium were enrolled. Sputum cell counts and FENO were collected at the end of the control day and at 7 and 24 h after exposure to the offending agent. RESULTS: Forty-one subjects had a negative SIC; 26 subjects had OA proven by a positive SIC. In subjects with positive SIC, there was a significant increase in sputum eosinophils at 7 h (9.0 [9.9]%) and 24 h (11.9 [14.9]%) after exposure compared with the baseline (2.8 [4.2]%), whereas there was a significant increase in FENO only 24 h after exposure (26.0 [30.5] ppb) compared with the baseline (16.6 [18.5] ppb). A 2.2% change in sputum eosinophil counts achieved a much higher sensitivity and positive predictive value than a 10-ppb change in FENO with similar specificity and negative predictive value for predicting a 20% decrease in FEV(1) during SICs. CONCLUSIONS: Sputum eosinophil counts constitute a more reliable tool than FENO to discriminate positive and negative SICs.

Frequency of work-related respiratory symptoms in workers without asthma.

BACKGROUND: Clinicians are faced with subjects complaining of work-related respiratory symptoms (WRS) without any evidence of asthma. We sought to assess the prevalence of subjects with WRS without asthma in a cohort of workers referred for possible work-related asthma (WRA) as well as compare the characteristics and the work environment of subjects with WRS to subjects with WRA. METHODS: A prospective observational study of workers referred for possible WRA over a 1-year period. Detailed medical and occupational questionnaires were administered. Pulmonary function tests as well as specific-inhalation challenges were performed. RESULTS: One hundred twenty workers were investigated. Fifty-one had WRA while 69 had WRS. The type and the severity of the respiratory symptoms were similar in both groups, except for wheezing which was more frequently reported in subjects with WRA (32 (62.7%)) than in subjects with WRS (16 (23.2%)) (P < 0.01). Both the workers with WRS and WRA were mainly employed in the manufacturing sector (64.7% (WRA) and 71% (WRS)). At the time of the first assessment 64.7% of subjects with WRA and 56.5% with WRS had left their workplace because of their bothersome respiratory symptoms. CONCLUSIONS: Subjects with WRS without asthma represent a large proportion of the subjects assessed in clinics specialized in the field of WRA. Like subjects with WRA, the population with WRS is likely to represent a significant medical burden. The similarity of the symptoms between the WRA and the WRS groups emphasizes the need to perform a thorough and objective investigation to diagnose WRA.

Cost-effectiveness of various diagnostic approaches for occupational asthma.

BACKGROUND: Diagnosis of occupational asthma (OA) by specific inhalation challenge (SIC) can be costly and is not always available. The use of sputum testing to avoid this in some patients may be a more cost-effective alternative. OBJECTIVES: To compare the cost-effectiveness of SIC with serial measurements of sputum cell counts (sputum testing) and peak expiratory flow (PEF) monitoring. METHODS: Clinical data and testing costs for OA in 49 patients were collected during a previously published trial, modelled and compared using TreeAge Pro. Clinical outcome was the percentage of accurately diagnosed patients, using SIC as the gold standard. The PEF approach used the most accurate assessment of five experts who were blinded to SIC results. Differences in the proportion of eosinophils during periods on and off work were used for the sputum testing approach and in PEF/sputum for the combined approach. Unit costs were estimated from charges in Canadian hospitals. Data were analyzed by one-way and two-way analyses, and by probabilistic sensitivity analysis using a Monte Carlo simulation technique. RESULTS: The PEF approach had an estimated accuracy of 52% and cost $365 per patient tested. Compared with PEF monitoring, sputum testing was more accurate and cost an estimated $255 for each additional OA patient correctly diagnosed. SIC costs per additional correct diagnosis were $11,032 compared with sputum testing and $6,458 compared with PEF monitoring. The combined PEF/sputum testing approach was not cost-effective in the base case analysis, but cannot be excluded according to probabilistic sensitivity analyses. CONCLUSIONS: Although SIC remains the reference test to diagnose OA, when this test is not available, sputum testing is a cost-effective alternative to PEF for diagnosis of OA.

An effective strategy for diagnosing occupational asthma: use of induced sputum.

Monitoring airway inflammation by means of induced sputum cell counts seems to improve the management of asthma. We sought to assess whether such monitoring at the end of periods at and away from work combined with the monitoring of PEF could improve the diagnosis of occupational asthma. We enrolled subjects suspected of having occupational asthma. Serial monitoring of PEF was performed during 2 weeks at and away from work. At the end of each period, induced sputum was collected. Specific inhalation challenge was subsequently performed. PEF graphs were interpreted visually by five independent observers. Forty-nine subjects, including 23 with positive specific inhalation challenge, completed the study. The addition of sputum cell counts to the monitoring of PEF increased the specificity of this test, respectively, by 18 (range [r] 13.7-25.5) or 26.8% (r 24.8-30.4) depending if an increase of sputum eosinophils greater than 1 or 2% when at work was considered as significant. The sensitivity increased by 8.2% (r 4.1-13.4) or decreased by 12.3% (r 3.1-24.1) depending on the cutoff value in sputum eosinophils chosen (greater than 1 or 2%, respectively). The addition of sputum cell counts to PEF monitoring is useful to improve the diagnosis of occupational asthma.

Airway inflammation and functional changes after exposure to different concentrations of isocyanates.

BACKGROUND: Isocyanates are a common cause of occupational asthma (OA). OBJECTIVES: We sought (1) to examine whether asthmatic reactions to isocyanates could be induced at concentrations as low as 1 ppb in subjects with OA caused by isocyanates previously diagnosed in our center and (2) to compare the inflammatory and functional changes after exposure to 1 and 15 ppb of isocyanates with similar total doses (concentration of isocyanates x duration of exposure). METHODS: Specific inhalation challenges were performed in 12 asthmatic subjects with previously confirmed OA caused by isocyanates. Eight subjects were exposed to 1 ppb at 10% of the dose of isocyanates that induced an asthmatic reaction at the time of the diagnosis. Seven subjects were exposed to the same total dose of isocyanates by using concentrations of 1 and 15 ppb 1 month apart. RESULTS: Exposure to 1 ppb at 10% of the dose that had induced functional changes at the time of diagnosis induced an asthmatic reaction in 3 of 8 subjects. There was a significant correlation between the percentage of maximum decrease in FEV(1) after exposure to 1 ppb and the increase in sputum neutrophils (rho = 0.8). By keeping the total dose (concentration of isocyanates x duration of exposure) of isocyanates similar, 4 of 7 subjects experienced an asthmatic reaction after exposure to 1 ppb, whereas only one subject experienced an 18.5% decrease in FEV(1) after exposure to 15 ppb. CONCLUSION: Isocyanates can induce functional and inflammatory changes (mainly neutrophilic) at concentrations as low as 1 ppb. For the same total dose of exposure, low concentrations of isocyanates are as harmful as or even more harmful than higher concentrations for subjects with OA to isocyanates.