Negative Specific Inhalation Challenge Research Articles

Inhalation Challenge Tests in Occupational Asthma: Why Are Multiple Tests Needed?

Occupational and environmental lung diseases are on the rise because of the widespread use of various toxic agents in industry. Asthma etiopathogenesis is unclear because of exposure to high and low molecular agents in workplaces. Approximately 15-25% of asthma in adults is reported to be related to occupational exposure. The prevalence of occupational asthma (OA) is predicted to be high. The difficulties in diagnosing OA results in inadequate treatment, permanent airway damage, and medicolegal and social problems. As with other occupational diseases, it is necessary to demonstrate a direct causal relationship between the suspected agent and OA. Spirometry, peak expiratory flow rate, and/or non-specific bronchial hyperresponsiveness are frequently used to show airway hyperresponsiveness at the workplace and away from work. However, there are some controversies about the specificity and sensitivity of these test methods. Furthermore, these tests do not identify the exposure agent, which could be the causative agent. Specific inhalation challenge (SIC) tests that demonstrate the direct causal relationship are currently the gold standard. However, their positive and negative predictive values have not yet been established; therefore, many low molecular weight agents could cause late or atypical reactions. Therefore, a negative SIC test cannot exclude the disease. This review describes the procedures for the SIC test and discusses the importance of using the combined test methods with the SIC test.

Characterization of Occupational Eosinophilic Bronchitis in a Multicenter Cohort of Subjects with Work-Related Asthma Symptoms

Occupational eosinophilic bronchitis (OEB) has been described only as anecdotal case reports. We investigated the clinical and inflammatory characteristics of subjects with OEB identified in a cohort of subjects who completed a specific inhalation challenge (SIC) with occupational agents. In this retrospective multicenter study, OEB was defined by (1) a fall in FEV1 less than 15% during the SIC and the absence of nonspecific bronchial hyperresponsiveness both before and after the SIC and (2) a postchallenge increase of 3% or more in sputum eosinophils. The subjects who fulfilled these criteria were compared with 226 subjects with a negative SIC and 30 subjects with a positive SIC who failed to show baseline nonspecific bronchial hyperresponsiveness. An isolated increase in postchallenge sputum eosinophils was documented in 33 of 259 subjects (13%) with a negative SIC. These subjects reported significantly more often an isolated cough at work compared with the negative and positive SIC controls. When compared with positive SIC controls, the subjects with OEB experienced less frequently work-related wheezing and reported a shorter duration of symptoms at work. The sensitivity of the post-SIC increase in fractional exhaled nitric oxide in identifying OEB among subjects with a negativeSIC was low, ranging from 43% to 24% using cutoff values of 8 ppb to 17.5 ppb, whereas the specificity was high (90%-97%). This study highlights the relevance of induced sputum analysis in the investigation of work-related asthma symptoms to identify isolated increases in sputum eosinophils that are consistent with a diagnosis of OEB.

An increase of fractional exhaled nitric oxide after specific inhalation challenge is highly predictive of occupational asthma.

An increase of fractional exhaled nitric oxide (FeNO) has been described after specific inhalation challenges (SICs) with occupational allergens, but the clinical role of FeNO measurements before and after SIC is unknown. It was the aim of this study to assess the diagnostic accuracy of FeNO measurements before and after SIC in subjects with suspected occupational asthma (OA). One hundred forty-eight patients with suspected OA were examined by SIC with various occupational allergens. Subjects were assigned to pulmonary responders, nonresponders or doubtful by standard lung function criteria. FeNO was measured before SIC (baseline) and 24h afterwards. Subjects with negative or doubtful SIC but increase of FeNO were evaluated individually by an overall expert rating. Effect modifiers of FeNO increases were assessed by regression analyses. Thirty-one patients (21%) were classified as pulmonary responders, 105 (71%) as nonresponders and 12 (8%) as doubtful. With the pulmonary responder status as gold standardan increase of FeNO ≥ 13ppb showed a specificity of 0.9 and a sensitivity of 0.5. Seventeen subjects with negative or doubtful responder status showed such an increase of FeNO, among them 13 subjects with definitive or probable OA after expert rating. Regression analyses revealed no significant modifiers for the FeNO increase. An increase of FeNO after SIC is highly predictive of OA and should be regarded as an additional criterion for the interpretation of SIC with occupational agents.

Diagnostic Accuracy of Inflammatory Markers for Diagnosing Occupational Asthma

The assessment of airway responsiveness andinflammation is key to the investigation of occupational asthma (OA). We sought to assess and compare the diagnostic accuracies of the blood and sputum eosinophil counts and the methacholine challenge for the diagnosis of OA. We conducted a retrospective study assessing 618 patients who underwent specific inhalation challenges (SICs) for symptoms suggestive of OA between 2000 and 2015. A sputum induction and a methacholine challenge were performed before and after SICs. Blood samples were collected in all subjects before the SICs and in 100 subjects before and after SICs. The diagnostic accuracies of blood and sputum eosinophil counts and methacholine challenge were calculated for diagnosing OA. The change in blood eosinophil count failed to differentiate workers with positive and negative SICs. The change in sputum eosinophil counts induced by the exposure to the offending agent had the highest diagnostic accuracy (receiver operating characteristic area under the curve: 86% [95% confidence interval: 0.8-0.9, P < .001]) for diagnosing OA compared with changes in concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 second (PC20) and blood eosinophils. Combining a 2-fold or greater decrease in PC20 or a 3% or greater increase in sputum eosinophil count achieved a sensitivity of 84% and a specificity of 74% with a negative predictive value of 91% for the diagnosis ofOA. Blood eosinophil counts do not appear to be an effective aid for diagnosing OA. The performance of both sputum cell count analysis and a methacholine challenge before and after exposure to the offending agent may represent an effective alternative in diagnosing OA when SICs are unavailable.

The role of allergen components for the diagnosis of latex-induced occupational asthma.

Recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergen components have been developed to assess the patients' allergen sensitization profile and to improve the diagnosis of NRL allergy. To examine whether the determination of specific IgE (sIgE) reactivity to a panel of recombinant allergen components would be helpful for diagnosing NRL-induced occupational asthma (OA) in predicting the outcome of a specific inhalation test. sIgE levels to NRL extract and 12 recombinant NRL allergen components were assessed in 82 subjects with OA ascertained by a positive specific inhalation challenge (SIC) with NRL gloves and in 25 symptomatic subjects with a negative challenge. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRL-sIgE level ≥0.35 kUA /l as compared to the result of SICs were 94%, 48%, 86%, and 71%, respectively. The positive predictive value increased above 95% when increasing the cutoff value to 5.41 kUA /l. Subjects with a positive SIC showed a significantly higher rate of sIgE reactivity to rHev b 5, 6.01, 6.02, and 11 than those with a negative SIC. A sIgE sum score against rHev b 5 plus 6.01/6.02 ≥ 1.46 kUA /l provided a positive predictive value >95% with a higher sensitivity (79%) and diagnostic efficiency (Youden index: 0.67) as compared with a NRL-sIgE ≥5.41 kUA /l (49% and 0.41, respectively). In suspected OA, high levels of sIgE against rHev b 5 combined with rHev b 6.01 or 6.02 are the most efficient predictors of a bronchial response to NRL.

Importance of specific inhalation challenge in the diagnosis of occupational asthma induced by quaternary ammonium compounds

Importance of specific inhalation challenge in the diagnosis of occupational asthma induced by quaternary ammonium compounds

Investigation of occupational asthma: Do clinicians fail to identify relevant occupational exposures?

Specific inhalation challenges (SIC) enable the identification of the agent responsible of occupational asthma (OA). A clinician may fail to identify a specific agent in the workplace, which may potentially lead to a misdiagnosis. The expert assessment method performed by an occupational hygienist has been used to evaluate occupational exposures in epidemiological studies. The broad aim of the present study was to evaluate the contribution of an expert assessment performed by an occupational hygienist to the diagnosis of OA. The specific aim was to compare workplace exposures identified by an occupational hygienist and by chest physicians in subjects with positive SICs and subjects with asthma, but with a negative SIC. SICs were performed in 120 cases: 67 were positive and 53 were negative. A clinician assessed occupational exposures to sensitizers during a routine clinical evaluation preceding the performance of the SIC. An expert assessment of occupational exposures was performed by an occupational hygienist blind to the result of the SIC. The occupational hygienist identified the causal agent in 96.7% of the 61 cases of positive SIC. In 33 (62.3%) cases of negative SICs, the occupational hygienist identified ≥1 sensitizing agent(s) that had not been identified by the clinician. The hygienist identified the causal agent in almost all subjects with OA. In contrast, the clinician failed to identify potential exposures to sensitizers in >60% of the negative SIC subjects, which may have resulted in some subjects being misdiagnosed as not having OA.

Edward Hamilton Paterson

The diagnosis of occupational asthma can be made by exposing workers to the relevant agent either in a hospital laboratory through specific inhalation challenges (SICs) or in the workplace. As...

Asthma related to cleaning agents: a clinical insight

ObjectiveTo 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...

Interferon-γ Promoter Is Hypermethylated in Blood DNA from Workers with Confirmed Diisocyanate Asthma

Risk factors have not been identified that determine susceptibility for development of diisocyanate-induced occupational asthma (DA). We hypothesized that diisocyanate (DI) exposure could modify gene promoter regions regulating transcription of cytokine mediators and thereby influence expression of DA. A cross-sectional study was designed to investigate the promoter methylation status of candidate genes in DI-exposed workers. Subjects consisted of 131 workers in three groups: 40 cases with DA confirmed by a positive specific inhalation challenge (SIC) (DA+), 41 exposed workers with lower respiratory symptoms and negative SIC (DA-), and 50 asymptomatic exposed workers (AWs). We studied four candidate genes (GSTM1, DUSP22, IFN-γ, and IL-4) for which altered promoter methylation has been previously investigated for relationships with a variety of other environmental exposures. Methylation status was determined using methylation-specific quantitative PCR performed on genomic DNA extracted from whole blood. Results showed that relative methylation of IFN-γ promoter was significantly increased in DA+ in comparison with both comparator groups (DA- and AW), and it exhibited good sensitivity (77.5%) and specificity (80%) for identifying DA workers in a multivariate predictive model after adjusting for type of DI exposure, smoking status, methacholine PC₂₀, and gender. IL-4 promoter was slightly less methylated only in DA+ compared with AW among nonsmoking workers. Both GSTM1 and DUSP22 promoter methylations were found not associated with DA. Our finding suggests that exposure to occupational chemicals could play a heretofore undefined mechanistic role via epigenetic modification of specific genes in the promoter region.

Genetic Variants in Antioxidant Genes Are Associated With Diisocyanate-Induced Asthma

Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.

Hexamethylene diisocyanate asthma is associated with genetic polymorphisms of CD14, IL-13, and IL-4 receptor α

Hexamethylene diisocyanate asthma is associated with genetic polymorphisms of CD14, IL-13, and IL-4 receptor α

Investigation of Occupational Asthma: Sputum Cell Counts or Exhaled Nitric Oxide?

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. 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. 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. Sputum eosinophil counts constitute a more reliable tool than FENO to discriminate positive and negative SICs.

Changes in Sputum Eicosanoids and Inflammatory Markers After Inhalation Challenges With Occupational Agents

An increase in cysteinyl-leukotrienes (LTs) after specific inhalation challenge (SIC) with common allergens in patients with atopic asthma has been shown previously, but there are scarce data with occupational agents. We sought to determine whether there are differences in lower airway inflammatory markers and the production of cytokines and eicosanoids between patients with a positive or negative SIC response to occupational agents. Twenty-six patients with suspected occupational asthma and 13 healthy control subjects were studied. Spirometry, methacholine challenge, and sputum induction were performed at baseline and 24 h after SIC with occupational agents. Several cytokines and inflammatory mediators, including eicosanoids, were measured in sputum. Twenty-six SICs were carried out with high-molecular-weight or low-molecular-weight agents, and the responses were positive in 18 patients. SIC elicited nine early asthmatic responses, two dual asthmatic responses, and seven isolated late asthmatic responses. Significant increments in sputum eosinophil counts were found only in patients with positive SIC responses compared with baseline values. Interleukin-10 levels were decreased in patients with positive and negative SIC responses compared to those in healthy control subjects. A significant increase (p < 0.05) in the LTC(4)/prostaglandin E(2) (PGE(2)) ratio was observed in patients after positive SIC responses compared to those with negative SIC responses. Overexpression of LTC(4), relative underproduction of PGE(2), and greater airway eosinophilia were observed in patients with positive SIC responses.

Workplace-specific challenges as a contribution to the diagnosis of occupational asthma

The diagnosis of occupational asthma can be made by exposing workers to the relevant agent either in a hospital laboratory through specific inhalation challenges (SICs) or in the workplace. As suggested by several authors, workers with negative laboratory SIC can be monitored at the workplace under supervision. The present study aims to assess the frequency of, and identify factors associated with, a positive workplace reaction in workers with negative SIC in the laboratory. The results of workplace challenges were examined in 99 workers who underwent negative SIC between 1994 and 2004. A positive reaction either in the SIC or in the workplace was defined as a sustained fall in forced expiratory volume in one second of > or =20%. In total, 22 (22.2%) workers showed positive responses at the workplace. These subjects more often had increased baseline methacholine responsiveness (90.5 versus 67.6%). They also underwent more days of SIC testing (4.9 versus 3.3 days) and were exposed more often to two or more agents (56 versus 28.4%) and for a longer period of time (363.3 versus 220.4 min) in the laboratory. The present study illustrates the usefulness of workplace monitoring of airway function in the investigation of occupational asthma and identifies factors that are more often associated with a positive reaction.

Induced sputum and exhaled nitric oxide as noninvasive markers of airway inflammation from work exposures

Noninvasive measures of airway inflammation are increasingly used in the investigation and management of asthma. Their role in the investigation of occupational lung diseases, however, is not as clearly established. The present article reviews the use of noninvasive methods - induced sputum and exhaled nitric oxide - in the assessment of airway inflammation during the investigation of occupational asthma and eosinophilic bronchitis, and reviews studies investigating the effect of exposure to various occupational agents on airway inflammation in healthy individuals. A number of studies have confirmed the association between exposure to occupational agents and the presence of eosinophilic airway inflammation after that exposure in individuals with occupational asthma. Individuals with positive specific inhalation challenges to occupational agents seem to show a greater increase in exhaled nitric oxide than those with negative specific inhalation challenges. Exposure to various agents associated with an increase in exhaled nitric oxide mainly induced a neutrophilic inflammation. Increasing evidence supports the use of induced sputum as an additional tool in the investigation of occupational asthma. The role of exhaled nitric oxide in the investigation of occupational asthma needs to be clarified due to conflicting evidence reported in the literature.

Socioeconomic outcome of subjects experiencing asthma symptoms at work.

The aim of this study was to investigate the socioeconomic outcomes of subjects who experienced work-related asthma symptoms in the absence of demonstrable occupational asthma (OA) and to compare these outcomes with those found in subjects with documented OA. Subjects (n=157) who were being investigated for work-related asthma, were surveyed. Of these 86 had OA, ascertained by a positive specific inhalation challenge (SIC), and 71 subjects had a negative SIC response. After a median interval of 43 months (range 12-85 months), the subjects were interviewed to collect information on employment status, income changes, and asthma-related work disability. Rates of work disruption and income loss at follow-up were similar in subjects with negative SIC (46% and 59%, respectively) and in those with OA (38% and 62%). The median loss as a percentage of initial income was 23% in subjects with negative SIC and 22% in subjects with OA. Asthma-related work disability, defined as any job change or work loss due to asthma, was slightly more common in subjects with OA (72%) than in those with negative SIC (54%). This study shows that, even in the absence of demonstrable occupational asthma, work-related asthma symptoms are associated with considerable socioeconomic consequences.

Changes in sputum cell counts after exposure to occupational agents: What do they mean?

Background: Exposure to occupational agents can induce eosinophilic inflammation in subjects with occupational asthma (OA). It might also induce nonspecific changes in airway inflammation in subjects without OA. Objectives: We sought to investigate the changes in airway inflammation induced by exposure to occupational agents in subjects with and without OA and to determine which changes in sputum eosinophil numbers and bronchial responsiveness to methacholine should be regarded as clinically significant for predicting a 20% fall in FEV1. Methods: We performed specific inhalation challenges (SICs) in 3 groups of subjects: subjects reporting a history consistent with OA with a positive SIC response (n = 17); subjects reporting a history consistent with OA with a negative SIC response (n = 14); and asthmatic subjects without any history of OA (n = 10). Induced sputum and methacholine challenges were performed at the end of the control day and again at the end of the last day of exposure; the last day of exposure was always performed in the laboratory. Results: There was an increase in median sputum eosinophil and neutrophil numbers in subjects with positive SIC responses. Cell counts remained unchanged after exposure in asthmatic subjects without OA. A combination of a greater than 0.26 106/mL increase in sputum eosinophil numbers and a decrease in the concentration of methacholine inducing a 20% fall in FEV1 of at least 1.8-fold compared with baseline values predicted a 20% fall in FEV1 in 96% (95% CI, 70%-99%) of patients. Conclusion: Exposure to occupational agents per se does not induce airway inflammation. Changes in both sputum eosinophil counts and methacholine responsiveness are satisfactory predictors of a significant bronchial responsiveness to occupational agents. (J Allergy Clin Immunol 2001;107:1063-8.)

Amniotic fluid N-acetyl-beta-D-glucosaminidase activity and renal abnormalities.

Amniotic fluid N-acetyl-beta-D-glucosaminidase (NAG) activity was measured in 21 normal pregnancies to determine reference values, and in 10 pregnancies with fetuses who had prenatally recognised renal and urinary tract malformations. The normal values obtained at 17-19 and 28-31 gestational weeks did not differ, and an activity of 105 units NAG/mmol creatinine was the upper limit of the normal range. Raised NAG activities were found in four fetuses with oligohydramnios and severe bilateral renal disease, and also in two infants with a normal amount of amniotic fluid, only unilateral renal lesions, and a normal renal function after birth. Three of four cases with normal NAG activities had malformations without kidney damage, but one baby with prune belly syndrome was subsequently found to have dysplastic kidneys and renal failure. Our preliminary results suggest that a high level of NAG activity in the amniotic fluid indicates unilateral or bilateral kidney damage but is not proof of intrauterine renal failure.