Comparison of FEV1 and specific airway conductance in assessing airway response to occupational agents

BACKGROUND: There is theoretical evidence that specific airway conductance (SGaw) could be more reliable than forced expiratory volume in 1 s (FEV1) for assessing changes in airway calibre. We investigated the changes in FEV1 and SGaw when assessing bronchial responses to occupational agents. METHODS: SGaw and FEV1 were measured during inhalation challenges with various occupational agents in 174 consecutive subjects investigated for possible occupational asthma. RESULTS: A decline in SGaw of 50% or greater was documented in 77 of 90 subjects (86%) who showed a >/=20% fall in FEV1 and in 11 of 84 subjects (13%) who failed to demonstrate such a fall in FEV1. Among subjects who developed a >/=20% fall in FEV1, those who failed to develop a >/=50% decline in SGaw had a lower baseline SGaw than those who did. Among the group without a >/=20% fall in FEV1, a >/=50% decrease in SGaw was associated with either an 'intermediate' fall in FEV1 (between 15 and 17% from baseline value) (n = 4), a significant postchallenge increase in nonspecific bronchial hyper-responsiveness to histamine (n = 2), or both features (n = 3). CONCLUSIONS: A decline in SGaw of 50% or greater may provide useful complementary evidence of a bronchial response during challenges that produce equivocal results in FEV1.     

T-cell activation in occupational asthma and rhinitis

BACKGROUND: Allergic asthma and rhinitis are described as associated with a Th2 activation. However, recent works indicate that a Th1 activation can also be associated with these diseases, concomitantly to a defect in regulatory T (Treg) cell activation. Occupational asthma (OA) and occupational rhinitis (OR) are peculiar cases of these diseases in which the T-cell activation profile is largely unknown. OBJECTIVE: To characterize T-cell activation induced after a specific inhalation test (SIT) in OA and OR. MATERIAL AND METHODS: A total of 21 subjects with OA, 10 subjects with OR, 10 exposed nonallergic (ENA) subjects, and 14 healthy volunteers were included. The SIT with the incriminated substance was performed in patients and ENA subjects. Blood and induced sputum were obtained before and after SIT. T cells were analysed for CD69, CD25, IL-13, and IFN-gamma expression by flow cytometry. IL-4 and IFN-gamma were assayed by enzyme-linked immunosorbent assay (ELISA) in cell culture supernatants. Treg cells were identified as CD4(+)CD25(+high)CD45RO(+)CD69(-) T cells in peripheral blood. RESULTS: Baseline IFN-gamma production was decreased in OA and OR compared with controls. The SIT induced an increase in both Th1 and Th2 cells in blood and sputum from OA. In this group, the proportion of peripheral Treg cells decreased after SIT. Similar results were found in the CD8(+) population. ELISA assays were concordant with flow cytometry. In OR, an attenuated activation profile was found, with an increase in the proportion of IL-13-producing T cells after SIT. By contrast, in ENA subjects, SIT induced Th2 activation, with an increase in Treg cells and a decrease in Th1 cells. CONCLUSIONS: Our results demonstrate a gradient of T-cell activation from a tolerating profile in ENA subjects to an inflammatory profile in OA, with an intermediate stage in OR.     

Sputum eosinophilia in cough-variant asthma as a predictor of the subsequent development of classic asthma

BACKGROUND: A significant proportion of patients diagnosed with cough-variant asthma eventually manifest classic asthma signs, such as wheezing and dyspnoea. The aim of this study was to investigate whether the percentage of eosinophils and/or concentration of eosinophilic cationic protein (ECP) in sputum induced from patients with cough-variant asthma can predict the development of classic asthma. METHODS: Sixty-two children with cough-variant asthma were prospectively studied for 4 years. At the initiation of the study, sputum was induced with hypertonic saline, and the sputum samples were analysed for total and differential cell counts, and for ECP. Each subject was checked clinically at least every 3 months, and details of classic asthma signs experienced during the intervening periods were taken. RESULTS: Twenty-four (47.1%) of the 51 subjects available for follow-up developed signs of classic asthma, while 27 did not. The only significant difference in the sputum parameters between these two groups was a higher percentage of sputum eosinophils in subjects who developed classic asthma. A significant association was found between sputum eosinophil percentage and classic asthma development, but not between the concentration of sputum ECP and classic asthma development. CONCLUSION: Sputum eosinophilia in cough-variant asthma may be a correlate of the later development of classic asthma. This suggests that sputum differential cell counts may be useful in the clinical management of patients with cough-variant asthma, as they may enable the prediction of the subsequent classic asthma development.     

Agents causing occupational asthma in Finland in 1986–2002: Cow epithelium bypassed by moulds from moisture-damaged buildings

BACKGROUND: Occupational asthma is an avoidable form of asthma. In Finland, the diagnosis of occupational asthma entitles substantial compensation to the employee. The diagnostics are based on symptoms, exposure assessment, allergologic investigations, follow-up of peak expiratory flow (PEF) at work and at home and, in many cases, specific challenge tests. OBJECTIVE: To study the causative agents of occupational asthma in Finland. METHODS: The causative agents and the numbers of new occupational asthma cases notified to the Finnish Register of Occupational Diseases (FROD) during 1986-2002 are reported. RESULTS: The number of occupational asthma cases increased from 1986 until 1995, after which a downward trend, stabilizing during the last few years, has been observed. The majority of the cases (59%) in the beginning of the period (1986-1990) were associated with agriculture, but the percentage has fallen thereafter (42% of the cases in 1998-2002) along with the fall in the total number of cases. Since 1995, indoor moulds from water-damaged buildings have caused an increasing number of cases and have become the most important causative agents (0.5% cases, in 1986-1990 and 18% of the cases in 1998-2002). Chemicals have caused 10-30% of the cases, a decreasing number since 1990. The most important chemicals causing occupational asthma have been diisocyanates and welding fumes, followed by hairdressing chemicals and formaldehyde. CONCLUSIONS: The number of occupational asthma cases in Finland reached its height in the mid-1990s. The decrease in the number of total cases is because of the decrease in agriculture-associated cases, reflecting the number of employees in agriculture-associated occupations, which has greatly decreased since Finland joined the EU in 1995. An epidemic of mould-induced asthma, affecting mostly white-collar employees working in moisture-damaged buildings, has taken place since 1995.     

Nasal eosinophilia: an indicator of eosinophilic inflammation in asthma

Background It is noteworthy that there is a clear clinical, epidemiological and pathophysiological association between upper and lower airway inflammation in rhinitis and asthma. Objective The aim of this study was to compare the eosinophil counts in induced sputum and nasal lavage fluids in asthma, checking their association and the accuracy of nasal eosinophilia as a predictor of sputum eosinophilia by a cross‐sectional study. Methods The clinical evaluation, asthma control questionnaire (ACQ), pre‐ and post‐bronchodilator spirometry, nasal and sputum sample was performed. The nasal eosinophilia was analysed by a receiver operating curve and logistic regression model. Results In 140 adults, the post‐bronchodilator forced expiratory volume in 1 s (FEV₁) did not differ between patients with or without sputum eosinophilia (0.18). After adjusted for upper airway symptoms, age, ACQ score and post‐bronchodilator FEV₁, sputum eosinophilia was associated with 52 times increase in odds of nasal eosinophilia, whereas each 1% increase in bronchodilator response was associated with 7% increase in odds of nasal eosinophilia. Conclusion This study brings further evidence that upper airway diseases are an important component of the asthma syndrome. Furthermore, monitoring of nasal eosinophilia by quantitative cytology may be useful as a surrogate of sputum cytology in as a component of composite measurement for determining airway inflammation.     

Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness

BACKGROUND: Although airway eosinophilia is seen as a cardinal feature of asthma, data eosinophilia are still lacking on the proportion of the asthma group exhibiting raised airway eosinophilia. This study aimed to assess the distribution of sputum eosinophil count and its relationship with methacholine bronchial hyperresponsiveness in mild to moderate steroid-naive asthmatic people. METHODS: Sputum was induced by inhalation of hypertonic saline (NaCl 4.5%) in 118 mild to moderate steroid-naive asthmatic people consecutively recruited from our outpatient clinic, and in 44 healthy people. The asthma group was selected on the basis of an forced expiratory volume in 1 s (FEV(1)) of > or = 70% predicted, and a provocative methacholine concentration causing a fall of 20% in FEV(1) (PC20 methacholine; PC(20)M) < or = 16 mg/ml. RESULTS: In the asthma group, the median (range) of the percentage and the absolute values of sputum eosinophils were 4.8% (0-75) and 38 10(3)/g (0-14,191), respectively, vs 0% (0-2.3) (P < 0.001) and 0 10(3)/g (0-53) (P < 0.001) in healthy participants. Based on the 95% percentile for normal values calculated from our healthy group, 69% of the asthma group had significantly raised sputum eosinophil count (that is > 2%). In the asthma group, multiple regression analysis followed by a stepwise procedure revealed that sputum eosinophil count was significantly and inversely associated with PC(20)M accounting for 16% of its total variance (P < 0.001) while neutrophil counts positively related to PC(20)M accounting for 4% of total variance (P < 0.05). By contrast, no significant relationship was found between either eosinophil or neutrophil counts and the slope of forced vital capacity (FVC) vs FEV(1) from the methacholine challenge. CONCLUSIONS: We conclude that two-thirds of people in the mild to moderate asthma group had increased sputum eosinophilia, which plays a limited role in determining the degree of methacholine airway hyperresponsiveness.     

Neutrophil activation following TDI bronchial challenges to the airway secretion from subjects with TDI-induced asthma

BACKGROUND: The immunopathological mechanism for occupational asthma induced by toluene diisocyanate (TDI) remains to be further clarified. There have been few reports suggesting involvement of neutrophils in inducing bronchoconstriction after TDI inhalation. OBJECTIVES: To further understand the role of neutrophils in the pathogenesis of TDI-induced asthma. MATERIALS AND METHODS: Eight TDI-induced asthmatic subjects were classified as group I, and five exposed workers who had complained of work-related symptoms and worked in the same workplace, but showed negative bronchial challenges were enrolled as controls (group II). Serum neutrophil chemotactic activity during TDI bronchial challenge test was measured by the Boyden chamber method. Induced sputum was collected before and after the TDI bronchial challenge test. The myeloperoxidase (MPO) and interleukin (IL) -8 levels in the sputum were measured using RIA and ELISA. RESULT: Serum neutrophil chemotactic activity significantly increased at 10 min (P = 0.01), then decreased at 60 min (P = 0.02) and remained unchanged for up to 420 min (P = 0.07) in group I subjects, while no significant changes were found in group II subjects (P > 0.05). MPO and IL-8 were abundantly present in the sputum of all the TDI-induced asthmatic subjects and they increased significantly at 420 min after the bronchial challenges (P = 0.02, P = 0.03, respectively), while no significant changes were noted in group II subjects (P > 0.05). CONCLUSION: These findings support the view that activated neutrophils may contribute to bronchoconstriction induced by TDI which may be associated with IL-8 release.     

Nasal response in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth

Background Subjects with occupational asthma (OA) often report nasal symptoms, but nasal reactions to inhalation challenges with occupational agents have not been well characterized. Methods Fifteen subjects with OA (eight due to high-molecular-weight agents - flour and guar gum - and seven due to isocyanates) underwent inhalational challenges using closed-circuit devices (dry particles for high-molecular-weight agents and gas generator for isocyanates) on two occasions, 2-4 weeks apart in a random fashion. On one occasion, they inhaled through the nose and, on another, through the mouth. The FEV, was monitored for up to 8 h afterward, and symptoms were documented with a standardized questionnaire on nasal symptomatology, assessment of nasal resistance by rhinomanometry, and nasal lavage for the examination of cells and mediators. Results Inhaling through the mouth and through the nose:

• 1) yielded similar asthmatic responses (25 ± 8% and 22 ± 10% maximum changes in FEV₁)
• 2) more than doubled the peak nasal symptoms and nasal resistance when the maximum daily response was compared with prechallenge results.

This increase occurred on the days of inhalational challenges through the mouth and through the nose. There were some significant responses assessed by nasal lavage in terms of cells and mediators, again with no differences between the days of challenges through the mouth and through the nose. Conclusions Inhaling occupational agents of high or low molecular weight, including isocyanates, whether through the mouth or nose:

• 1) results in a similar asthmatic response
• 2) causes a significant nasal response in terms of symptoms and an increase n i nasal resistance
• 3) causes some significant changes in inflammatory cells and mediators.

     

Occupational asthma in a grain worker due to Lepidoglyphus destructor, assessed by bronchial provocation test and induced sputum

BACKGROUND: Occupational asthma (OA) can be a debilitating disease even when removal from the workplace is achieved. Today, the "gold standard" in the assessment of OA is the bronchial provocation test (BPT). Induced sputum is a non-invasive method of exploring airway inflammation which can provide additional information about such challenges and thus could be applied in OA diagnosis and monitoring. METHODS: We report the study carried out in a grain worker sensitized to Lepidoglyphus destructor (Ld), who suffered from mild asthma at the workplace. Skin prick test and specific serum IgE were measured. Ld-BPT was performed, and the changes in eosinophil rates, and ECP and tryptase levels in induced sputum were studied 30 min and 18 h after Ld-BPT. We also determined the changes in nonspecific bronchial hyperresponsiveness (NSBH), given as PD20 values. To assess the specificity of the changes, we also carried out sputum induction and methacholine challenge after barley-BPT. RESULTS: An isolated immediate response was obtained with Ld-BPT, while barley-BPT was negative. Induced sputum showed higher tryptase levels 30 min after Ld-BPT, and higher eosinophil and epithelial cell percentages and ECP levels 18 h after Ld-BPT. There was also a decrease in methacholine PD20 values after Ld-BPT. Those changes were not observed after barley-BPT. CONCLUSIONS: The study of eosinophilic and mast-cell markers in induced sputum provides additional knowledge about the inflammatory process occurring in the airways, suggesting that the study of induced sputum should be considered in the assessment of OA.     

Glutaraldehyde: an occupational hazard in the hospital setting.

BACKGROUND: We report a series of 24 health-care workers with respiratory symptoms suggestive of occupational asthma due to glutaraldehyde exposure. METHODS: The history of asthmatic symptoms was investigated with peak expiratory flow rate (PEFR) monitoring, and in eight of the subjects, the specific bronchial provocation test (SBPT) was applied as reference standard for diagnosis of occupational asthma. Levels of glutaraldehyde were monitored in the challenge chamber during the SBPT. Work environmental levels of glutaraldehyde were measured from air samples collected at least once during the PEFR monitoring of endoscopy and theatre nurses. Specific IgE antibodies to glutaraldehyde were measured with a series of glutaraldehyde modified proteins. RESULTS: In the eight workers who underwent SBPT, the diagnosis of occupational asthma was confirmed by a positive reaction (late and dual reaction in five and in three subjects, respectively). The mean level of glutaraldehyde observed during the challenge tests was 0.075 mg/m3 (range 0.065-0.084 mg/m3). In 13 out of the 16 remaining workers, the serial PEFR monitoring showed a work-related effect. In three workers, there was no physiological confirmation of occupational asthma. Levels of glutaraldehyde from the air samples collected in the workplace were as follows: personal short-term samples (mean 0.208 mg/m3; median 0.14 mg/m3; range 0.06-0.84 mg/m3), personal long-term samples (mean 0.071 mg/m3; median 0.07 mg/m3; range 0.003-0.28 mg/m3). Measurements of specific IgE antibodies to glutaraldehyde-modified proteins were positive in seven patients (29.1%) according to a cutoff value of 0.88% RAST binding. The presence of atopy to common environmental allergens and smoking was not associated with specific IgE positivity (P>0.05; Fisher's exact test). CONCLUSIONS: Our report indicates the importance of glutaraldehyde as an occupational hazard among exposed health-care workers. Intervention in the workplace, training of personnel handling this chemical, and accurate health surveillance may reduce the risk of developing occupational asthma due to glutaraldehyde.     

Sputum cellular and cytokine responses to inhaled endothelin-1 in asthma

BACKGROUND: Endothelin (ET)-1 is a 21-amino acid peptide which has potent bronchoconstrictor activity. Animal studies show elevation of ET-1 during experimental airway inflammation, and inhibition of inflammation by endothelin-antagonists, suggesting pro-inflammatory activity for ET-1. OBJECTIVE: We wanted to assess any acute influence that bronchoconstrictor doses of inhaled ET-1 might have on cells, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, nitrite (NO2) and albumin in induced sputum in asthma. METHODS: Bronchial challenge was performed using nebulized ET-1 (nebulized dose range 0.96-15.36 nmol) and placebo in 10 adult asthmatic subjects in a randomized double-blind placebo-controlled cross-over study. Sputum induction was performed 30 min and 4 h after placebo or ET-1 bronchial challenge. RESULTS: All subjects experienced dose-dependent bronchoconstriction to inhaled ET-1 with a mean (range) PC15 forced expiratory volume in 1 s (FEV1) to ET-1 of 9.45 (1.2-21.7) nmol. Comparing ET-1 with placebo inhalation, there was no change in sputum differential cell counts, TNFalpha, IL-1beta, NO2 or albumin at 30 min or 4 h after inhalation, nor was there a difference in these parameters at 4 h compared with 30 min after ET-1 inhalation. There was no fall in FEV1 at 4 h after ET-1 inhalation, suggesting that ET-1 inhalation is not associated with a late bronchoconstrictor response. CONCLUSIONS: We conclude that inhaled ET-1 does not appear to stimulate an acute inflammatory response in asthma as assessed by differential cell count, TNFalpha, IL-1beta, NO2 and albumin concentrations in induced sputum.     

Rye flour induces a stronger early bronchial response than wheat flour in occupational asthma

BACKGROUND: Our aims were to compare the doses of wheat and rye flour that induce early bronchial responses in occupationally exposed asthmatic subjects and to assess the effects of the dose of inhaled flour, the duration of exposure and the dose rate. METHODS: Ten patients underwent tests with lactose, wheat flour and rye flour. We compared the decrease in forced expiratory volume in 1 s (FEV(1)) observed during the challenge with flour and with lactose. We also calculated the amount of flour that was instantaneously active. RESULTS: Seven subjects had significantly decreased FEV(1) values following exposure to wheat and rye flour and two subjects only did so for rye flour. The provocative dose (PD, dose required to reduce FEV(1) by 15%) of rye was lower than that of wheat flour (geometric mean; PD(15) rye: 95 microg; wheat: 368 microg). The calculated doses of rye and wheat flour were better correlated with the change in FEV(1) than were the cumulative doses. CONCLUSION: The bronchial response was greater with rye than with wheat flour. The response was related to the dose of allergen inhaled and to the dose rate.