Environmental factors associated with baseline and ...

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OEM Online First, published on May 20, 2016 as 10.1136/oemed-2015-103005 Workplace

ORIGINAL ARTICLE

Environmental factors associated with baseline and serial changes in fractional exhaled nitric oxide (FeNO) in spice mill workers Anita Van der Walt,1 Roslynn Baatjies,1,2 Tanusha Singh,3,4 Mohamed F Jeebhay1 1

Centre for Environmental and Occupational Health Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa 2 Faculty of Applied Sciences, Department of Environmental and Occupational Studies, Cape Peninsula University of Technology, Cape Town, South Africa 3 National Institute for Occupational Health (NIOH), NHLS, Johannesburg, South Africa 4 Department of Clinical Microbiology & Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa Correspondence to Professor Mohamed F Jeebhay, Centre for Environmental and Occupational Health Research, School of Public Health and Family Medicine, University of Cape Town, Room 4.47, Fourth Level, Falmouth Building, Anzio Road, Observatory, Cape Town 7925, South Africa; [email protected] Received 8 April 2015 Revised 27 April 2016 Accepted 4 May 2016

ABSTRACT Background This study evaluated the determinants of high fractional exhaled nitric oxide (FeNO; >50 ppb) and serial changes in FeNO over a 24-hour period in spice mill workers at risk of work-related allergic respiratory disease and asthma. Methods A cross-sectional study of 150 workers used European Community Respiratory Health Survey (ECRHS) questionnaires, Phadiatop, serum-specific IgE (garlic, chilli pepper, wheat; Phadia, ImmunoCAP), spirometry and FeNO. A hand-held portable nitric oxide sampling device (NIOX MINO, Aerocrine AB) measured FeNO before and after the 8-hour shift and after 24 hours from baseline. Results The mean age of workers was 33 years; 71% were male, 46% current smokers and 45% atopic. Among workers with garlic sensitisation, 13% were monosensitised and 6% were co-sensitised to chilli pepper. Baseline preshift FeNO geometric mean (GM=14.9 ppb) was similar to the mean change across shift (GM=15.4 ppb) and across the 24-hour period (GM=15.8 ppb). In multivariate linear models, smoking (β=−0.507) and atopy (β=0.433) were strongly associated with FeNO. High FeNO (>50 ppb) was significantly associated with asthma-like symptoms due to spice dust (OR=5.38, CI 1.01 to 28.95). Sensitisation to chilli pepper was more strongly correlated with FeNO (r=0.32) and FeNO>50 ppb (OR=17.04, p=0.005) than garlic. FeNO increase (>12%) across 24 hours demonstrated a strong association with elevated exposures to spice dust particulate (OR=3.77, CI 1.01 to 14.24). Conclusions This study suggests that chilli pepper sensitisation is associated with high FeNO (>50 ppb), more strongly compared with garlic, despite the low prevalence of sensitisation to chilli. Elevated inhalant spice dust particulate is associated with a delayed elevation of FeNO across the 24-hour period.

INTRODUCTION

To cite: Van der Walt A, Baatjies R, Singh T, et al. Occup Environ Med Published Online First: [please include Day Month Year] doi:10.1136/oemed2015-103005

Spices are widely used to enhance flavour and aroma of food. Spice dust allergens are generally high molecular weight sensitisers and aerosolisation of spice dust has been associated with an enhanced airway inflammatory response causing rhinitis and asthma. These manifestations are via IgE crossreactivity pathways, but direct irritative and other non-IgE-mediated respiratory mechanisms may also play a role.1 2 Fractional exhaled nitric oxide (FeNO) is an important non-invasive marker for eosinophilic

What this paper adds ▸ Few epidemiological studies have investigated the determinants of serial changes in fractional exhaled nitric oxide (FeNO) among workers at increased risk of work-related allergic respiratory disease and asthma. ▸ Inhalant chilli pepper sensitisation is associated with high FeNO (>50 ppb) possibly more strongly than sensitisation to garlic, although the prevalence of those sensitised to chilli is low. ▸ A delayed increase in FeNO occurs after 24 hours in spice mill workers exposed to elevated inhalable spice dust particulate containing spice allergens. ▸ Serial FeNO measurements across the working week could be of value in the early detection of high molecular weight sensitiser-induced occupational asthma.

airway inflammation, indicative of underlying asthma.3 Bronchial allergen challenge tests have demonstrated a delayed elevation in FeNO.4 5 The role of FeNO measurement has emerged as providing a complementary role alongside existing pulmonary function tests6 in asthma diagnosis. High FeNO levels (>50 ppb) are considered a marker of significant Th2-driven local inflammation, specifically of the bronchial mucosa, rather than general eosinophilic inflammation, as measured by blood or induced sputum.7 Early and late inflammatory responses are characteristic of asthma, with the latter occurring in 30–70% of patients.8 9 The associated FeNO increase 24 hours after allergen exposure in those with a positive bronchial challenge test is highly dependent on the nature of the allergen challenge than on basal FeNO.4 In patients with occupational asthma, high molecular weight agents are more consistently associated with an increase in FeNO after specific bronchial challenge.5 While measurement of FeNO is recognised as an accurate, reproducible and important non-invasive surrogate marker for airway inflammation in occupational settings,8 10 inconsistent results have questioned the utility of this measure in the medical surveillance of workers with occupational allergy and asthma.11 In our previous study, spice mill workers exposed to inhalable spice dust particulate (mean>2 mg/

Van der Walt A, et al. Occup Environ Med 2016;0:1–7. doi:10.1136/oemed-2015-103005

Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence.

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Workplace m3), containing garlic and chilli pepper allergen (0.24–0.44 mg/ m3), had an increased risk of work-related lower respiratory symptoms, allergic sensitisation and obstructive lung disease including asthma.2 Furthermore, the sensitisation patterns to garlic and chilli pepper were highly correlated and pointed to the presence of cross-reactive high molecular weight allergens present in chilli pepper and garlic (50–52 kDa).12 It is well known that the high molecular weight proteins present in aerosolised spice dust1 can potentially induce an immediate or dual asthmatic reaction.10 The objective of this study was to evaluate the association between FeNO (baseline, across an 8-hour shift, across the 24-hour period) and airborne exposures to spice dust particulate, spice allergens (garlic, chilli) and endotoxin concentration levels. This study follows on from our previous studies of bakery workers that highlighted the limitations of using once-off basal FeNO measurements in identifying individuals exposed to respiratory sensitisers having possible work-related asthma.13

MATERIALS AND METHODS Study design and population A cross-sectional epidemiological study of all current permanent (n=139) and casual (n=11) workers in the spice mill having a mean employment duration of 6.9 years in the factory and 3.2 years in the current job formed the basis for this investigation. Ethical approval for the study was obtained from the University of Cape Town (Cape Town, South Africa).

Environmental exposure assessment Work processes in this mill predominantly involve weighing, blending and packing of various spices. Dry raw materials such as paprika and chilli peppers (Capsicum annuum) are separately ground by a milling process. Dried garlic flakes, powder or granules, which are independently manufactured, are essential ingredients of most of the spice recipe products. The details of the environmental sampling measurements are described elsewhere.2

Questionnaire Each worker completed an interviewer-administered European Community Respiratory Health Survey (ECRHS) questionnaire designed for the investigation of asthma14 and adapted for the spice work environment as previously described.2

Immunological tests Serum analysis for common inhalants (Phadiatop test) as well as specific IgE for garlic (f47; Allium sativum), chilli pepper (f279; Capsicum frutescens) and wheat (f4; Triticum aestivum) was performed using the UniCAP assay procedure (ImmunoCap 100e System; Phadia, Uppsala, Sweden) according to the manufacturer’s instructions. An ImmunoCAP value of ≥0.35 kUA/L was considered positive.

Spirometry Lung function was measured by spirometry according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines15 as previously reported. A flow volume Koko Spirometer was used. Reference values of the European Community for Coal and Steel (ECCS) were used for spirometry interpretation, with lower limits corresponding to the 95th centile.16 Spirometry was performed before and after inhalation of a short-acting ß2-agonist salbutamol (400 mg) using a metered dose inhaler with a maximum of six attempts to produce acceptable/reproducible results. 2

Serial FeNO measurements FeNO was determined prior to spirometry using ATS/ERS criteria.17 A hand-held portable nitric oxide sampling device (NIOX MINO Airway Inflammation Monitor, Aerocrine AB, Solna, Sweden) was used.18 FeNO measurements were performed by each participant (mean of three efforts) on a Monday during the 8-hour work shift after having confirmed that there was no spice dust exposure for 48 hours prior to testing. Information on reported chest infections, current smoking, alcohol consumption, recent (within the previous 24 hours) green leafy vegetable intake and/or exercise, medication usage and/or spirometry was collected. Tested individuals were required to abstain from smoking tobacco, eating or drinking at least 1 hour before testing. Additional information on the presence of upper airway infection 3 weeks prior to the test was recorded. This information was collected to assess potential confounders for the change in FeNO observed.19 Absolute FeNO values are expressed in ppb, and changes across shift and across 24 hours are expressed as a percentage of the initial value (Δ%). A high preshift baseline FeNO of >50 ppb level was considered to be indicative of a high probability of underlying asthma as this level is associated with a significant Th2-driven airway inflammation.3 7 The serial FeNO measurements (baseline preshift, postshift day 1 and preshift day 2) constituted a dynamic assessment of FeNO concentration to assess the extent of FeNO increase across the 8-hour shift and across the 24-hour period, and also served as a signal of allergen-triggered Th2-driven inflammation in these workers.4 20 Studies by Pedrosa et al4 have suggested that >12% ΔFeNO provided maximal sensitivity (0.81) and specificity (0.92) for predicting a positive outcome 24 hours after the bronchial allergen challenge.

Statistical analysis Statistical analyses were performed using the STATA V.11 computer software (StataCorp, College Station, Texas, USA). Key associations of interest involved investigating determinants (exposure status, host factor attributes) of FeNO measured over a 24-hour period and various clinical end points (respiratory symptoms, immunological status, pulmonary function). These associations were explored using bivariate and multivariate analyses. Variables that were not normally distributed, such as exposure metrics and FeNO levels, were log transformed (natural log, ln) before statistical model development. A p-value of 0.10 was used as a criterion to determine the best predictive model for FeNO, using the stepwise forward and backward model selection procedure. This analysis included all predictor variables for FeNO that were significant in the univariate regression analysis, which resulted in some variables not remaining in the final model. Models were adjusted for gender, atopy, smoking and recent green leafy vegetable intake. Construction of other more refined multivariate models that used composite outcome variables, which included symptoms in addition to pulmonary function and FeNO indices, was not possible due to lack of statistical power.

RESULTS Data from all 150 workers were included in the statistical analyses for this study. The demographic characteristics of the spice mill workers and determinants of baseline preshift FeNO are outlined in table 1. The mean age of this predominantly male (71%) workforce was 33.4 years with 46% being current smokers and 45% atopic. Recent green leafy vegetable intake was recorded in 44% and recent exercise was reported by 10% Van der Walt A, et al. Occup Environ Med 2016;0:1–7. doi:10.1136/oemed-2015-103005


Workplace Table 1 Demographic factors and univariate analysis of determinants associated with baseline preshift FeNO (ln) levels among spice mill workers Determinant (n=150) Age (years) Height (m) Weight (kg) BMI (kg/m²) Blood pressure Systolic (mm Hg) Diastolic (mm Hg) Hypertension* Gender (%M:F) Smoking† Atopy‡ Recent alcohol intake§ Recent exercise§ Recent green leafy vegetable intake§ Recent steroid use§ Reported chest infection¶ Lung function test during previous week Work-related respiratory symptoms WRURS due to spice dust WRLRS due to spice dust Allergic sensitisation (specific IgE≥0.35 kUA/L) Garlic (G++C+) Garlic monosensitisation (G++C−) Chilli pepper (C++G+) Wheat (W+G+C+) Any one spice dust allergen Exposure category Particulate mass concentration (mg/m3) Medium vs low High vs low Garlic allergen concentration (μg/m3) Medium vs low High vs low Chilli pepper allergen concentration (μg/m3) Medium vs low High vs low Endotoxin concentration (EU/m3) Medium vs low High vs low

Mean±SD No (%)

β

GM ratio

r²

33.4±7.7 1.68±0.9 74.33±15.9 26.28±5.7

−0.005 1.130 0.003 −0.002

0.995 3.096 1.003 0.998

0.0033 0.0178 0.0048 0.0001

0.486 0.103 0.401 0.892

112.63±12.7 67.54±9.8 10 (7%) 71:29 69 (46%) 67 (45%) 47 (31%) 15 (10%) 66 (44%) 6 (4%) 5 (3%) 4 (3%)

0.002 0.0002 0.322 0.221 −0.453 0.444 −0.029 −0.261 0.234 0.297 −0.181 0.640

1.002 1.0002 1.380 1.247 0.636 1.559 0.971 0.770 1.264 1.346 0.834 1.897

0.0013 0 0.0115 0.0181 0.0906 0.0866 0.0003 0.0109 0.0239 0.0060 0.0019 0.0189

0.665 0.976 0.192 0.101 1.180.090.06644.8612%) over the baseline was slightly higher across the 24-hour period (23%) than across the shift (21%; table 2). In the final multiple linear regression model, the variables that explained the greatest variability in baseline FeNO were smoking (β=−0.507), atopy (β=0.433), recent green leafy vegetable intake (β=0.306) and male gender (β=0.266). These variables explained 23% of the variability in FeNO in the model (data not shown). While a positive trend was observed between airborne spice dust particulate and serial changes in FeNO in multiple linear regression models, these were not statistically significant

(table 3). Multivariate logistic regression models, however, demonstrated that an FeNO increase (>12%) across a 24-hour period was significantly associated (OR=3.77) with exposures to higher spice dust particulate (medium>1.1812%) across the 8-hour work shift. There were also no significant associations observed between endotoxin exposures and serial changes in FeNO. In other multivariate logistic regression analyses, after adjusting for confounders (male gender, atopy, smoking, recent green leafy vegetable intake), work-related asthma-like symptoms due to spice dust was associated with high baseline FeNO (>50 ppb; (OR=5.38, CI 1.01 to 28.95; table 4).

DISCUSSION This study of spice mill workers has demonstrated that asthmalike symptoms due to spice dust were significantly associated with high FeNO (>50 ppb) in exposed workers. Furthermore, chilli pepper sensitisation was more strongly associated with high FeNO (>50 ppb) compared with garlic sensitisation. However, some studies have suggested that underlying airway inflammation occurs even in the absence of asthma symptoms.8 As a result, high FeNO may be a predictor of subsequent allergic respiratory disease and a possible marker for the future development of asthma among non-asthmatic atopic individuals. Since elevation of FeNO precedes airway symptoms, it can also predict the development of new-onset rhinitis in asymptomatic individuals.21 Our previous study showed that spice mill workers sensitised to garlic and chilli pepper (G++C+) were at increased risk of reporting spice dust-related asthma-like symptoms.2 Similarly, work-related ocular–nasal and asthma-like symptoms due to spice dust were strongly associated with airborne garlic allergen levels. A novel aspect of this study was the serial use of FeNO measurements to assess the presence of probable work-related asthma in a reasonably large group of mill workers exposed to inhalable spice dust particulate. The study demonstrated that elevated inhalant spice dust particulate is associated with a delayed elevation of FeNO across the 24-hour period. Clinical

Table 3 Multivariate continuous linear regression models of occupational inhalant exposures and serial changes of FeNO in spice mill workers Particulate mass concentration (mg/m³)

Endotoxin concentration (EU/m³)

Garlic allergen concentration (μg/m³)

Chilli pepper concentration (μg/m³)

Estimate (β1)

p-value

Estimate (β1)

p-value

Estimate (β1)

p-value

Estimate (β1)

p-value

FeNO Baseline FeNO preshift FeNO per cent change across an 8-hour shift* FeNO per cent change across a 24-hour period†

0.002 2.052 1.318

0.998 0.107 0.589

0.067 0.0809 0.028

0.334 0.466 0.897

0.482 2.398 −1.709

0.667 0.178 0.616

−0.215 1.313 0.528

0.704 0.144 0.759

δ p≤0.05; continuous regression model adjusted for confounders: male gender, atopy, smoking, recent green leafy vegetable intake. *Per cent change in FeNO across shift: (postshift day 1−preshift baseline)/baseline×100. †Per cent change in FeNO across a 24-hour period (preshift day 2−preshift baseline)/baseline×100. FeNO, fractional exhaled nitric oxide.

4



Workplace Table 4 Multivariate logistic regression model of factors associated with work-related changes in serial measurement changes of FeNO in spice mill workers Predictors (OR, CI) Exposure variables (reference low exposure group OR=1) Particulate mass concentration (mg/m³) Medium High Chilli pepper concentration (μg/m³) Medium High Garlic allergen concentration (μg/m³) Medium High Endotoxin concentration (EU/m³) Medium High Allergic sensitisation (Reference group not sensitised to putative allergen) Garlic (G++C+) Garlic monosensitisation (G++C−) Chilli pepper (C++G+) Wheat (W+G+C+) Any one spice dust allergen Work-related respiratory symptoms WRURS due to spice dust WRLRS due to spice dust

Baseline FeNO (>50 ppb) preshift

FeNO increase (>12%) across 8-hour shift

FeNO increase (>12%) across 24-hour period

0.22 (0.02 to 2.49) 0.91 (0.20 to 4.19)

2.12 (0.51 to 8.82) 2.35 (0.75 to 7.31)

3.77 (1.01 to 14.24) 2.27 (0.75 to 6.90)

0.23 (0.03 to 1.63) 0.72 (0.15 to 3.56)

1.50 (0.37 to 6.14) 2.11 (0.63 to 7.03)

2.57 (0.68 to 9.72) 2.08 (0.63 to 6.82)

0.51 (0.04 to 6.80) 1.31 (0.31 to 5.53)

1.64 (0.31 to 8.63) 1.89 (0.71 to 5.05)

1.05 (0.21 to 5.18) 1.21 (0.50 to 2.91)

1.49 (0.21 to 10.49) 2.63 (0.47 to 14.60)

1.01 (0.28 to 3.53) 1.51 (0.54 to 4.25)

1.92 (0.57 to 6.50) 1.93 (0.67 to 5.54)

0.66 0.53 1.05 0.27 0.57

1.20 (0.42 1.85 (0.60 0.35 (0.04 0.22 (0.03 1.02 (0.36

6.80 (1.35 0.74 (0.07 17.04 (2.30 4.84 (0.88 4.46 (1.01

to to to to to

34.20) 7.83) 126.03) 26.74) 19.70)

0.97 (0.22 to 4.29) 5.38 (1.0 to 28.94)

(0.19 (0.11 (0.18 (0.03 (0.17

to 2.27) to 2.54) to 5.95) to 2.30) to 1.93)

0.93 (0.39 to 2.22) 0.54 (0.14 to 2.04)

to to to to to

3.43) 5.69) 3.15) 1.83) 2.87)

0.93 (0.41 to 2.10) 1.74 (0.64 to 4.71)

Any one spice dust allergen: garlic, chilli and/or wheat sensitisation; logistic regression model adjusted for confounders: male gender, atopy, smoking, recent green leafy vegetable intake; allergic sensitisation: specific IgE≥0.35 kUA/L. Particulate mass concentration (mg/m³) tertiles: high>3.78; medium>1.180.090.06644.8650 ppb at baseline.3 7 Interestingly, none of the individuals with significant airflow reversibility demonstrated high FeNO (>50 ppb). These findings suggest a lack of sensitivity of the spirometry data and possible underdetection of asthma using conventional means. However, this could also point to a different occupational asthma phenotype associated with exposure to different workplace agents.5 It is possible that high endotoxin exposures, aside from allergen exposures, may also contribute to the pro-inflammatory role of airborne spice dust particulate since controlled Van der Walt A, et al. Occup Environ Med 2016;0:1–7. doi:10.1136/oemed-2015-103005

exposure to coarse as well as fine ambient particles can independently induce systemic inflammatory responses.30 In our previous cross-sectional study of supermarket bakery workers, sensitisation to cereal flour allergens was the major determinant of high FeNO,13 suggesting that FeNO can be considered a marker of persistent allergen exposure in sensitised participants.20 In this study of spice mill workers, those sensitised to chilli pepper (C++G+) among the garlic sensitised individuals were much more likely to have high FeNO>50 ppb (OR 17, CI 2.30 to 126.03). However, these wide CIs, related to small sample sizes, limit conclusive deductions about this relationship. This suggests a possible role for chilli pepper sensitisation in modifying the IgE response to garlic in an enhanced manner. This was evident by the strong association between high FeNO>50 ppb and chilli pepper sensitisation that persisted even after adjusting for atopy and other host factors. It is also notable that inhalable spice dust levels (mean=2.06 mg/m³) demonstrated much higher levels overall of chilli pepper allergen (mean=0.44 μg/m³) than garlic allergen (mean=0.24 μg/m³) as reported previously.2 Interestingly, in our study, sensitisation to chilli pepper explained a greater proportion of the variability in FeNO (r²=0.06) than to garlic allergen (r²=0.03). This study demonstrated that mean baseline preshift FeNO (GM=14.9 ppb) among these spice mill workers was very similar to the mean measurements after the shift (GM=15.4 ppb) and after the 24-hour period (GM=15.8 ppb), masking any real increase that may have occurred in individual 5


Workplace workers. Further exploration of this in multiple linear regression models did not demonstrate any statistically significant relationships. However, a more detailed logistic regression analysis demonstrated that although no significant increase in FeNO across shift was shown in relation to inhalant allergen exposures, a delayed increase in FeNO across the 24-hour period was strongly associated (OR=3.77) with spice dust particulate exposures when comparing the medium and low exposure groups. This association was, however, not evident for inhalant allergen and endotoxin exposures. The strong association of FeNO across the 24-hour period, demonstrable for spice dust particulate exposures but absent for other exposure variables, could be due to a number of reasons. These include the presence of other potential allergens such as flour and preservatives, which are essential common ingredients of most spice blends that were not formally investigated. Various studies of bakery workers, including our own, have demonstrated that exposures to flour dust are associated with increased risk of sensitisation and workrelated respiratory symptoms in a dose-dependent manner.31 Interestingly, a delayed increase across the 24-hour period was not observed between the high and low exposure groups. This may be due to the healthy worker effect in that 7% of the spice mill workers in this workforce had reported a job change due to work-related chest symptoms.2 A previous study of laboratory animal allergy also posited serial measurements of FeNO in relation to workplace exposures in identifying participants with underlying asthma.28 It is well known that similar findings have also been reported following specific bronchial challenge tests in occupational and non-occupational settings. Early and late inflammatory responses are characteristic of asthma, although the extent of these may vary in individual patients.8 Recent studies have shown that the continuous increase of FeNO in exhaled air 72 hours after allergen inhalation in grass pollen-sensitive participants is independent of the bronchial obstruction observed.32 Most occupational studies, however, obtained the last measurement of FeNO 20–24 hours after allergen challenge,23–27 while the maximum increase in FeNO occurred 48 hours after allergen challenge with Dermatophagoides pteronyssinus in atopic participants with dual asthmatic responses.10 33 The results of this study are similar to those in reports showing elevated FeNO after allergen challenges at the time of the late response,34 as has been demonstrated by the serial FeNO measurements over the 24-hour period, which was associated with a delayed increased FeNO response as a result of exposure to relatively high aerosolised general spice dust particulate. Further studies are, however, needed to confirm the possibility of delayed induced asthmatic responses (24–48 hours) through serial measurement of FeNO and other cell activation markers and cytokine profiles to characterise the inflammatory patterns following exposure to inhalable spice aeroallergens. In conclusion, this study suggests that chilli pepper sensitisation is associated with high FeNO (>50 ppb), more strongly compared with garlic sensitisation, despite a low prevalence of sensitisation to chilli pepper. Furthermore, the delayed elevation of FeNO across the 24-hour period observed for spice dust particulate merits further investigation through more detailed exposure assessment studies which include evaluating other potential allergens such as flour dust. Evaluation of other working populations at increased risk of occupational asthma can be investigated through well-designed longitudinal epidemiological studies designed beyond the clinical setting by assessing serial FeNO measurements across the working week and their value in the early detection of high molecular weight 6

sensitiser-induced occupational asthma. In this way, the utility of FeNO in routine medical surveillance can be evaluated further. Acknowledgements The authors’ gratitude goes to Alta Olckers from the UCT Lung Institute for conducting the spirometry testing on-site as well as to Dawn Venter for assisting with the collection of fractional exhaled nitric oxide measurements. The authors thank all the workers without whose willingness to participate this study would not have been possible. The Allergy Society of South Africa-Glaxo Smith Kline Research Award, the National Research Foundation and the Medical Research Council of South Africa supported the project. Contributors MFJ was responsible for the overall study design and overseeing the analysis and write-up. AVdw was responsible for overseeing the fieldwork, data analysis, preparation and submission of the manuscript. RB was primarily involved with the statistical analysis of the data including the model development and interpretation of data analysis in the writing of this article. TS supervised the laboratory analysis of the environmental samples for particulate mass, allergen as well as endotoxin concentrations. TS supervised the analysis of the serum samples for determination of allergen-specific IgE in the writing of this article. Funding National Research Foundation and the Medical Research Council of South Africa, The Allergy Society of South Africa-Glaxo Smith Kline Research Award. Competing interests None declared. Patient consent Obtained. Ethics approval Ethics approval was obtained from the Research Ethics Committee, University of Cape Town, prior to the study being conducted. Provenance and peer review Not commissioned; externally peer reviewed.

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Environmental factors associated with baseline and serial changes in fractional exhaled nitric oxide (FeNO) in spice mill workers Anita Van der Walt, Roslynn Baatjies, Tanusha Singh and Mohamed F Jeebhay Occup Environ Med published online May 20, 2016

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