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Abstract
Background Occupational exposure to irritants is associated with poor asthma control, but the long-term clinical characteristics of irritant-induced occupational asthma (IIA) are poorly known.
Objective To evaluate whether any distinguishable features contribute to IIA patients’ poor outcomes and whether clinical characteristics change over time.
Methods We re-evaluated 28 IIA patients with a median of 6.8 years (IQR 4.6–11.1) after their diagnosis at the Finnish Institute of Occupational Health in 2004–2018. We measured their lung function, non-specific bronchial hyper-responsiveness, inflammation profile and exercise capacity using an ergometric bicycle test. The participants also underwent an Asthma Control Test (ACT) and responded to questionnaires assessing their laryngeal hypersensitivity (LHQ) and dysfunctional breathing (Nijmegen Questionnaires, NQ).
Results At follow-up, 22 (79%) participants used inhaled corticosteroids, 4 (14%) had asthma exacerbation within 1 year, 11 (39%) had ACT<20 (ie, poor asthma symptom control), 7 (26%) had abnormal spirometry and 8 (36%) had a positive methacholine challenge test result. 17 (61%) participants showed at least one elevated eosinophilic inflammation marker. Six (23%) had an abnormal LHQ score and 7 (26%) had an abnormal NQ score. 15 (58%) participants showed reduced physical capacity that was related to extensive asthma medication, poor asthma symptom control and acute IIA phenotype. A higher ACT score was the only significant change between diagnosis and follow-up (p=0.014).
Conclusion Most of the IIA patients had normal lung function at follow-up, which had only changed a little over time. Reduced physical capacity was a common finding and appears to be related to poor asthma symptom control.
- Asthma
- Occupational Health
- Allergy and Immunology
Data availability statement
No data are available. The data are archived in the repository of Finnish Institute of Occupational Health, however, the data are publicly unavailable due to ethical reasons.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Occupational exposure to irritants can cause irritant-induced asthma (IIA). IIA patients frequently have poor asthma symptom control, but the long-term clinical characteristics of IIA are poorly known.
WHAT THIS STUDY ADDS
In this study, spirometry showed that only a minority of IIA patients had airway obstruction when they used regular asthma medication. However, many of them showed poor exercise capacity.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Clinicians should consider other treatments besides regular asthma medication for IIA patients. These patients might benefit from physical rehabilitation.
Introduction
Irritant-induced occupational asthma (IIA) refers to asthma that is considered to develop via irritant mechanism.1 2 The European Academy of Allergy and Clinical Immunology’s position paper proposes that acute and subacute IIA cases can show sufficient evidence of a causal relationship between occupational exposure and asthma.1 According to surveillance data, acute IIA represents 4%–15% of new occupational asthma cases.3–5 However, IIA has remained poorly understood; only one study has clinically evaluated the long-term outcome of acute IIA.6
Previously, we have observed that IIA patients show poorer asthma outcomes at diagnosis than those whose occupational asthma has developed via immunological mechanisms.7 A follow-up questionnaire revealed that four-fifths of the IIA patients whose asthma was uncontrolled 6 months after diagnosis still had poor asthma control.8 Therefore, the current study aimed to assess whether any distinguishable features contribute to IIA patients’ poor asthma symptom control and whether their clinical characteristics had changed after the diagnosis.
Methods
We identified 69 patients who were diagnosed with acute or subacute IIA at the Finnish Institute of Occupational Health (FIOH) in 2004–2018.7 The diagnostic criteria were (1) no evidence of active asthma in adulthood before the exposure; (2) exposure to a high concentration of an airborne irritant; (3) occurrence of asthma symptoms in a close temporal relationship with the exposure; (4) asthma verification by reversible obstruction or non-specific bronchial hyper-responsiveness; (5) persistence of symptoms for ≥3 months and (6) no other pulmonary disorder that explained the symptoms. We classified 30 patients with only one high-level exposure event within 24 hours as acute IIA and 39 patients with repeated exposure to high levels of irritants during a period of more than 24 hours as subacute IIA.7
28 (41%) of the 69 identified IIA patients were willing to participate and gave their written, informed consent to a follow-up evaluation at FIOH between May 2021 and August 2022. The participants had shorter duration of asthma symptoms before baseline and time since the first exposure to follow-up than the non-participants (online supplemental table 1). The latter group also had a tendency for higher doses of asthma medication and IgE level than the former. Otherwise, the groups seemed comparable.
Supplemental material
Spirometry, non-specific bronchial hyper-reactivity (NSBH), fractional exhaled nitric oxide (FeNO), blood eosinophilia (B-Eos) were measured and the Asthma Control Test (ACT) was performed at both the time of diagnosis (baseline) and follow-up. At follow-up, the participants also underwent a high-sensitivity C reactive protein test (S-hs-CRP) and induced sputum and completed the Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ) and the Nijmegen questionnaires (NQ), which screen for laryngeal hypersensitivity and dysfunctional breathing, respectively.
At follow-up, 26 (93%) participants underwent a bicycle ergometric test. We measured the predicted mean workload attained during the last 4 min of the test (Wmax4%), and a Wmax4% of ≥80% is generally considered normal exercise capacity.9 10 The detailed methodology is presented in online supplemental material.
Results
The participants’ median interval from baseline was 6.8 years (IQR 4.6–11.1). 18 participants had been working at baseline, and we could not rule out continued exposure to the causal agent for 6 of them. These figures were 17 and 1 at follow-up, respectively. The causative agents were mixtures (seven cases), acid aerosols or fumes (six cases), base aerosols or fumes (four cases), dusts (three cases), endotoxins (three cases), a mixture of acid and base aerosols or fumes (two cases), inorganic gases (one case), oxidising agents (one case) and other chemicals (one case).
Table 1 displays the participants’ clinical characteristics at baseline and follow-up. The majority (93%) were male, and 11 (39%) had acute IIA. At follow-up, 13 (46%) had ≥2 comorbidities, and 12 (43%) had a body mass index (BMI) of ≥30 kg/m2. 11 (39%) had a smoking history of ≥10 pack-years—1 more than at baseline. 12 (43%) participants used high-dose inhaled corticosteroids, 18 (64%) were on GINA 4–5 step asthma medication, 4 (15%) had 1 exacerbation and none had a hospital stay during the previous year. Seven (25%) needed a daily short-acting beta-agonist, and 11 (39%) obtained an ACT score of ≤19. Six (22%) participants had a forced expiratory volume in 1 s (FEV1%) of <80% and three (11%) an FEV1/forced vital capacity (FVC) of <0.70, whereas eight (36%) showed hyper-reactivity in the methacholine challenge test.
Characteristics of participants at time of diagnosis (baseline) and at follow-up
Seven (25%) participants had a FeNO of ≥25 ppb and 10 (36%) a B-Eos of ≥300 µg/L. 19 had analysable induced sputum sample, and 8 (42%) had ≥2% eosinophils. Overall, 17 (61%) participants had at least one elevated eosinophilic inflammation marker. Six (32%) had ≥61% sputum neutrophils, and seven (25%) had S-hs-CRP of ≥3 mg/L indicating systemic inflammation. Six (23%) obtained an abnormal score in the LHQ and seven (26%) in the NQ. Both questionnaires were abnormal for five (20%) participants.
15 (58%) participants had reduced exercise capacity in the bicycle ergometric test. These had acute IIA (60% vs 9%, p=0.014), were on GINA 4–5 step asthma medication (80% vs 36%, p=0.043) and their LHQ and NQ scores were abnormal (43% vs 0, p=0.024; and 43% vs 0, p=0.020, respectively) more often than those with a normal outcome (online supplemental table 2). Wmax4% correlated positively with ACT (Spearman correlation (rs)=0.476, p=0.014) and negatively with B-Eos and S-hs-CRP (rs=−0.422, p=0.032; rs=−0.412, p=0.036, respectively). ACT correlated negatively with BMI and S-hs-CRP (rs=−0.444, p=0.018; rs=−0.717, p<0.001, respectively) and positively with LHQ (rs=0.512, p=0.007).
A higher ACT score at follow-up was the only significant difference from baseline (p=0.014); however, only 17 (61%) participants had completed this questionnaire at baseline.
Discussion
We examined 28 IIA patients with a median of 11 years after their exposure to respiratory irritants. We observed that most of them had good lung function when they used regular asthma medication. On the other hand, poor exercise capacity was a common finding and was related to a poor ACT score and frequent use of GINA 4–5 step asthma medication. Our findings also suggested that comorbid conditions, such as laryngeal hypersensitivity, might have contributed to some of the participants’ poor outcomes. Acute IIA patients showed poorer exercise capacity than those with subacute IIA. Otherwise, their results were similar.
Our participants’ lung functions had remained stable over time: Only a minority had an obstruction in spirometry at baseline or at follow-up. In their study, Malo et al 6 evaluated 35 patients with acute IIA a mean of 13.6 years after exposure and reported that 54% had an FEV1 of <80%, 34% had an FEV1/FVC of <0.70 and 74% showed hyper-reactivity in NSBH. In our study, these proportions were 18%, 18% and 38% for the acute IIA patients, respectively. Fewer of Malo’s participants used inhaled corticosteroids at follow-up (34% vs 82%), and they were more frequently smokers than our participants which might explain some of the differences.6 We are not aware of any other studies that have evaluated the long-term outcome of subacute IIA.
Our findings suggest that IIA patients’ inflammation profile contributes to their outcome: 17 (61%) of our participants had at least one elevated eosinophilic inflammation marker, and those with reduced physical capacity frequently had a high blood or sputum eosinophil count. Similarly, both poor physical capacity and poor asthma symptom control were connected to the level of S-hs-CRP. However, other factors likely play a greater part, and we lacked data on induced sputum and CRP levels at baseline; therefore, these results need to be interpreted with caution.
Regarding laryngeal hypersensitivity and dysfunctional breathing, one-fifth of this study’s participants obtained an abnormal LHQ and NQ score, and all of them had reduced physical capacity. ACT scores showed a positive correlation with LHQ, and at least two of our participants expressed strong laryngeal symptoms during the exercise test. These results imply that laryngeal hypersensitivity probably contribute to IIA patients’ poor outcomes. However, the diagnostic accuracy of these questionnaires is uncertain among asthmatics.11 12
Our study had several limitations. We had no reference group, and our sample size was modest, meaning that we were unable to perform a multivariate analysis. We cannot rule out our selection bias because there were also some differences in baseline characteristics between the participants and the non-participants. Laryngeal hypersensitivity and dysfunctional breathing were assessed using questionnaires instead of a clinical approach. We were unable to evaluate breathing patterns or gas exchange during the bicycle ergometry, and other factors, such as obesity and smoking, might have contributed to the outcome. Finally, for safety reasons, those who had the poorest outcomes did not undergo the NSBH or sputum induction, which might have led to underestimated hyper-reactivity and affected sputum cell counts. Nevertheless, we consider our findings noteworthy as very little available literature on the prognosis of IIA is available.
In conclusion, our results suggest that, despite poor asthma symptom control, many acute and subacute IIA patients tend to have good lung function but poor exercise capacity several years after exposure to irritants. These findings imply that IIA patients could benefit from other treatments besides regular asthma medication. Pulmonary rehabilitation, for instance, might increase their physical activity and capacity. Clinicians should also consider laryngeal hypersensitivity and dysfunctional breathing in this patient group.
Data availability statement
No data are available. The data are archived in the repository of Finnish Institute of Occupational Health, however, the data are publicly unavailable due to ethical reasons.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and the Ethics committee of the Helsinki University Central Hospital approved this study (approval number HUS of 611/2020). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors would like to thank Research Nurse Elina Hällström and the personnel of the Finnish Institute of Occupational Health for their help in the re-evaluation visit.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors JL had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. JL, HS, HJ and IL contributed substantially to the study design, data collection, analysis and interpretation, and the writing of the manuscript.
Funding This project is funded by the Finnish Work Environment Fund, grant number 190390, and the Finnish Institute of Occupational Health. JL is supported by the Research Foundation of the Pulmonary Diseases and the Foundation of the Finnish Anti-Tuberculosis Association, and by a grant from the University of Helsinki donated by Finance Finland, Finnish Workers’ Compensation Center, and the FinnishMotor Insurers’ Centre.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.