Airway hyperresponsiveness (AHR) is a key feature of asthma. In certain occupational settings, such as the military, AHR to mannitol is used to assess asthma and the risk of exercise induced-bronchoconstriction (EIB). Reduced airway calibre in the form of lower normal spirometry and more significant AHR (moderate to severe AHR to mannitol) predict a slower response to ICS treatment if the goal is to abolish AHR. Therefore, assessing AHR to mannitol along with spirometry prior to treatment may be useful to help predict the speed one can benefit from using daily ICS therapy, and the likelihood to abolish AHR.

Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and is responsible for exercise-induced bronchoconstriction (EIB) (1). EIB commonly occurs in those where asthma is active and is characterised by bronchospasm following vigorous exercise. Indirect bronchial provocation tests (BPT) (e.g., exercise, eucapnic voluntary hyperpnoea, inhaled mannitol) can be performed to diagnose asthma and to identify EIB (2). Indirect BPT provokes bronchoconstriction by causing a release of inflammatory mediators from mast cells and eosinophils in the airways (2). Daily treatment with inhaled corticosteroids (ICS) decreases the number of inflammatory cells in the airway (3). AHR to mannitol can be attenuated using daily ICS treatment over 6–9 weeks of therapy (4). A reduction in the number of inflammatory cells may be reflected by attenuation of AHR, therefore AHR may be useful to monitor therapeutic response to daily ICS (5). Loss of AHR may also be a potential surrogate marker for EIB inhibition following daily treatment with ICS. The optimal goal of treatment when using indirect BPT to monitor the therapeutic response of using ICS treatment is to abolish AHR (6). This is particularly relevant for people with asthma or those with EIB who may work in occupations that involve vigorous exercise, thus EIB needs to be inhibited (7).

Strenuous physical exertion is integral in occupations such as in the military, police, and firefighters. Screening of individuals prior to recruitment into such professions using indirect BPT has been shown to be useful to identify those with AHR and at risk of EIB (8, 9). AHR may prevent optimal exercise performance, require the need for acute rescue therapy, and in very rare cases induce a fatal attack of asthma (10). Due to these risks associated with AHR, the objective identification of AHR using indirect BPT is required by both the Australian Defence Force (ADF) and the New South Wales Police Force (NSWPF). Candidates or “recruits” applying for positions in the ADF and NSWPF with a history of asthma are referred to pulmonary function laboratories (PFL) as part of a medical assessment for investigation of possible AHR using the mannitol BPT. Where significant AHR is demonstrated, ICS naïve recruits are prescribed ICS either alone or in combination with a long-acting beta-agonist (LABA). Any recruits already taking ICS have their dose of ICS either maintained or adjusted. Recruits with asthma may be accepted into the ADF and NSWPF if they can demonstrate resolution of AHR to mannitol following daily treatment with ICS. However, while AHR can be attenuated in some individuals, AHR can persist despite therapy. It is not known if there are characteristics that predict the persistence of AHR to mannitol.

We performed a retrospective analysis of occupational recruits having AHR to mannitol monitored in the presence of daily ICS. We also determined the proportions of recruits in whom AHR to mannitol was abolished and if baseline characteristics might determine persistence of AHR.

A total of 155 recruits with at least two visits over an average of 143 days [20.4 weeks] were analysed (Table 1). The majority were male [83%], in early adulthood [22 years ± 5], and were seeking employment in the ADF [72%] as opposed to applying for the NSWPF. Only one quarter [24%] were taking ICS prior to their baseline visit (Table 1). During the follow-up period, the majority were taking ICS alone [86%] with the remainder taking ICS with LABA in combination. A sub-analysis of those taking LABA in combination with ICS vs ICS alone found there were no differences in demographics or lung function characteristics between the groups and this also included no differences in AHR. However the numbers taking combination LABA/ICS (24%) were lower than those taking ICS alone (86%) (Table 1). At the baseline visit, group mean values for spirometry [FEV₁ 95% predicted ± 11] were within normal reference limits and the geometric mean (Gmean) PD₁₅ represented mild AHR [Gmean (95%CI) PD₁₅ 184 mg (159 to 212)] (Table 1).

In this population of occupational recruits with a past or current history of asthma and AHR to mannitol, AHR was abolished in the majority following approximately 4 months of daily treatment with ICS. Even in this population with overall normal lung function, small but significant improvements in spirometry were still observed. Improvements in spirometry were weakly associated with the attenuation of AHR to mannitol. In a small proportion of the study population, AHR persisted following daily ICS treatment. However, this group achieved a modest improvement in responsiveness to mannitol while still having significant AHR (PD₁₅ <635 mg) suggesting active EIB would still be present. This group with persistent AHR had more severe airway sensitivity (lower PD₁₅) and reactivity (higher RDR₁₀₀) to mannitol at baseline than those in whom AHR was abolished at follow-up. They also had significantly lower lung function at baseline; however, spirometry parameters did not improve. Further, this group was more likely to already be using ICS at the baseline assessment and had a longer follow-up duration, hence a longer treatment period. With daily ICS treatment, approximately one-third of recruits achieved no AHR (i.e., a flat dose response curve) and this airway reactivity resolved similar to what is seen in normal non-asthmatic subjects who have no AHR. Those that achieved a flat dose response curve with ICS treatment had the mildest AHR severity and most normal lung function at baseline.

Airway hyperresponsiveness to mannitol has been shown to be a useful screening tool used in occupational assessments of those at risk of asthma (8, 9). It has been demonstrated in people with mild asthma symptoms but no clinical asthma diagnosis. AHR to mannitol was 1.4 times more likely to identify AHR compared to a laboratory exercise test (19). Underreporting of asthma symptoms is common in similar occupational cohorts (8, 9). Therefore, the use of a reliable objective marker is preferable to the use of other more accessible clinical indicators of disease activity, such as symptoms and spirometry. The identification and subsequent resolution of AHR with ICS treatment enable the enlistment of persons with a history of asthma, reducing the risks of EIB during their employment.

These results, in a population being assessed for asthma or EIB as part of an occupational assessment, have replicated findings in prior clinical trials that have assessed the effectiveness of ICS on AHR to mannitol in people with confirmed asthma (4, 6, 20). Furthermore, AHR to mannitol identifies those with active asthma that can be treated effectively with low daily doses of ICS (20, 21). Thus, the ADF policy requires recruits to be treated with ICS alone at a maximum dose equivalent to 200 μg/day of beclomethasone for a 3-month trial period before reassessment (22). We were not able to identify the actual dose of daily ICS for all patients. However, as the majority of our cohort were ADF recruits and on low doses of ICS, these data support the findings of the efficacy of low daily doses of ICS that are useful to attenuate AHR to mannitol (20, 21). Overall, the group studied were determined to have clinically mild or intermittent asthma during their medical assessments carried out by occupational physicians and their spirometry was normal to near normal. However, many still had demonstrable AHR to mannitol, a feature identifying those whose asthma was currently active who would benefit from treatment with ICS. While significant improvements in spirometry were seen, these changes alone would not necessarily represent a discernible clinical benefit due to the normality of the measurements at baseline. Consistent with previous studies, we found only a weak relationship between AHR to mannitol and spirometry prior to therapy, and between changes in airway reactivity and spirometry with ICS treatment (4, 6). These findings reinforce the limitations of using spirometry to monitor ICS. It is expected that over 90% of the overall improvement in airway calibre with the commencement of ICS occurs over the first 2 weeks of treatment in people with asthma who have AHR to an indirect test (23). However, these data also highlight that if the patient is identified as having AHR by an indirect test, they have active airway inflammation, and thus further and potentially meaningful improvements in airway calibre are possible following many weeks of daily treatment, even if baseline spirometry is normal.

While AHR to mannitol is useful at predicting clinical response to ICS, a small proportion of recruits were observed to have persistent AHR despite daily ICS treatment. We expected that adherence to ICS treatment would have been high in our cohort as they were motivated by the goal of recruitment into their desired occupation. However, poor adherence may still have been a factor for some of these recruits, and we could not objectively document adherence to ICS in this clinical setting. However, we investigated variables that may predict the likelihood of slower or reduced ICS responsiveness. The data suggests that a slower improvement in AHR to mannitol in response to daily ICS is more likely if there is evidence of more significant airway obstruction before treatment assessment, and AHR to mannitol is in the moderate to severe range. These findings suggest these patients may have more active airway inflammation and possibly established airway remodelling, considering the lack of observed improvement in airway calibre. In people with asthma who are not taking regular ICS, moderate to severe AHR to mannitol (≤155 mg) is associated with significant sputum eosinophilia (median 8%), compared to the absence of sputum eosinophils (median <2%) in those with mild AHR (>155 mg) (2, 17, 24). These findings suggests that those with moderate to severe AHR to mannitol have a greater inflammatory contribution to their airway pathology. This increased inflammation may contribute to the slow initial response to daily treatment with ICS observed in the recruits with more severe AHR.

The number of recruits with AHR (PD₁₅) persisting in this group was small relative to those in whom AHR was abolished. These individuals may be less steroid responsive, as they had a longer treatment period and may potentially need more time on ICS to inhibit their AHR more effectively (6). However, compared to those in whom AHR was abolished, a larger proportion of those where AHR persisted were already taking ICS at the baseline visit, supporting the suggestion of a more established or more active disease. Considering this, they were also a group with a higher proportion with an abnormal FEF_25−75% and FEV₁/FVC at baseline. This may indicate the presence of a more fixed component of airway obstruction where it was also observed there was no improvement in spirometry, compared to those in whom AHR was abolished.

While most recruits abolished AHR to mannitol (noPD₁₅), approximately one-third (32%) of the recruits still had a PD₁₀ on follow-up. A PD₁₀ has been found to be associated with the presence of EIB (14). Therefore, recruits with a PD₁₀ alone following ICS may still be at risk of EIB, though it is likely to be mild. To further reduce the risk of EIB, resolving the PD₁₀ to mannitol through extending the monitoring period may be desirable and achievable in occupational recruits. Flattening the dose response curve and suppressing airway reactivity (i.e., RDR₁₀₀ <1) to a level of responsiveness seen in people without asthma was achieved in over a third (36%) of recruits (16). Demonstrating no AHR to mannitol is achievable with daily ICS treatment and maybe a more desirable goal of treatment, as the risk of EIB while performing occupational duties would be greatly reduced (25).

We performed a logistic regression model that predicted the liklihood of the persistence of AHR in this predominately young adult male population. For spirometry variables, lower measurements for FEV₁ and FEV₁/FVC increased the likelihood of AHR persisting. Greater airway reactivity (higher RDR₁₀₀) also increased the likelihood of AHR persisting. However, in the final multivariate model, a lower FEF_25−75% reduced the likelihood of AHR persisting. Importantly, the probability of this model predicting response would likely change depending on the pre-test probability of the population to be tested. This model should be investigated further to determine if it can be validated and extrapolated to other populations, such as those with active asthma. Such a predictive capacity may assist with choosing different treatment regimens to increase the success of resolving AHR in recruits.

The main limitation of this study is that the data were collected retrospectively. Retrospective studies can introduce bias and while like other uncontrolled studies investigating ICS on AHR to indirect stimuli (4, 6, 20, 21, 25) this remains a limitation. In addition, adherence to ICS was not monitored objectively and future studies could include more objective markers of daily ICS adherence using electronic adherence monitors. Furthermore we were not able to collect additional clinical information in these recruits such as asthma symptoms, asthma control, allergic status, disease duration or prior therapy. This would be important to obtain while considering that recruits may not be willing to fully admit symptom burden due to the desire to enter a chosen occupation (8, 9). However, this is a real-world study that has produced similar findings to previous clinical trials, validating findings in a large clinical population showing that AHR to mannitol can be attenuated and abolished with daily ICS treatment (4, 6, 21). Further studies are needed to investigate if routine monitoring of ICS using AHR to mannitol is useful to achieve sustained clinical benefits in asthma symptom control. Further, it would be useful to establish if the resolution of AHR to mannitol represents the attenuation of asthma pathophysiology. While the resolution of AHR to mannitol increases the likelihood of resolution of EIB, future studies may be useful to confirm this likelihood.

Airway hyperresponsiveness to mannitol can be abolished with 20 weeks of daily treatment with ICS, in recruits who are seeking employment in careers that require strenuous physical exertion. This was achieved in the majority with low daily doses of ICS alone without LABA. Reduced pre-treatment spirometry variables and increased airway reactivity to mannitol predict the likelihood of an incomplete or slower response to daily ICS. Assessing AHR to mannitol with daily ICS may provide a useful objective marker to identify clinically meaningful attenuation of airway inflammation.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Western Sydney and Sydney Local Health District Human Research Ethics Committees. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

CL contributed to trial design, data collection, preparation and analysis, manuscript preparation, and review. KW contributed to trial design, oversight of analysis, manuscript preparation, and review. CP contributed to data collection and manuscript review. HK contributed to trial design and manuscript review. JB contributed by supervising all aspects of the research, including the study concept and trial design, oversight of analysis, and manuscript preparation and review. All authors contributed to the article and approved the submitted version.

JB receives a 10% share of royalties for the sale of Aridol after distribution to Royal Prince Alfred Hospital in countries outside Australia and owns shares in Pharmaxis Ltd. CP owns shares in Pharmaxis Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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