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. 2025 Aug 21;12(1):2546677. doi: 10.1080/20018525.2025.2546677

Airway hyperresponsiveness to mannitol in relation to inspiratory and expiratory resistance in subjects with asthma, COPD, and healthy smokers

Abir Nasr a, Georgia Papapostolou a, Linnea Jarenbäck a, Kerstin Romberg b, Alf Tunsäter a, Jaro Ankerst a, Leif Bjermer a, Ellen Tufvesson a,✉
PMCID: PMC12372479  PMID: 40860456

ABSTRACT

Background

Airway hyperresponsiveness (AHR), a key feature of asthma, leads to airway narrowing in response to bronchoconstrictor stimuli. Notably, AHR is also observed in individuals with chronic obstructive pulmonary disease (COPD). The Mannitol challenge test is an indirect method to assess airway hyperresponsiveness.

Objective

The primary aim of this study was to explore airway hyperresponsiveness to mannitol in subjects with asthma and COPD regarding inspiratory and expiratory resistance and reactance. A secondary aim was to investigate fractional exhaled nitric oxide (FeNO), blood eosinophils, allergen sensitization, and symptom scores concerning airway hyperresponsiveness to mannitol.

Methods

The Mannitol challenge test was conducted on 292 subjects: 238 with asthma, 25 with COPD, 14 healthy smokers, and 15 healthy never-smokers. The response was assessed using both spirometry and respiratory oscillometry, with inspiratory and expiratory resistance and reactance measured separately.

Results

A positive mannitol test was confirmed in 84 (35%) subjects with asthma, 13 (52%) with COPD, and 7 (50%) of healthy smokers. Subjects with asthma who had a positive mannitol test had a higher inspiratory R5 and R19 at baseline, and also greater change in both inspiratory and expiratory R5, R5-R19, and X5 (but not R19), compared to asthma subjects with a negative test. A similar tendency was seen among subjects with COPD and healthy smokers. Subjects with asthma with a positive mannitol test had more symptoms than subjects with a negative test (median 21 versus 22; p = 0.036).

Conclusion

Inspiratory resistance, as measured by respiratory oscillometry, was shown to predict hyperresponsiveness to mannitol in asthma patients. Furthermore, respiratory oscillometry revealed a significant increase in resistance, primarily in the peripheral airways, following a mannitol challenge in these subjects. Integrating resistance and reactance measurements, along with traditional spirometry may offer a more comprehensive understanding of the hyperreactive airway response.

KEYWORDS: Airway hyperresponsiveness, mannitol, respiratory oscillometry, resistance, asthma, COPD, smoker

Background

Airway hyperresponsiveness (AHR) is an abnormal increase in airflow limitation following exposure to a broncho-constrictive stimuli. AHR is a key feature of asthma but occurs also in specific phenotypes of chronic obstructive pulmonary disease (COPD). Detection of the presence of AHR can be assessed using direct triggers, such as methacholine and histamine, or by indirect methods using mannitol or exercise [1–5]. The direct challenge tests use methacholine or histamine which act directly on the airway smooth muscle. In contrast, indirect challenge tests trigger airway narrowing by acting on inflammatory cells, epithelial cells, and nerves, which upon stimulation release mediators or cytokines that provoke smooth muscle contraction. Inhalation of mannitol causes dehydration and an increased osmolarity of the airway surface in a way that mimics the effect of exercise [6–8]. Regardless, these tests may have less sensitivity than direct tests for the detection of asthma, but they tend to have a higher specificity for asthma and revealing airway inflammatory pathology [9]. Assessment of AHR using indirect tests is valuable as a diagnostic tool to understand the underlying pathophysiology of asthma phenotypes by reflecting the ongoing airway inflammation. Therefore, these tests are suggested to be more specific to detect active inflammation due to asthma [10].

Bronchial hyperreactivity to mannitol has been shown to be associated with increased involvement of the peripheral airways [11,12], and measurement of impairment in small airways physiology is therefore crucial when assessing AHR to mannitol. The response to bronchial provocation is most recognised by a drop in forced expiratory volume in 1 s (FEV1). Though, FEV1 primarily reflects resistance in the large airways, there is a need to find other methods that may provide additional information of the obstructive pattern in the peripheral airways as well [13]. Respiratory oscillometry, known as forced oscillometry technique (FOT), is a simple manoeuvre conducted during tidal breathing. The procedure does not require active cooperation of the patient, it is non-invasive, rapid, easy to perform, and does not involve forced manoeuvres that could influence the bronchial tone. During forced oscillometry, pressure waves with different frequencies are superimposed on tidal breathing. Signals at low frequencies reflect the resistance and reactance of the total lung, while signals at high frequencies reflect the central airways. The parameters are generally reported as an average over the entire breathing cycle, or as an average over the inhalation or the exhalation phase of the breathing cycle, separately [14,15]. Respiratory oscillometry is also proposed as an alternative method for measuring changes in airway resistance, thus providing sensitive indices for assessing airflow obstruction, bronchodilator responsiveness, and AHR in patients with asthma and COPD [12].

The aim of this study was to explore AHR to mannitol in asthma and COPD in respect to inspiratory versus expiratory resistance and reactance. A secondary aim was to investigate inflammation markers, such as fractional exhaled nitric oxide (FeNO), blood eosinophils, allergen sensitization, and symptom scores in relationship to AHR to mannitol.

Method

The individuals were recruited within a larger study [16]. All subjects with FEV1 > 70% of predicted normal were asked to participate in the mannitol challenge test. In total, 293 subjects (239 with asthma, 25 with mild COPD, 14 healthy smokers, and 15 healthy never-smokers) accepted and performed a mannitol challenge test. Healthy smokers were defined as current or former-smokers with a smoking burden of >5 pack-years, with preserved spirometry and without self-reported respiratory symptoms. Asthma and COPD were diagnosed by a physician according to the Global Initiative for Asthma (GINA) [17] or Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [18], respectively. Healthy subjects were matched with patients with asthma and served as their control group, while healthy smokers were matched with individuals with COPD and served as their control group. Subject characteristics are presented in Table S1. Prior to the mannitol challenge test, subjects were instructed to withhold their short-acting beta2-agonist (SABA) for at least 6 h, inhaled corticosteroid (ICS) and long-acting β2agonists (LABAs) for 12 h, theophylline and leukotriene-antagonist for 24 h, antihistamines for 72 h and smoking for 4 h before the visit. No subjects have had any airway infection during the last 8 weeks prior to the trial.

Fractional exhaled nitric oxide (FeNO) and spirometry were measured prior to the mannitol challenge. To perform FeNO measurement, subjects inhaled NO depleted air and exhaled at a rate of 50 ml/s in a nitric oxide analyzer Medisoft FENO+ (Sorinnes, Belgium) or CLD 88 sp (ECO Medics AG, Switzerland, used for 10 participants). Spirometry was performed according to the European Respiratory Society/American Thoracic Society guidelines [19] using a spirometer from Medisoft (Sorinnes, Belgium). Blood samples were collected for analysis of eosinophil count and atopic sensitization (using Phadiatop).

Questionnaires

All subjects were asked to evaluate their daily symptoms using questionnaires. Subjects with asthma completed the asthma control test (ACT) [20], the asthma control questionnaire (ACQ) [21] and mini Asthma Quality of Life Questionnaire (mini AQLQ) [22]. Subjects with COPD and healthy smokers completed the Medical Research Council Questionnaire (MRC) [23], the Clinical COPD Questionnaire (CCQ) [24], and the COPD Assessment Test (CAT) [25]

Mannitol challenge test

A Mannitol powder kit was used (Aridol®; Pharmaxis, Frenchs Forest, Australia) according to manufacturer’s instructions. Up to eight incremental steps of mannitol were administered to a maximal cumulative dose of 635 mg with a maximum of 2 min between each dose. Subjects were asked to exhale completely before taking a deep inspiration and hold their breathes for 5 sec before breathing out.

FEV1 was measured three times before the challenge, and the highest value was selected as baseline value. Thereafter, FEV1 was measured between each mannitol dose. A positive response to mannitol was defined as a decrease in FEV1 of 15% compared to baseline values or if FEV1 decreased more than 10% between consecutive doses. Thereafter, no more doses of mannitol were given, and the test was considered completed. Directly following the bronchial challenge with mannitol, subjects inhaled 800 mg of salbutamol. FEV1 was measured 15 min after the administration of bronchodilator to secure the recovering of the subjects.

Respiratory oscillometry

Respiratory oscillometry was performed using Resmon Pro Full (Restech srl, Milan, Italy) before the test and directly after the FEV1 manoeuvre after the last dose of mannitol. Subjects wore a nose clip and pressed their palms against the cheeks to avoid upper airway shunting and the test was completed when 10 valid breathes were registered. The variables used in this study were the absolute values of inspiratory and expiratory resistance at 5 Hz (R5) as a measure of resistance of the total respiratory system, at 19 Hz (R19) reflecting the central airways, R5-R19 representing the peripheral airways, and 5 Hz (X5) as a measure of airway reactance. FOT indices used for analyses were also specifically inspiratory and expiratory resistance at 5 Hz (R5insp and R5exp), at 19 Hz (R19insp and R19exp), the difference between R5 and R19 (R5-R19insp and R5-R19exp) and inspiratory and expiratory reactance at 5 Hz (X5insp and X5exp).

Ethics

All subjects gave written informed consent prior to inclusion in the study, and the study was approved by the Regional Ethical Review Board in Lund, Sweden (2016/1069) in accordance with the Declaration of Helsinki.

Statistical analysis

Most variables were not normally distributed; therefore, non-parametric tests were used. Data are presented as medians (interquartile ranges). Baseline values, the absolute change, and the relative change as percent of baseline were used in the analysis of FOT-measurements and spirometry. The absolute change of the variables was calculated by subtracting the value at baseline from the value after the last dose (post values minus pre values), and the relative change were calculated using the absolute change divided by the baseline value. GraphPad Prism version 10.2.2 was used for statistical analyses. Mann–Whitney U-test was used for comparisons between two groups (negative versus positive mannitol test). The Kruskal–Wallis test was used for comparisons among the different subject groups, with a post hoc test based on Dunn’s multiple comparisons test to compare the separate groups. Chi2-test was used to analyse categorical variables. Correlation analyses were performed using the Spearman correlation test. A p-value <0.05 (two tailed) was considered significant.

Results

Airway hyperresponsiveness to mannitol

A total of 84 (35%) subjects with asthma, 13 (52%) with COPD, and 7 (50%) of healthy smokers had a positive response to mannitol challenge test, Table S1. There were no differences in age, sex, height, and eosinophil count between subjects with a positive versus negative mannitol test within any of the groups, and neither were there any differences in proportion of subjects on ICS. In subjects with COPD, those with a positive mannitol test had lower FEV1 as % of predicted, but this was not seen in absolute values of FEV1 or in any of the other groups.

Airway resistance and reactance in response to mannitol in subjects with asthma

Baseline measurements showed that subjects with asthma with a positive response to the mannitol challenge test had an increased inspiratory resistance at 5 Hz and 19 Hz; R5insp (p = 0.027) and R19insp (p = 0.036), see Figure 1, compared to those with a negative response.

Figure 1.

Figure 1.

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Inspiratory (Insp) and expiratory (Exp) baseline measurements of R5, R19, R5-R19, and X5, in subjects with asthma with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses were performed using Mann–Whitney U-test and * = p < 0.05.

A larger absolute increase in inspiratory and expiratory total (R5) and peripheral (R5-R19) resistance was shown from baseline to the last dose measurements; ΔR5insp (p = 0.014), ΔR5exp (p = 0.0024), ΔR5-R19insp (p = 0.036) and ΔR5-R19exp (p = 0.017) in subjects with a positive mannitol test compared with subjects with a negative mannitol test, see Figure 2. Moreover, the change in reactance from baseline to after last dose was larger (resulting in more negative values) in subjects with a positive mannitol test compared to negative; X5insp (p = 0.0049) and X5exp (p = 0.0032). Similar results were shown in relative change of total resistance and reactance: R5insp (p = 0.024), R5exp (p = 0.0048), X5insp (p = 0.023), and X5exp (p = 0.014), see figure S1.

Figure 2.

Figure 2.

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Inspiratory (Insp) and expiratory (Exp) FOT-indices, R5, R19, and X5, presented as the absolute change from baseline to last dose of mannitol in subjects with asthma with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses were performed using Mann–Whitney U-test and * = p < 0.05 and ** = p < 0.01.

Airway resistance and reactance in response to mannitol in subjects with COPD

Subjects with COPD with positive response to the mannitol challenge test had a tendency of higher resistance and more negative reactance compared to those with negative response at baseline, although the differences were not statically significant, see Figure 3.

Figure 3.

Figure 3.

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Inspiratory (Insp) and expiratory (Exp) baseline measurements of R5, R19, R5-R19, and X5, in subjects with COPD with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses were performed using Mann–Whitney U-test.

The absolute change from baseline to last dose demonstrated no significant differences between subjects with a positive response and those who had a negative mannitol test, see Figure 4. On the other hand, when investigating the relative change, there was a larger difference in X5 in subjects with a positive compared to negative mannitol test, but not statistically significant, see figure S2.

Figure 4.

Figure 4.

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Inspiratory (Insp) and expiratory (Exp) FOT-indices, R5, R19, R5-R19, and X5, presented as the absolute change from baseline to last dose of mannitol in subjects with COPD with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses were performed using Mann–Whitney U-test.

Airway resistance and reactance in response to mannitol in healthy and healthy smokers

No difference in resistance or reactance at baseline was found between healthy smokers with negative versus positive response to mannitol, see Figure 5. Neither were there any statistically significant differences in response to mannitol, neither as absolute change, see Figure 6, nor as relative change, see figure S3, between healthy smokers with negative versus positive response to mannitol. However, healthy smokers with negative response had increased expiratory R5 expiratory R5-R19 at baseline compared to healthy never-smokers (p = 0.049; p = 0.011 respectively) see Figure 5.

Figure 5.

Figure 5.

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Inspiratory (Insp) and expiratory (Exp) baseline measurements of R5, R19, R5-R19, and X5, in healthy never-smokers and healthy smokers with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses between healthy never-smokers and smokers with a negative mannitol test, as well as between healthy smokers with a negative versus positive test, were performed using Mann–Whitney U-test and * = p < 0.05.

Figure 6.

Figure 6.

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Inspiratory (Insp) and expiratory (Exp) FOT-indices, R5, R19, R5-R19, and X5, presented as the absolute change from baseline to last dose of mannitol in healthy never-smokers and healthy smokers with a negative (neg) versus positive (pos) response to mannitol challenge test. Statistical analyses between healthy never-smokers and smokers with a negative mannitol test, as well as between healthy smokers with a negative versus positive test, were performed using Mann–Whitney U-test and * = p < 0.05.

Correlations between FEV1 and respiratory oscillometry variables

Initially, correlations between baseline values of FEV1 and respiratory oscillometry variables were investigated to analyze the baseline status of the airways (Table S2). In subjects with asthma, both with or without a positive response to the mannitol challenge test, there were negative correlations between baseline measurements of FEV1 and airway resistance (R5 and R19) and reactance (X5), in both inspiratory and expiratory values, Table S2.

In subjects with COPD, both with or without a positive response to the mannitol challenge test, there were similar negative correlations between baseline measurements of FEV1 and airway resistance (R5 and R5-R19) and reactance (X5), but more pronounced among subjects with a positive compared to negative response, and in expiratory compared to inspiratory values.

Additionally, we did not find any corelations between FEV1% of predicted at baseline and any of the % of predicted values for R5, R19, or X5 at baseline in any of the group (data not shown).

To investigate the effect in the airways as response to mannitol, the absolute change from baseline to last dose was analysed as correlation between change in FEV1 (ΔFEV1) and change in respiratory oscillometry variables (Table S3). No overall correlation patterns could be seen between ΔFEV1 and change in respiratory oscillometry variables, more than for ΔR5insp and ΔR19insp in asthma subjects with a positive mannitol test and to ΔR5exp in those with a negative mannitol test.

To minimize the impact of the differences in lung volumes, correlations between the relative change in % from baseline to last dose in FEV1 (Δ%FEV1) and the relative change in % of the respiratory oscillometry variables (Table S2) was also analysed. In the asthma groups there were no correlations between Δ%FEV1 and relative changes in respiratory oscillometry variables. However, in subjects with COPD with a negative mannitol test, there was a correlation between Δ%FEV1 and the relative change in inspiratory X5 (Δ%X5insp), Table S2. Weak correlations were also observed in the healthy smokers between Δ%FEV1 and Δ%R5exp Δ%R19exp.

Symptoms and quality of life

Asthmatic subjects with a positive response presented with more asthma symptoms by ACT (p = 0.036) compared with asthmatic subjects with negative response, and also a tendency in both ACQ (p = 0.062) and mini AQLQ (p = 0.10), see figure S4. In a sub-analysis, the subjects were divided into those who responded to a lower dose of mannitol, (a dose below median) compared to subjects who responded to a higher dose of mannitol (above median), but there was no difference in symptoms between the groups.

Subjects with COPD and healthy smokers did not exhibit any significant differences in the symptom scores reported through CCQ, CAT, and MRC between those with a positive versus negative response to the mannitol challenge test, see figure S4. Neither were there any differences when investigating the scores from only the questions regarding lung-specific symptoms, such as coughing, phlegm production, and shortness of breath during physical activities.

FeNO

A comparison among the different groups showed that subjects with asthma had higher levels of FeNO compared to both COPD-subjects (p = 0.046) and healthy smokers (p = 0.0023), see figure S5A.

Subjects with asthma with a positive mannitol test showed a tendency of having an elevated level of FeNO compared with individuals with a negative mannitol test (p = 0.10). No similar differences were found in subjects with COPD or in healthy smokers, see figure S5B.

Blood eosinophils and allergic sensitisation

Subjects with COPD had higher levels of blood eosinophils compared with healthy subjects who have never smoked (p = 0.037) and a tendency for a higher level of eosinophils compared with healthy smokers (p = 0.053), see figure S5C. Similarly, subjects with asthma showed a tendency to have an increased level of blood eosinophils compared with healthy subjects (p = 0.095).

The level of blood eosinophils did not differ between subjects with a positive mannitol test compared with subjects with a negative mannitol test within all groups, see figure S5D.

Among subjects with asthma, 54 (64%) individuals with a positive mannitol test and 94 (61%) individuals with a negative mannitol test had positive sensitization to airborne allergens.

Discussion

Mannitol challenge test is an indirect bronchial provocation test used to define ongoing inflammation in the airways. In the present study, a positive mannitol test was confirmed in 35% of subjects with asthma, and about half of the subjects with COPD and healthy smokers. Respiratory oscillometry showed that subjects with asthma who had a positive mannitol test had a higher inspiratory total (R5) and central (R19) airway resistance already at baseline compared to those who did not have a positive response. Similar trends were seen in subjects with COPD. In addition, subjects with asthma who had a positive mannitol test also had more change in both inspiratory and expiratory resistance in the total and peripheral airways, but not in the central airways, in response to mannitol.

Difficulties to breath in properly is a cardinal phenomenon in asthma, and we have previously presented an increased inspiratory resistance in asthma compared to healthy subjects [26]. It has also been shown that inspiratory resistance was higher than expiratory resistance in subjects with severe bronchoconstriction in response to methacholine [27]. In the present study, we show that already at baseline, subjects that will turn out to have a positive mannitol test have a higher inspiratory resistance, which is in line with previous findings in our group [11]. This is an important finding, since the clinically significant disadvantage of an impaired inspiratory resistance is the reduced drug delivery of inhalation medications [28].

The increased airway resistance, as an effect of the bronchoconstriction following the mannitol challenge test, was found to be primarily located in the peripheral parts of the lung in asthmatic subjects. An increase in total and peripheral airway resistance was seen together with a more affected airway reactance reflecting the peripheral airways, but not in central airways. Mannitol deposition reaches the peripheral airways [29] and, therefore, possibly mimic exercise induced asthma [30] that is known to involve the peripheral airways.

Subjects with asthma with a positive mannitol test reported more symptoms compared with individuals with a negative test. This suggests that individuals with more symptoms, and thereby less controlled disease, also have more AHR and additionally have a higher airway resistance at baseline. The self-reported symptoms in subjects with COPD and healthy smokers did not reflect the tendency for having AHR. This might be due to the selection bias of subjects with COPD since only subjects with a mild grade of airway obstruction (FEV1 > 70% of predicted) were included to perform a mannitol test in the current study.

FeNO was elevated in subjects with asthma compared to COPD and healthy smokers, which was expected [31]. There was, however, no difference in subjects with a positive compared to negative response to the mannitol test. This contrasts with a previous study showing an association between mannitol responsiveness and FeNO, but in a setting of patients not being treated with ICS [32]. FeNO levels are known to be lowered by ICS [7,33], and since many of the subjects in the present study were on ICS, this may be the cause of overall relatively low FeNO levels, as well as a lack of association between FeNO and AHR to mannitol. Similarly, blood eosinophils were elevated in both asthma and COPD, but no difference in subjects with a positive compared to a negative response to the mannitol test was found.

We found associations between baseline spirometry and respiratory oscillometry in measurements reflecting both the central and peripheral airways, and both during inspiratory and expiratory breathing in subjects with asthma or COPD. This is in line with our previous studies where FEV1 correlated with the measurements obtained by impulse oscillometry technique [34,35]. Despite correlation to spirometry, respiratory oscillometry has been shown to have higher sensitivity in exercise-induced bronchoconstriction [36], which is in accordance with the findings in our study. Jara et al. [12] used respiratory oscillometry to detect AHR in children and concluded that the indexes R5 and X5 were comparable with FEV1 in assessing AHR. In the present study, we took this a step forward and investigated the change in airway resistance and reactance in response to mannitol in comparison to change in FEV1, to study the pathophysiology in central and peripheral airways. The correlations were no longer evident, neither as absolute nor relative changes, suggesting that oscillometry is sensitive to dynamic changes in airway function, offering additional insights beyond baseline spirometric indices. The ability of oscillometry to reflect both static and dynamic aspects of airway mechanics highlights its potential value in evaluating bronchial responsiveness and airway pathology in obstructive lung diseases.

This trial is, as mentioned earlier, a part of a larger multisite study [16] where AHR to mannitol was tested. The other sites did not include respiratory oscillometry measurement and were, therefore, not included into the present study. In the larger study population, a positive response to mannitol was confirmed in 48% of the subjects with asthma and 44% of the subjects with COPD. This is to some extent a higher percentage of AHR to mannitol compared to the present study with 35% in subjects with asthma, but a similar in COPD (52%)

We noticed in a few subjects with COPD with positive response to the mannitol test that the resistance was unexpectedly decreased in comparison with the baseline measurements. A possible explanation to this phenomenon may be that some individuals respond to bronchial constriction by raising their respiratory mode. The elastic recoil would then increase and cause an expansion in the small bronchioles and consequently a reduction in the airway resistance.

A strength of the study is the high number of subjects with asthma, which gives the results a high power. Unfortunately, the number of subjects with COPD or healthy subjects with or without smoking history, were fewer which has a limiting effect on the interpretation of the results. Another limitation is that the second respiratory oscillometry measurement was performed after the spirometry. Optimally, the respiratory oscillometry measurement should be performed before the spirometry, but that was not possible in this setting. However, the mannitol provocation affects the airways to a larger extent, so the possible effect of the spirometry manoeuvre on the FOT-measurement is of minor importance. Another limiting factor is the calculation of relative change in R5-R19, which due to methodological reasons cannot be performed if the baseline value = 0. We have, therefore, chosen to not present relative change in R5-R19 in the present study.

The utility of respiratory oscillometry could be additionally enhanced by integrating reference-predicted values, and that establishing specific cut-off thresholds for Forced Oscillation Technique (FOT) indices, indicative of a positive bronchial challenge test outcome, requires further investigation. The clinical implication of the increased baseline resistance in association to higher likelihood of positive mannitol response in asthma also needs further investigation. The mannitol challenge test is still needed to confirm the presence of AHR; however, there is an added value of respiratory oscillometry in enhancing the interpretation of the test outcomes and the understanding of AHR.

Conclusion

Inspiratory resistance, as measured by respiratory oscillometry, was identified as a predictive marker of airway hyperresponsiveness to mannitol in subjects with asthma. Individuals who exhibited a positive response to the mannitol challenge demonstrated significantly elevated baseline resistance values. In addition, this response was more localised to the peripheral airways rather than the central airways. Incorporating resistance and reactance measurements, in conjunction with traditional spirometry, may enhance our understanding of the hyperreactive airway response.

Supplementary Material

Supplemental Material
ZECR_A_2546677_SM5982.zip (304.5KB, zip)

Funding Statement

This work was supported by the Astma- och Allergiförbundet; Hjärt-Lungfonden; Interreg ÖKS [NYPS20201002]; Astra-Zeneca; TEVA.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data sharing statement

The data supporting the findings of this study are not publicly available because they were not included in the original consent forms. The anonymized data are available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/20018525.2025.2546677

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