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(Chest. 2004;125:1985-1992.)
© 2004 American College of Chest Physicians

Coughing During Mannitol Challenge Is Associated With Asthma*

Heikki O. Koskela, MD; Liisa Hyvärinen, MD; John D. Brannan, PhD; Hak-Kim Chan, PhD and Sandra D. Anderson, PhD, DSc

* From the Department of Respiratory Medicine (Drs. Koskela and Hyvärinen), Kuopio University Hospital, Kuopio, Finland; the Department of Respiratory Medicine (Drs. Brannan and Anderson), Royal Prince Alfred Hospital, Camperdown, NSW, Australia; and the Department of Pharmacy (Dr. Chan), University of Sydney, NSW, Australia.

Correspondence to: Heikki Koskela, MD, Department of Respiratory Medicine, Kuopio University Hospital, PL 1777, 70210 Kuopio, Finland; e-mail: heikki.koskela{at}kuh.fi


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To define whether coughing during mannitol challenge is a nonspecific side effect of this challenge or is associated with asthma.

Design: A prospective study.

Setting: University hospital.

Participants: Thirty-seven steroid-naive, asthmatic subjects and 10 healthy subjects.

Measurements: The participants completed a symptom questionnaire, recorded peak expiratory flows (PEFs), and underwent spirometry, skin tests, and bronchial provocations with mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were treated with budesonide, 800 µg per day, and the measurements were repeated after 3 and 6 months of treatment. Coughs were recorded during the mannitol challenges, and the cough sensitivity was expressed as the cumulative number of coughs divided by the cumulative dose of mannitol.

Results: The asthmatic subjects coughed more during the mannitol challenge than the healthy subjects (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001). Even those asthmatic subjects who did not develop bronchoconstriction after the maximal cumulative dose of mannitol (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21]; p = 0.003). Budesonide treatment decreased the cough sensitivity (p = 0.023), which was significantly associated with improvements in overall symptom frequency, cough frequency, diurnal PEF variation, FEV1, and bronchial hyperresponsiveness.

Conclusions: Coughing during mannitol challenge is associated with asthma and occurs independently of bronchoconstriction. It can be used to study the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on this common disorder.

Key Words: asthma • bronchial hyperresponsiveness • bronchial provocation • cough • cough reflex • mannitol challenge


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Bronchial provocation using the dry powder of mannitol is a novel test for demonstrating airway hyperresponsiveness.1 Mannitol,2 in keeping with other non–iso-osmolar substances,34567 can provoke cough when inhaled. The mechanisms of the mannitol-provoked cough are not known. It might simply be due to the nonrespirable, large particles of mannitol powder, which impact in the upper airways during inhalation, causing nonspecific mechanical irritation of the laryngeal rapidly adapting receptors (RAR).28 If this were the case, the mannitol-provoked cough might be minimized by changing the preparation of dry powder and the device used for delivery, thus minimizing the impaction of the particles in the upper airways. Another possibility is that the mannitol-provoked cough is related to the increased sensitivity of the asthmatic airways to various osmotic stimuli.9 If so, it could be due to at least two mechanisms. First, mannitol-provoked cough might be secondary to mannitol-induced bronchoconstriction, since tracheobronchial RARs can be stimulated by bronchoconstriction.8 Second, mannitol could stimulate RARs or other airway receptors in the lower airways directly, and independently of bronchoconstriction. If the mannitol-provoked cough is associated with asthma, it would provide a new, noninvasive index to study the mechanisms of asthma. The present study was conducted to find out whether the mannitol-provoked cough is associated with asthma and, if so, whether it is secondary to mannitol-induced bronchoconstriction or whether it occurs independently.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The material for the present study is obtained from two prospective clinical studies that have been carried out in our institute. The first study10 was carried out to compare mannitol challenge with cold air and histamine challenges to demonstrate airway hyperresponsiveness in subjects with steroid-naive, difficult-to-diagnose asthma. The second study11 was carried out to investigate the effect of inhaled budesonide on the responsiveness to those three challenges in a subgroup of the asthmatic subjects who participated in the first study. To explore the significance of mannitol-provoked cough, all coughs were manually recorded during every mannitol challenge in the studies.

Subjects
We recruited consecutive subjects with a new diagnosis of asthma in our outpatient clinic over a period of 18 months. The diagnosis of asthma was based on patient history and clinical examination findings, in addition to objective evidence of reversible airway obstruction, according to the Finnish Social Insurance Institute criteria.12 At least one of the following criteria had to be fulfilled for the diagnosis of asthma: (1) at least a 15% fall in FEV1 after exercise challenge; (2) at least a 15% improvement in FEV1 after inhaling a bronchodilating drug in spirometry; (3) at least a 20% spontaneous diurnal peak expiratory flow (PEF) variation in home peak flow monitoring on at least 2 days; and (4) at least a 15% improvement in PEF after inhaling a bronchodilating drug during home peak flow monitoring on at least 2 days. The exclusion criteria were previous use of inhaled or oral corticosteroids, febrile respiratory tract infection within 4 weeks, and FEV1 of < 50% predicted.13 Subjects were also excluded if the staff physician considered COPD to be the most probable diagnosis, even if the reversibility criteria were fulfilled.

Forty-two asthmatic subjects were included. Five subjects discontinued the study, three due to personal reasons not related to the study, one due to unstable asthma, and one due to acute sinusitis. Of the 37 asthmatic subjects who completed the study, criterion 1 was fulfilled in none of the subjects (exercise challenge is not included in the routine clinical evaluation in the authors’ hospital), criterion 2 was fulfilled in four subjects, criterion 3 was fulfilled in 12 subjects, and criterion 4 was fulfilled in 28 subjects. In many subjects, more than one criterion was fulfilled. The subjects had refrained from taking short-acting ß2 agonists for 6 h before the challenges. In addition, 10 healthy volunteers were recruited. They had no chronic respiratory diseases or symptoms and were lifelong nonsmokers. These 47 subjects formed the group that completed the first study, and their basic characteristics are given in Table 1 .


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  		Table 1. Summary Characteristics of the 47 Subjects Who Participated in the First Study*

 
Nineteen asthmatic subjects who were found to be hyperresponsive to both mannitol and histamine in the first study were recruited to the second study assessing the effects of budesonide treatment. One patient discontinued the treatment within 1 month due to hoarseness, and another patient discontinued treatment without giving a reason. The remaining 17 asthmatic subjects formed the group that participated in the second study, and their basic characteristics are given in Table 2 . The Finnish National Agency of Medicines and the institutional ethics committee approved the studies, and all subjects gave their informed written consent for participation.


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  		Table 2. Basic Characteristics of the 17 Asthmatic Patients Who Participated the Second Study*

 
Protocol
In the first study, the subjects completed a symptom questionnaire, and the information of the diagnostic home PEF monitoring was recorded. Spirometry (model M9449; Medikro Ltd; Kuopio, Finland) was carried out before and 15 min after inhalation of 0.4 mg salbutamol (Ventoline Evohaler; GlaxoSmithKline Ltd; Uxbridge, UK) according to the American Thoracic Society guidelines.14 Skin prick tests were carried out against 16 common aeroallergens (Soluprick SQ; ALK-Abelló; Hörsholm, Denmark). Atopy was defined as the appearance of a wheal reaction of at least 3 mm to any of the allergens. After these assessments, mannitol, cold air, and histamine challenges were carried out in random order, on separate days. The cold air challenge consisted of a single 4-min period of frigid air hyperpnea.15 The histamine aerosol was delivered by a dosimetric nebulizer in progressively increasing doses.16 In the second study, the measurements were repeated after 3 and 6 months of treatment with inhaled budesonide (Pulmicort Turbuhaler, 400 µg per dose; AstraZeneca Ltd; Lund, Sweden), one dose twice a day. The investigators asked about compliance with treatment, and the inhalation technique was checked during each visit.

Questionnaire
In a self-administered questionnaire, questions were asked about the frequency of dyspnea, cough, wheezing, and sputum production during the last month. The possible answers for each symptom were as follows: less than once per month (1 point on the sum symptom score); one to five times per month (2 points); about once per week (3 points); several times per week (4 points); and daily (5 points). The sum symptom score was calculated as the sum of points for the four symptoms asked about. The daily use of bronchodilating drugs during the last month was defined, as well as the smoking habits. On the basis of symptom frequency and lung function information before treatment, the subject’s asthma severity was determined using the Global Initiative for Asthma classification.17

Home PEF Monitoring
The asthmatic subjects documented three PEF values in the morning and in the evening for 2 weeks (Mini Wright; Clement Clarke International; Harlow, UK), and the best of three values was used in the analysis. The variation for each day was calculated by dividing the difference between the evening and the morning PEF values by the mean of these values, expressed in percentages.18 The mean of these values for 14 days was calculated. In four subjects, the baseline monitoring was not technically satisfactory, and these recordings were omitted.

Mannitol Challenge
The mannitol powder was prepared by spray drying, and 57% of the emitted particles were < 7 µm in size when measured by dispersion (Multi-Stage Liquid Impinger; AstraZeneca Ltd) at 60 L/min using the same device (Inhalator; Boehringer Ingelheim Pty LTD; Ingelheim, Germany) that was used to deliver the mannitol to the subjects. The mannitol powder was weighed (5, 10, 20, and 40 mg) into gelatin capsules and was inhaled in doubling doses (0, 5, 10, 20, 40, 80, and 160 mg). The 80-mg and 160-mg doses were given in multiples of 40-mg capsules, and the 160-mg dose was delivered three times.1 After every dose, the coughs were manually recorded. The test continued until the FEV1 had fallen 15% or until the maximal cumulative dose of 635 mg had been administered. The response-to-dose ratio (RDR) was calculated as the percentage fall in FEV1 after the last dose, divided by the cumulative dose of mannitol. The coughs-to-dose ratio (CDR) was calculated as the cumulative number of coughs from the inhalation of the first capsule to the last measurement of FEV1, divided by the cumulative dose of mannitol, in milligrams. To get more easily understandable values, this value then was multiplied by 100 and, thus, represents the number of coughs per 100 mg mannitol administration. The partial CDR (CDRp) was similarly calculated but using the cumulative number of coughs from the inhalation of the first capsule up to the inhalation of the dose causing the FEV1 to fall permanently > 5% from baseline (the coughs induced by that dose were not included).

Statistical Analysis
The difference in the distribution of the cough indexes from normal distribution was studied using one-sample Kolmogorov-Smirnov test. The distribution of the absolute number of coughs per challenge was sufficiently close to normal in the asthmatic subjects (p = 0.34). On the contrary, the CDR and CDRp values were not normally distributed in them (p = 0.017 and 0.004, respectively). Therefore, log-transformed CDR and CDRp values (p = 0.75 and p = 0.69, respectively) were used in the statistical analysis. If no coughs had occurred, one cough was added to be able to perform the log transformation. The RDR values were also log-transformed. The results are given as the mean and 95% confidence interval (CI), except for CDR, CDRp, and RDR values, which are geometric means and 95% CIs.

The difference of the responses between the groups was analyzed using the Student unpaired t test. When small groups of subjects were compared, the nonparametric Mann-Whitney test also was used. The Pearson correlation coefficient was used in the correlation analysis. The association of various subject characteristics with the CDR and CDRp was studied by linear regression analysis. Repeated-measures analysis of variance was used to analyze the effects of budesonide on the various indexes. A p value of < 0.05 was considered to be statistically significant. All analyses were carried out using a statistical software package (SPSS for Windows, version 11.0.1; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In the asthmatic subjects, the number of coughs provoked by mannitol was proportional to the actual dose of mannitol inhaled, and the higher the dose, the greater the number of coughs, without signs of refractoriness (Fig 1 ). By contrast to the asthmatic subjects, mannitol provoked only infrequent coughing in the healthy subjects and the frequency was unrelated to the dose administered. Thus, the values for CDR and CDRp were significantly greater in the 37 steroid-naive asthmatic subjects compared with those for the 10 healthy subjects (CDR: 8.3 coughs per 100 mg [95% CI, 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001; CDRp: 11.2 coughs per 100 mg [95% CI, 7.3 to 17.1] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001) [Fig 2 ]. Of note in the asthmatic subjects, 60% of the total number of coughs occurred before the dose of mannitol that induced a > 5% fall in FEV1 was administered. At that stage, 57% (mean, 272 of 474 mg) of the total dose of mannitol had been inhaled.



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  		Figure 1. Relation of the noncumulative doses of mannitol to the mean noncumulative number of coughs provoked by the doses in 10 healthy subjects and 37 asthmatic patients. All healthy subjects tolerated the maximal dose of mannitol, but the number of asthmatic patients diminished with the higher mannitol doses. Error bars are omitted for clarity.

 


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  		Figure 2. CDR values (top) and CRPp values (bottom) in 10 healthy subjects and 37 asthmatic patients (p < 0.0001 between the groups).

 
There were 18 steroid-naive asthmatic subjects and all 10 healthy subjects in whom the change in FEV1 was < 15% from baseline after the maximal cumulative dose of mannitol. Within this group of 28, there were significantly more coughs in the asthmatic subjects compared with the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21], respectively; p = 0.003) [Fig 3 ]. In 8 of the 18 asthmatic subjects, the final fall in FEV1 was < 4.5%, a value similar to the greatest fall documented in a healthy individual. Even in these eight asthmatic subjects, mannitol provoked significantly more coughs than in the healthy subjects (52 coughs [95% CI, 20 to 83] vs 12 coughs [95% CI, 4 to 21], respectively; p = 0.006 [Student unpaired t test] or p = 0.005 [Mann-Whitney test]).



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  		Figure 3. Number of coughs during the entire mannitol challenge in the subjects with a < 15% fall in FEV1 after the maximal dose of mannitol was administered (p = 0.003 between the groups).

 
The cough indexes were not associated with age, sex, atopy, dermatographism, current smoking status, or smoking history. Table 3 shows the correlation of the CDR and CDRp values with each other, and with airway responsiveness to mannitol, cold air, and histamine.


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  		Table 3. Pearson Correlation Coefficients Between CDR and CDRp Values, and Between Them and Indices of Airway Hyperresponsiveness in 37 Steroid-Naive Subjects With Asthma

 
The treatment of the asthmatic subjects with inhaled budesonide decreased their CDR and CDRp values, which approached those in the healthy subjects after 6 months of therapy (CDR, 3.0 coughs per 100 mg [95% CI, 1.4 to 6.5]; CDRp, 4.6 coughs per 100 mg [95% CI, 1.7 to 12.4]) [Fig 4 ]. Budesonide also significantly decreased the sum symptom score, cough frequency, daily use of bronchodilating drugs, diurnal PEF variation, and mannitol, cold air, and histamine airway responsiveness, as previously reported.11 The magnitude of the budesonide-induced change in the cough indexes was highly significantly associated with improvements in sum symptom score, cough frequency, diurnal PEF variation, FEV1, and bronchial hyperresponsiveness (Table 4 ).



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  		Figure 4. The change in CDR and CRPp during treatment with inhaled budesonide in 17 subjects with asthma (p = 0.023 for the change in CDR; p = 0.05 for the change in CDRp).

 

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  		Table 4. Pearson Correlation Coefficients Between the Budesonide-Induced Changes in CDR and CDRp Values and Budesonide-Induced Changes in Several Indices of Asthma Severity*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows that coughing during mannitol challenge is not just a nonspecific side effect of the challenge but is related to the increased sensitivity of the asthmatic airways to various osmotic stimuli. The following findings of the present study support this view: first, there were statistically highly significant differences in cough indexes between asthmatic and healthy subjects; second, there were significant associations between the cough indexes and airway responsiveness to mannitol and cold air; third, the cough indexes decreased during treatment with the inhaled budesonide; and fourth, there were highly significant associations between the budesonide-induced decrease in cough indexes and the budesonide-induced changes in several indexes of asthma severity.

This study also shows that mannitol-provoked cough in asthmatic subjects is not simply a manifestation of mannitol-induced bronchoconstriction, as documented by changes in FEV1. This was demonstrated by the following findings. First, in asthmatic subjects, 60% of all coughs had occurred before inhalation of the dose causing a > 5% fall in FEV1. Second, asthmatic subjects coughed more than the healthy subjects before any significant bronchoconstriction was documented. Third, even those asthmatic subjects who had < 4.5% fall in FEV1 in response to the maximal dose of mannitol coughed significantly more than the healthy subjects.

The difference in cough sensitivity between healthy and asthmatic subjects may be more than quantitative. The number of coughs increased with each doubling dose of mannitol only in the asthmatic subjects, whereas the infrequent coughing in the healthy subjects was unrelated to the dose. This finding suggests that coughing is not a normal response to a rise in airway lining fluid osmolarity but is a pathologic response that is associated with asthma. This view is supported by the observations that spontaneous cough is usually not provoked by the inhalation of hypertonic saline solution in patients with chronic bronchitis or cystic fibrosis, although it increases the mucociliary clearance in those patients.19 The coughing of the healthy subjects may be due to a nonspecific irritation of the upper airways by the impaction of the powder or to some other phenomena unrelated to airway lining fluid osmolarity.

It is generally accepted that laryngeal and tracheobronchial RARs are the afferent nerves that are most probably associated with the cough reflex in healthy subjects.820 There is evidence showing that airway lining fluid hyperosmolarity can fire RARs.21 Hyperosmolarity also could induce airway mucosal mast cells to release histamine, a stimulant of lung RARs.822 Hyperosmolarity also can fire the unmyelinated, capsaicin-sensitive bronchial C-fibers.21 However, the role of airway C-fibers in initiating cough is uncertain.23 C-fibers may participate in the cough reflex by releasing sensory neuropeptides, which in turn stimulate RARs.8

We have previously shown that nasal challenge with mannitol is associated with a rapid release of 15-hydroxyeicosatetraenoic acid (HETE) to nasal lavage fluid in subjects with allergic rhinitis, but not in healthy subjects.24 15-HETE is the major arachidonic acid metabolite in human bronchi, and its source is probably the airway epithelial cell.25 Interestingly, 15-HETE is one of the most potent activators of C-fiber capsaicin (vanilloid) receptors.26 Thus, mannitol could stimulate the airway epithelial cells of asthmatic subjects to release 15-HETE, which, in turn, could stimulate airway C-fibers, resulting in coughing. This theory could explain the great difference in the severity of mannitol-provoked coughing between healthy and asthmatic subjects.

Previous studies27282930313233 using capsaicin, citric acid, or tartaric acid to document the cough threshold have consistently failed to show statistically significant differences between asthmatic and healthy subjects, and this has limited the use of these tests in asthma research. On the contrary, mannitol provoked significantly more coughs in the asthmatic patients than in the healthy subjects. Therefore, asthma-associated cough may be stimulus-specific and should probably be studied by using mannitol rather than by the substances used previously. The significance of coughing during histamine and cold air challenges remains obscure because we did not record the coughs during these challenges.

The present study can give some clinically useful information. First, if a subject with a suspicion of asthma does not develop an abnormal fall in FEV1 during the mannitol challenge, the challenge result is usually considered to be negative.1 However, if such a subject coughs frequently (ie, > 35 coughs approximately) during the challenge, a clinician is given a hint that the subject might still be experiencing an asthma-like airway pathology. It is clear from the literature that there are patients with eosinophilic bronchial inflammation and respiratory symptoms who have normal lung function and no significant airway responsiveness.343536 Mannitol challenge combined with cough recordings would appear to be an attractive alternative to investigate such patients.

Second, the cough indexes proved to be valid in monitoring the effect of treatment with inhaled corticosteroids. Validity in this study represents convergence validity (ie, the relationship of the instrument to other instruments that measure the same thing).37 During the budesonide treatment, the CDR values decreased most in subjects who also showed the greatest improvements in sum symptom score, cough frequency, diurnal PEF variation, FEV1, and bronchial hyperresponsiveness. In other words, a decrease in CDR in an individual subject during treatment with inhaled corticosteroid probably indicates a healing of asthma and not just the presence of therapy. Therefore, cough recordings may increase the usefulness of mannitol challenge in monitoring the effect of antiasthma therapy.38 CDR was superior to CDRp in this respect and may thus be the index of choice to be used in the future.

Although the magnitude of the budesonide-induced change in CDR was highly significantly associated with the improvement in the sum symptom score, it should be remembered that a self-administered symptom questionnaire has limitations. Significant proportions of asthmatic subjects tend to underestimate or overestimate their symptoms compared with objective measurements of lung function.39 Therefore, the use of a self-administered questionnaire may be a potential weakness in the present study.

In conclusion, this study shows that coughing during mannitol challenge occurs independently of bronchoconstriction and is associated with asthma. This phenomenon may add to our understanding about the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on patients with this common disorder.


   Acknowledgements
 
The authors thank Pirjo Vänttinen, RN, for her assistance.


   Footnotes
 
Abbreviations: CDR = coughs-to-dose ratio; CDRp = partial coughs-to-dose-ratio; CI = confidence interval; HETE = hydroxyeicosatetraenoic acid; PEF = peak expiratory flow; RAR = rapidly adapting receptor; RDR = response-to-dose ratio

This study was supported by Kuopio University Hospital.

Received for publication August 14, 2003. Accepted for publication November 25, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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