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(Chest. 2002;121:1853-1859.)
© 2002 American College of Chest Physicians

Exhaled Nitric Oxide and Bronchial Responsiveness to Adenosine 5'-Monophosphate in Subjects With Allergic Rhinitis*

Luis Prieto, PhD; Valentina Gutiérrez, PhD and Sonia Uixera, MD

* From the Sección de Alergología (The NAOMI Project), Universidad de Valencia, Valencia, Spain.

Correspondence to: Luis Prieto, PhD, Sección de Alergología, Hospital Universitario Dr. Peset, C/Gaspar Aguilar 90, 46017 Valencia, Spain; e-mail: prieto_jes{at}gva.es


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To determine differences in exhaled nitric oxide (ENO) between subjects with allergic rhinitis with and without increased responsiveness to direct and indirect bronchoconstrictor agents.

Study design: Cross-sectional study with the order of challenge tests randomized.

Setting: Specialist allergy unit in a university hospital.

Patients: Thirty-eight subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects.

Measurements and results: Participants were challenged with increasing concentrations of adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but not to methacholine. The geometric mean (range) ENO values were significantly higher in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5 ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2 ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007). No correlation was found between ENO and either of the provocative concentrations of methacholine or AMP causing a 20% fall in FEV1.

Conclusions: In subjects without asthma but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP is associated with increased ENO concentrations. However, elevated concentrations of ENO are detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.

Key Words: adenosine 5'-monophosphate • airway responsiveness • allergic rhinitis • methacholine • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Airway hyperresponsiveness, a characteristic feature of asthma, can be defined as an increase above normal in both the ease and magnitude of airway narrowing with exposure to a number of nonsensitizing bronchoconstrictive stimuli.1 Clinically and for research purposes, airway responsiveness is measured by bronchial challenge, usually with methacholine or histamine.2 Both agonists predominantly induce bronchoconstriction through a direct effect on airway smooth muscle. In contrast, adenosine 5'-monophosphate (AMP) acts indirectly, causing primed mast cell degranulation and the release of proinflammatory mediators (histamine and leukotrienes) with subsequent smooth-muscle contraction.3 4 5 Bronchial responsiveness measured by this indirect method may provide different information on airway inflammation that is obtained with direct-acting bronchoconstrictor agents.6

Nitric oxide (NO) levels are increased in exhaled air from subjects with asthma compared with healthy control subjects, and several studies7 8 strongly suggest that exhaled NO (ENO) measurements reflect airway inflammation. Different technical factors can have significant effects on absolute values of ENO, but efforts have been made to standardize measurement procedures.9 Multiple investigations2 10 have shown that some patients with allergic rhinitis but no history of asthma exhibit airway hyperresponsiveness to direct bronchoconstrictor agents (histamine or methacholine). In addition, some reports11 have indicated that, in subjects without asthma but with allergic rhinitis, the presence of airway hyperresponsiveness to inhaled methacholine is associated with increased ENO levels. In these studies,11 however, the relationship between ENO levels and methacholine responsiveness, despite being statistically significant, was relatively weak. This might reflect a different cause for methacholine hyperresponsiveness, such as structural changes in the airways.

In addition to sensitivity to methacholine, an important proportion of subjects with allergic rhinitis also have increased sensitivity to inhaled AMP.12 13 Because bronchoconstriction induced by AMP depends, at least in part, on the state of activation of airway mast cells,3 4 5 the bronchial response to AMP may be a more direct marker of allergic airway inflammation than direct bronchoconstrictors such as histamine or methacholine. In line with these speculations, Polosa et al14 demonstrated a significant correlation between the provocative concentration causing a 20% fall in FEV1 (PC20) of AMP, but not the PC20 of methacholine, and sputum eosinophils in subjects without asthma but with allergic rhinitis.

In previous studies,13 15 we have shown that a significant proportion of subjects with allergic rhinitis without bronchial hyperresponsiveness to methacholine had bronchoconstriction in response to AMP. Thus, at least in subjects with allergic rhinitis, the results of the methacholine and AMP challenge tests are not mutually interchangeable, and these test results may complement each other in determining airway responsiveness.

The purpose of the present study was to determine differences in ENO concentrations between subjects with allergic rhinitis with and without bronchial hyperresponsiveness. Therefore, measurements of ENO and determinations of bronchial responsiveness to both the direct spasmogen methacholine and the indirect spasmogen AMP were performed in patients with allergic rhinitis, and the results were compared with the same measurements made in nonatopic volunteers.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Forty-eight adult subjects (38 subjects with allergic rhinitis and 10 healthy volunteers) were studied. Subjects with allergic rhinitis were selected from the authors’ outpatient Allergy Clinic, whereas healthy subjects were recruited from volunteers in the laboratory and among students. All 48 subjects were lifelong nonsmokers, and none had history of chronic bronchitis, emphysema, or respiratory tract infections during the 4 weeks before the study. Each subject was required to have an FEV1 of at least 80% of the predicted value. Current smokers or ex-smokers, pregnant women, and patients with significant renal, hepatic, or cardiovascular disease were specifically excluded. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all participants.

Subjects with allergic rhinitis were defined as those individuals with a characteristic history of perennial or seasonal allergic rhinitis (rhinorrhea, sneezing, obstruction, and pruritus) who also had skin sensitization to perennial or seasonal allergens. No subject had a history of asthma (wheezing, dyspnea, chest tightness, chronic cough, or exercise wheeze).

Healthy subjects had no history of asthma, allergic rhinitis, atopic eczema, or other relevant disease, and were receiving no medications. All subjects were nonatopic, as defined by a negative skin test result for six common airborne allergens (Dermatophagoides pteronyssinus, mixed grass pollen, olive, parietaria judaica, and cat and dog dander).

Study Design
Subjects with allergic rhinitis with only seasonal symptoms and skin sensitization to pollen allergens were studied during a period of natural pollen exposure (April to June). Subjects attended the laboratory on three visits. On the first day, all subjects were evaluated for suitability and spirometry was performed. On each of the next two visits (at least 7 days but not > 9 days apart), spirometry and concentration-response studies with either methacholine or AMP were performed. Methacholine and AMP challenges were conducted on separate days with the order of challenge randomized and with baseline FEV1 varied by < 10%. At the second visit, ENO was measured before the challenge test.

Pulmonary Function
Spirometry was performed with a calibrated dry rolling seal spirometer (model 2130; SensorMedics; Yorba Linda, CA), according to standardized guidelines.16 Baseline FEV1 and FVC were measured until three reproducible recordings differing < 5% were obtained. Maneuvers were accepted as technically satisfactory if the back-extrapolated volume was < 100 mL or 5% FVC, and if the expiratory time was at least 6 s. Highest values were used for analysis. Reference values were those of the European Community for Coal and Steel.17

Inhalation Challenge Tests
Inhalation provocation tests were performed using the method described by Chai et al18 with some modifications.19 Subjects were instructed to withhold their treatment for at least 2 weeks (nasal topical corticosteroids and nasal topical cromoglycate) and 3 days (antihistamines) before each challenge.

Methacholine and AMP (Sigma Chemical; St. Louis, MO) were dissolved freshly in 0.9% saline solution to produce a doubling concentration range of 0.39 to 25 mg/mL for methacholine and 1.56 to 400 mg/mL for AMP. Each solution was administered from a jet nebulizer attached to a breath-activated dosimeter (Mefar MB3; Mefar; Brescia, Italy) at a nebulization time of 1 s and a pause time of 6 s. The nebulizer delivered particles with an aerodynamic mass median diameter of 3.5 to 4.0 µm at an output of 10 µL per breath. Subjects inhaled the aerosolized methacholine and AMP solutions in five inhalations from functional residual capacity to total lung capacity through a mouthpiece with the subject’s nose clipped. Normal saline solution was inhaled initially, followed by five breaths of doubling concentrations of methacholine or AMP at 2- to 3-min intervals. Due to the effect of a deep inspiration on subsequent airway tone,20 only one measurement for FEV1 was performed 60 to 90 s after inhalation of each concentration, unless the forced expiratory maneuver was judged to be technically unsatisfactory. The test was interrupted when a >= 20% decrease in FEV1 from the post-saline solution value was recorded or when the highest concentration was reached.

A log concentration-response curve was constructed for each challenge, and the PC20 was calculated by logarithmic interpolation.21 Two inhalations of albuterol, 200 µg total dose, from a metered-dose inhaler were then administered to each subject, and the FEV1 was measured 15 min later.

ENO Measurement Technique
On the basis of the recommendation of the American Thoracic Society,9 the ENO concentration was measured by means of a rapid-response chemiluminescent NO analyzer (NIOX; Aerocrine; Solna, Sweden) with a sensitivity of 1.5 parts per billion (ppb) and a detection range of 0 to 200 ppb. The sampling flow was 300 mL/min, and the response time was < 0.8 s. The analyzer was calibrated regularly according to the guidelines of the manufacturer using certified calibration gases containing 200 ppb (AGA; Lidingö, Sweden). Zero-point determination used instrument-filtered zero-air. We used a restricted-breath technique, which used exhalation via a high resistance, and positive mouth pressure to close the velum, thus excluding nasal NO. Subjects inhaled ambient air that was passed through a filter to reduce inhaled NO concentrations to < 5 ppb. Subjects inhaled without a nose clamp to total lung capacity, and immediately exhaled while targeting a constant pressure of 20 cm H2O with the aid of a visual feedback display. This produced an expiratory flow rate of 45 mL/s. Water vapor was absorbed by means of an NO-inert filter in the tube. An end-expiratory plateau of at least 3 s, where flow varied ± 10% of the target flow, was the end point of the measurement. Participants repeated the maneuver until three acceptable tests were performed. The average of the three plateau values was recorded.

Statistical Analysis
Results are presented as mean values with SEM unless stated otherwise. Airway responsiveness to methacholine and AMP was analyzed as a categorical variable (presence or absence of bronchoconstriction in response to each agonist). Normality of distributions was assessed using Kolmogorov-Smirnov tests. If p < 0.05 was obtained, the distribution was normalized by logarithmic transformation. This was carried out for ENO values. The distribution of all other numerical variables was not significantly different from a standard normal distribution; hence, parametric tests (t tests and one-way analysis of variance) were applied. Bonferroni’s correction was applied to allow for multiple comparisons. Categorical variables were analyzed with the Fisher exact test. The relationship between numerical variables was calculated using the Spearman rank ({rho}) correlation test. Probability values are two sided, and p < 0.05 were considered statistically significant. Data were analyzed with software (Statistical Package for the Social Sciences for Windows version 6.01; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The clinical and pulmonary function data at baseline for subjects with allergic rhinitis and healthy volunteers are presented in Table 1 . The two groups were similar with regard to age, sex, and pulmonary function. Mean baseline FEV1 values were not significantly different within the two groups before the two different provocation tests (Table 1) .


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  		Table 1.. Subject Characteristics and Prevalence of Bronchoconstriction in Response to Either Methacholine or AMP*

 
The proportion of subjects with bronchoconstriction in response to AMP (Table 1) was higher (p = 0.04) in subjects with allergic rhinitis than in healthy control subjects. However, the prevalence of bronchoconstriction in response to methacholine was similar in the two groups. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis. Among the 28 subjects with allergic rhinitis who were normoreactive to methacholine, 4 subjects (14%) demonstrated > 20% decrease in FEV1 during the AMP challenge. In three of the four subjects, the decreases in FEV1 at the highest methacholine concentration of 25 mg/mL were 4%, 7%, and 10%, respectively, whereas in one subject it was 18% below the post-saline solution value. Among the 25 subjects with allergic rhinitis who were normoreactive to AMP, only 1 subject (4%) showed bronchoconstriction in response to methacholine. In healthy control subjects, inhaled methacholine induced bronchoconstriction in two subjects, whereas none had bronchoconstriction in response to AMP.

The geometric mean (range) ENO values were significantly higher (Fig 1 ) in subjects with allergic rhinitis than in healthy control subjects: 33.1 ppb (5.7 to 108.5 ppb) vs 11.2 ppb (5.0 to 31.5 ppb; p < 0.001). The geometric mean (range) ENO in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP (n = 14) was 51.3 ppb (22.0 to 108.5 ppb), compared with 25.1 ppb (5.7 to 102.9 ppb) in subjects with allergic rhinitis with normal responsiveness to both bronchoconstrictor agents (p = 0.007) and 11.2 ppb (5.0 to 31.9 ppb) in healthy control subjects (p < 0.001). In subjects with allergic rhinitis and normal responsiveness to both bronchoconstrictors, the ENO level was significantly greater than in healthy control subjects (p = 0.007).



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  		Figure 1.. ENO concentrations in subjects with allergic rhinitis and healthy control subjects; horizontal lines indicate geometric means.

 
Although the small number of subjects with increased responsiveness to each bronchoconstrictor agent precluded a formal comparison of the ENO levels, there was considerable overlap between subjects with allergic rhinitis and with increased responsiveness to AMP only and subjects with positive response to both bronchoconstrictor agents (Fig 2 ). In subjects with allergic rhinitis, no correlation was found between ENO and either PC20 of methacholine (n = 10, {rho} = 0.17, p = 0.64) or PC20 of AMP (n = 13, {rho} = - 0.25, p = 0.40), when it was measurable.



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  		Figure 2.. ENO concentrations in subjects with allergic rhinitis responsive to either methacholine or AMP, in subjects with allergic rhinitis not responsive to both methacholine and AMP, and in healthy control subjects. Closed circles indicate subjects with allergic rhinitis responsive to both bronchoconstrictors; open circles indicate subjects with allergic rhinitis responsive to methacholine or AMP only; horizontal lines indicate geometric means.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this cross-sectional study, we found that subjects with allergic rhinitis with bronchoconstriction in response to methacholine and/or AMP have higher ENO concentrations than subjects with normal responsiveness to both bronchoconstrictor agents. Furthermore, our data clearly demonstrate that levels of ENO are elevated even in subjects with allergic rhinitis but without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness to direct or indirect bronchoconstrictor agents is not the only factor that determines the increased NO levels detected in exhaled air of subjects with allergic rhinitis.

The present study suggests that, in subjects with allergic rhinitis, additional information on airway responsiveness may be obtained with AMP challenge. It has long been appreciated that the various stimuli used to assess bronchial responsiveness act through different mechanisms and reflect different components of asthma pathogenesis.22 Consistent with this notion, in the present study we have shown that increased responsiveness to AMP is not necessarily accompanied by bronchoconstriction in response to methacholine. This confirms our previous observations.13 Differences in the response to both bronchoconstrictors cannot be explained by different conditions of airway challenge, because baseline airway caliber as assessed by FEV1 prior to bronchial challenge was not significantly different between the 2 study days. This is relevant to the evaluation of PC20 because airway geometry has an important influence on assessing airway responsiveness to a bronchoconstrictor agent.23 In addition, it has been demonstrated that inhaled AMP was, on average, 17 times less potent than methacholine in constricting the airways of patients with asthma.13 24 Because the maximal administered dose of AMP in our study was only ninefold greater than methacholine on a molar basis, it is unlikely that the response to AMP in subjects with normal response to methacholine was caused by an excessive dose of AMP. Although the critical features that determine the presence of increased responsiveness to direct and indirect bronchoconstrictors in subjects with allergic rhinitis are not yet identified, some studies3 5 have demonstrated that AMP caused mast cell degranulation in the lower airways. Because mast cells are believed to play a predominant role in asthmatic airway inflammation, the response to AMP may reflect acute inflammatory changes in the bronchial mucosa, whereas methacholine responsiveness might be predominantly dependent on structural changes of the airways, such as thickening of the airway wall, smooth-muscle contraction, and lung elastic recoil.25

In keeping with previous reports,11 26 27 we have observed that patients with allergic rhinitis have higher levels of ENO than nonatopic volunteers. The increased concentration of NO in exhaled air in allergic rhinitis cannot be explained by technical factors. Contamination of the exhaled air by NO-rich air from the nasal cavity is unlikely, because the soft palate elevates when expiration is performed against a resistance.28 However, the ENO levels measured in this study tend to be somewhat higher than those measured in other reports.11 26 27 The reasons for such discrepancies might be related to important differences in methodology or to diversity in the disease activity in the subjects studied. It has been shown that there is a marked flow dependence of ENO values, with lower values measured at high flow rates and vice versa.28 We used an expiratory flow of 45 mL/s, which is lower than the flow used in other studies.11 26 27 Additionally, there is convincing evidence that, in subjects with pollen induced rhinitis, natural allergen exposure during a pollen season results in increased concentrations of ENO.11 Pollen sensitive subjects in the present study were tested during a period of natural pollen exposure and this may also have contributed to the elevated concentrations of ENO in the subjects with allergic rhinitis. Other factors known to influence the concentration of ENO, such as a history of asthma, current smoking, and acute upper and chronic lower respiratory tract infections, were absent in the subjects studied.

The primary aim of the study was to determine differences in ENO concentrations between subjects with allergic rhinitis with increased responsiveness to methacholine and/or AMP and subjects with normal responsiveness to both bronchoconstrictor agents. The results of our study demonstrate that the presence of increased responsiveness to direct and/or indirect stimuli is associated with increased concentrations of ENO. However, increased concentrations of ENO were also detected in subjects with allergic rhinitis with normal responsiveness to both bronchoconstrictors. If ENO levels reflect the presence of airway inflammation, the findings of this study suggest that airway inflammation is detected predominantly, but not exclusively, in allergic rhinitis subjects with increased responsiveness to direct or indirect bronchoconstrictor agents. This is consistent with previous studies showing that allergic rhinitis patients without bronchial hyperresponsiveness to direct bronchoconstrictor agents have bronchial inflammation in induced sputum, BAL fluid, and bronchial biopsy specimens29 30 31

There are, however, several possible reasons for the elevated concentrations of ENO in subjects with allergic rhinitis. First, it may reflect subclinical airway inflammation. Although ENO has been proposed as a marker of airway inflammation7 8 in asthma, the correlations between ENO and direct measures of airway inflammation have been of relatively small magnitude.32 33 In addition, although several reports4 29 31 34 35 have shown that subjects with allergic rhinitis may have inflammatory changes in the airways, the relationship between ENO levels and histologic markers of bronchial inflammation has not been studied in subjects with allergic rhinitis. Therefore, the precise mechanism that links NO with airway inflammation and whether it reflects airway inflammation remain to be elucidated. A second explanation could be an independent effect of atopy on NO production. NO is produced in the airways by constitutive NO synthase, of which there are two isoforms, and by an inducible form of NO synthase in epithelial cells and various inflammatory cells.36 It has been demonstrated that ENO concentrations are significantly higher in subjects with allergic rhinitis compared with subjects with nonallergic rhinitis.27 In addition, ENO is elevated in asymptomatic subjects sensitized to inhaled allergens.37 This indicates that atopic status might be the most important determinant of enhanced NO production. Thus, inhalation of allergens in sensitized individuals may have a direct effect on NO synthase activity, regardless of the presence of inflammation in the airways, and the presence of atopy per se may be sufficient to increase ENO.

We were not able to show a significant relationship between ENO values and either PC20 of methacholine or PC20 of AMP. These findings suggest that ENO levels are not dependent on the degree of bronchial hyperresponsiveness. Our results confirm the findings of Henriksen and coworkers,11 who were not able to find a significant correlation between the PC20 of methacholine and ENO values in subjects with allergic rhinitis. Furthermore, the results of this study show for the first time that the PC20 of AMP was not related to ENO values. However, methacholine and AMP PC20 values were measurable in only 10 subjects and 13 subjects, respectively; therefore, failure to demonstrate such a relationship could have been due to either a small sample size or narrow ranges of the PC20 values in these subjects.

In conclusion, the results of this study confirm the presence of bronchoconstriction in response to AMP in a significant proportion of subjects with allergic rhinitis with normal responsiveness to inhaled methacholine. Although subjects with allergic rhinitis with and without bronchoconstriction in response to either methacholine or AMP have elevated ENO levels, the highest NO concentrations were seen in subjects with increased responsiveness. If ENO levels reflect the presence of airway inflammation, it would be interesting to speculate that allergic rhinitis subjects with increased responsiveness to methacholine or AMP and a higher degree of subclinical airway inflammation are at an increased risk for the development of asthma. Obviously, this needs to be examined in careful prospective studies.


   Acknowledgements
 
The authors thank B. Camps and R. Rojas for their technical assistance, and Laboratorios Bial-Arístegui (Bilbao, Spain) for their help and collaboration during the study.


   Footnotes
 
Abbreviations: AMP = adenosine 5'-monophosphate; ENO = exhaled nitric oxide; NO = nitric oxide; PC20 = provocative concentration causing a 20% fall in FEV1; ppb = parts per billion

Received for publication July 5, 2001. Accepted for publication November 12, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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L. Prieto, L. Bruno, V. Gutierrez, S. Uixera, C. Perez-Frances, A. Lanuza, and A. Ferrer
Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects
Chest, October 1, 2003; 124(4): 1325 - 1333.
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