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Br J Clin Pharmacol. Apr 2003; 55(4): 354–359.
PMCID: PMC1884241

An evaluation of short-term corticosteroid response in perennial allergic rhinitis using histamine and adenosine monophosphate nasal challenge

Abstract

Aims

To evaluate the role of AMP nasal challenge as a measure of short-term treatment response in patients receiving intranasal corticosteroids. Adenosine monophosphate (AMP) challenge has been shown to be a good inflammatory surrogate in the lower airways, but it has not been properly evaluated as a nasal challenge test.

Methods

Fourteen patients with perennial allergic rhinitis (PAR) were randomized to receive 2 weeks treatment with placebo (PL) or 200 µg intranasal mometasone furoate (MF) once daily in a randomized single-blind crossover study. AMP (25–800 mg ml−1) and histamine (0.25–8 mg ml−1) nasal challenge testing were performed after each treatment period with 30% decrease in minimal cross-sectional area (MCA). Domiciliary symptom data were collected.

Results

There was a significant (P < 0.05) improvement in PC30 MCA and nasal volume with AMP but not with histamine comparing MF vs PL. This amounted to a 2.8 (95% CI 1.5, 4.0) and 0.7 (95% CI −0.5, 1.9) doubling-dose change for AMP and histamine challenges, respectively. There were significant (P < 0.05) improvements in nasal symptoms and quality of life.

Conclusions

AMP nasal challenge using acoustic rhinometry may be a useful test to assess short-term treatment response in patient with PAR.

Keywords: acoustic rhinometry, adenosine monophosphate, allergic rhinitis, histamine, mometasone, nasal challenge

Introduction

Perennial allergic rhinitis is an important condition as it results in an impaired quality of life, decreased productivity and increased risk of complications such as asthma and sinusitis [1]. Nasal-challenge testing has been used as a way of investigating the mechanisms of upper-airway inflammation and evaluating the response to treatment [2].

The stimulus for the provocation test can be either a specific substance such as allergen [3] or aspirin [4, 5], or nonspecific such as histamine [6], methacholine [7] or adenosine monophosphate (AMP). Histamine and methacholine are examples of direct challenges that are thought to be less representative of the clinical situation than indirect challenges with, for example, AMP when used as bronchial challenge tests. Furthermore, AMP bronchial challenge has confirmed that it is more sensitive than other challenges such as methacholine [8, 9] and is more closely related to airway inflammation and atopic status [10, 11].

There are remarkably few data regarding nasal challenge with AMP. Crimi et al. [12] demonstrated that nasal challenge with AMP-reproduced rhinitis symptoms. Polosa et al. [13] have published data showing that challenging the nasal mucosa with AMP but not placebo results in increased histamine concentrations compared with baseline. Furthermore, AMP nasal challenge significantly increased nasal symptoms scores and there were significant differences between the responses of patients with allergic rhinitis and healthy volunteers. We decided to evaluate the response to both intranasal histamine and AMP with acoustic rhinometry in patients who had been treated with intranasal mometasone furoate.

Methods

Patients

Fourteen patients with perennial allergic rhinitis, according to current criteria [14] (10 females, 4 males; mean ± SE age 30.6 ± 2.1 years) were recruited into the study. Patients were required to demonstrate nasal hyper-responsiveness, in terms of change in minimal cross-sectional area, to nasal adenosine monophosphate. All patients had normal spirometry (mean FEV1 99.4 ± 2.2 % predicted), 7 patients were skin-prick positive to grass, 11 to house dust mite, 8 to cat and 5 to dog. Three patients were taking intranasal corticosteroids (beclomethasone, budesonide and triamcinolone) but no patients were taking oral antihistamines prior to enrolment into the study. Two subjects were taking inhaled bronchodilators as required but no subjects were taking inhaled corticosteroids. Anterior rhinoscopy was performed on all subjects to exclude causes for fixed nasal airways obstruction, including polyps or significant septal deviation. All subjects were nonsmokers and had normal full blood count, biochemical profile and urinalysis. Approval for the study was obtained from the Tayside Medical Ethics Committee and all patients gave their written informed consent.

Methodology

The study was performed as a single (investigator)-blind, placebo-controlled, crossover study. All treatment including intranasal steroids, nasal decongestants and antihistamines was withdrawn for 1 week prior to the beginning of the study. Patients received the following, in random order, for 10–14 days: (1) 200 µg intranasal aqueous mometasone furoate (Nasonex; Schering-Plough, Herts, UK; two squirts of 50 µg in each nostril) at 08.00 h, or (2) placebo nasal spray (two squirts up each nostril) at 08.00 h. There was no placebo washout period between the randomized placebo and active treatment period, as many of the patients found difficulty withholding their medication for a prolonged period of time. The nasal sprays were masked in order to conceal the identity of the contents and the placebo nasal sprays contained benzylkonium chloride, methylcellulose and saline so that the viscosity was similar to the active drug. As the placebos were not identical to the drug, it is possible, but unlikely, that this would have significantly affected the patients’ symptom scoring. It is very unlikely to have changed the primary endpoint, which was AMP nasal challenge.

The nasal sprays were masked and sealed in envelopes by a pharmacist along with instruction sheets at the beginning of the trial. All treatments were dispensed by a third party. Each subject received a simple tick chart as an aid to compliance. The challenge tests were performed at least 48 h apart at the same time of day for each patient. The challenge tests were performed in random order.

AMP nasal challenge

Patients had baseline measurements of acoustic rhinometry and this was repeated 2 min after receiving a placebo nasal spray. AMP was then administered via a nasal spray in doubling concentrations from 25 mg ml−1 to 800 mg ml−1 with the measurements repeated 2 min after each dose. The challenge was terminated if the patient experienced severe symptoms and felt he/she could not continue. The physician would terminate the challenge if peak inspiratory flow rate or minimal cross-sectional nasal area was below that detectable by the peak inspriatory flow rate meter or acoustic rhinometer, respectively. Patients were then offered topical xylometazoline (Otrivine, Norvartis Consumer Health, West Sussex, UK) and observed until their symptoms of nasal blockage subsided.

Nasal histamine challenge

Nasal histamine challenge was performed in the same manner as AMP challenge. After a placebo baseline, patients were given doubling concentrations of histamine from 0.25 mg ml−1 to 8 mg ml−1 [15].

Acoustic rhinometry

Acoustic rhinometry was measured using an AI Executive acoustic rhinometer (GM Instruments, Kilwinning, Ayrshire UK). A probe was inserted 0.5 cm into each nostril such that a seal was obtained without distorting the nasal architecture. Patients were asked to hold their breath during the procedure and a probe-stand was used in order to ensure correct positioning of the probe [16]. Measurements were made of the minimum cross-sectional area (MCA) at the nasal valve (approximately 2 cm from the nasal orifice). The sum of the MCA for left and right nostrils was calculated and used for the purposes of statistical analysis.

Domiciliary diary card data

Patients recorded their perennial allergic rhinitis symptoms on a twice-daily basis under nasal symptoms as ‘runny nose’, ‘blocked/stuffy nose’, ‘itchy nose’ and ‘sneezing’. All symptoms were documented according to a four-point scale with 0 indicating no symptoms and 3 indicating severe symptoms. Patients were also asked to record how much their symptoms were interfering with their daily activity on an 11-point scale, with 0 representing no symptoms and 10 representing maximal symptoms. For statistical analysis the sum of the individual nasal symptoms was calculated on a daily basis (nasal symptoms). Nasal inspiratory flow rate was measured using an In-check™ flow meter (Clement Clarke international Ltd Harlow, UK) while in the sitting position, with a good seal around a purpose-built facemask after blowing their nose, also on a twice-daily basis.

Statistical analysis

As this was a pilot study and AMP nasal challenge had not been performed in a manner similar to this previously, it was not possible to power the study. However, it had been possible to detect a significant difference with intranasal corticosteroid therapy in 11 patients with perennial allergic rhinitis in a previous study [17]. For this reason we felt that 14 patients would be sufficient for this study.

Log dose–response curves were produced for MCA measured by acoustic rhinometry. Provocation concentrations producing a 30% reduction in MCA from baseline values were determined by interpolation of the log dose–response curve using Microsoft Excel 97 (Microsoft, Seattle, Washington, USA). A value of twice the highest concentration was assigned where the change in MCA was less than 30% at 8 mg ml−1 of histamine or 800 mg ml−1 AMP (i.e. 16 mg ml−1 and 1600 mg ml−1, respectively). For diary-card data, the sum of nasal symptoms (nasal symptoms) was used for analysis.

Overall comparisons between mometasone furoate therapy and placebo were made by multifactorial analysis of variance using subject, treatment and period as factors. Nasal challenge data were analysed geometrically. This was followed by Bonferroni's multiple range testing (set at 95% CI) in order to obviate multiple pair-wise comparisons. Consequently comparisons are only denoted as being significant (P < 0.05, two-tailed) or not significant. The analysis was performed using Statgraphics statistical software package (STSC Software Publishing Group, Rockville, MD, USA). Spearman's rank correlation was used to evaluate whether there was a relationship between the response to AMP and that to histamine.

Results

There was no significant carryover effect with any outcome measure. There was also no significant carryover effect from one challenge to the other, i.e. there was no AMP/–histamine challenge order effect. There was no significant difference between the baseline values before AMP nasal challenge for MCA with either MF 1.0 ± 0.1 cm2) or PL 0.9 ± 0.1 cm2 (Figure 1). Baseline values before histamine were also not significantly different (MCA: MF 1.1 ± 0.1 cm2, PL 1.0 ± 0.1 cm2) (Figure 1). There was a significant difference with MF compared with PL for AMP PC30 MCA (Figure 2). This amounted to a 2.8 (95% CI 1.5, 4.0) doubling-dose change. However, with histamine PC30 there was no significant difference between MF or PL with MCA (Figure 2). This amounted to 0.7 (95% CI −0.5, 1.9) doubling-dose change. There was a significant difference in the doubling-dose change between AMP and histamine challenge (95% CI 0.8, 3.7). In one patient it was not possible do obtain a PC30 for histamine challenge after treatment with placebo. There was no difference in the results when the analysis was therefore repeated with this patient's data removed (i.e. n = 13). AMP PC30 MF vs PL 2.5 (95% CI 1.3, 3.7), histamine PC30 MF vs PL 0.4 (95% CI −0.7, 1.46), AMP vs histamine (95% CI 0.6, 3.7).

Figure 1
Scatter plots showing individual values for baseline mean cross-sectional area (MCA) measured by acoustic rhinometry after therapy with mometasone furoate (MF) and placebo (PL) but before the nasal challenge testing with (a) adenosine monophosphate (AMP) ...
Figure 2Figure 2
Scatter plot showing individual values for (a) adenosine monophosphate (AMP) and (b) histamine provocation concentration causing a 30% fall in minimum cross-sectional area PC30 (mg ml−1) after 2 weeks treatment with placebo (PL) or intranasal ...

For the domiciliary diary card data (Table 1) there was a significant improvement with mometasone compared with placebo with morning peak inspiratory flow (PIF), nasal discharge, sneezing and total nasal symptoms but not for nasal blockage or nasal itch. For evening symptoms there was a significant difference with active treatment with nasal discharge but no significant difference with other measures.

Table 1
Mean (SE) values for domiciliary diary card data. There was a significant improvement with mometasone compared with placebo with morning peak inspiratory flow (PIF), nasal discharge, sneezing and total nasal symptoms but not for nasal blockage or nasal ...

When analysing the Spearman's rank correlation coefficient comparing AMP and histamine PC30 there was no significant correlation (r = −0.28, P = 0.45).

Discussion

We have shown that AMP nasal challenge with acoustic rhinometry is a suitable outcome measure in response to short-term treatment with intranasal mometasone in patients with perennial allergic rhinitis. There was a significant improvement in treatment response with AMP nasal challenge, which was in keeping with a statistically significant improvement in patients’ symptoms, but not with histamine nasal challenge.

Furthermore, there was no significant treatment response detected by baseline acoustic rhinometry. In keeping with this finding, we have previously shown that laboratory measures of acoustic rhinometry are less sensitive than domiciliary measures in determining the response to treatment with intranasal mometasone furoate [18].

Few investigators have evaluated direct and indirect nasal challenges. Braat et al. [19] have previously compared an indirect nasal challenge (intranasal cold dry air) with nasal histamine challenge in nonallergic noninfectious perennial rhinitis or healthy volunteers using mucus production and nasal blockage as assessed by rhinomanometry. In that study, there was comparable sensitivity for the challenge tests but a greater specificity for the cold dry air. However, response to treatment with these challenges was not assessed.

There does not seem to be a standard protocol for the concentration of histamine used in the challenges. Rudblad et al. used 1, 2 and 4 mg ml−1 [20], Baroody et al. used 3, 10 and 30 mg ml−1 [21] and Godnic-Cvar et al. used doubling doses from 0.0625 to 16.0 mg ml−1 [22]. The protocol for histamine challenge in our study was in keeping with those of Gerth van Wijk et al. [15], who used doubling doses from 0.25 mg ml−1 to 4 mg ml−1 of histamine.

There was no relationship of response to AMP and response to histamine nasal challenge (r = −0.28 P = 0.45). However, this is not unexpected given the lack of response with histamine challenge. In addition, the sample size was quite small and this type of analysis may be misleading. The study was not designed to compare AMP challenge in the nose and lungs. However, when looking at the individual data, the two patients who were receiving bronchodilators did not have greater response to nasal AMP than the other patientss. In fact, one of those patients was a nonresponder to nasal AMP. Of the two patients who showed an increased response to AMP following intranasal mometasone, one patient was taking intranasal corticosteroids before the study, and the other patient was not.

One of the entry criteria for the study was that patients were required to exhibit nasal hyper-responsiveness to AMP by having a PC30 less than 800 mg ml−1 as this was the primary endpoint. One patient however, did not have a measurable histamine PC30. This may have explained the lack of response with histamine challenge. Therefore the results were reanalysed, for both the histamine and AMP challenges, with that patient's data removed. The results from this second analysis were the same as the first, with a significant difference with AMP but not histamine challenge.

It would have been interesting to look at the inflammatory response of the nasal mucosa directly by means of nasal biopsy or lavage. In this respect Kanniess et al. [23] found a significant improvement with induced sputum eosinophil counts and AMP bronchial hyper-responsiveness with ciclesonide therapy. However, this study was not designed to correlate the degree of inflammation as assessed by nasal lavage or biopsy with AMP nasal challenge. Further studies would be required to investigate this in more detail.

Acknowledgments

The authors would like to thank TENOVUS (Scotland) for their sponsorship of the study.

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