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Keywords:

  • ARIA;
  • allergic asthma;
  • allergic rhinitis;
  • Italy;
  • rhinitis therapy

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Introduction:  The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines provide a stepwise treatment to rhinitis, which classifies the disease according to its duration and severity.

Objectives:  The aim of the study was to verify whether these variables influence drug prescriptions for rhinitis and asthma.

Methods:  A multi-centre cross-sectional pharmaco-epidemiological survey was carried out on 1610 allergic rhinitis patients and the relationship between the clinical features of rhinitis and drug therapy for rhinitis and asthma was evaluated.

Results:  A total of 1321 adult patients were enrolled. Mild intermittent rhinitis was diagnosed in 7.7%of the patients, moderate/severe intermittent in 17.1%, mild persistent in 11.6%, and moderate/severe persistent in 63.6%. A high level of rhinitis-asthma comorbidity (616/1321 = 46.6%) was found. The majority of patients [1060 (80.24%)] were treated. Significant associations between the severity of rhinitis and the presence of therapy (= 0.008), the use of oral antihistamines (< 0.001), topical nasal steroids (= 0.020) and systemic steroids (= 0.005) were found. A weak association was found between the features of rhinitis and the therapy for asthma, and vice versa the comorbidity with asthma increases the prescription of inhalant (< 0.001) and oral steroids (= 0.015) to treat rhinitis.

Conclusion:  The severity of rhinitis influences patient request for rhinitis therapy and the type of medication more than the duration. These features of rhinitis seem to poorly influence asthma therapy. As the ARIA classification is able to reveal a relevant impairment notwithstanding therapy, its role in treated patients merits further study.

Allergic rhinitis is a common disease whose prevalence is increasing, particularly in Western countries. A relevant impact on patient quality of life, ever-increasing evidence of comorbidity with asthma and a significant financial burden on the health service were associated with the disease (1–5). Allergic rhinitis was previously classified as seasonal, perennial and occupational, depending on the causative allergen (6–8).

In order to overcome the intrinsic limits of this classification, reviewed elsewhere (5, 9), the ARIA guidelines emphasize the unitary model of the allergic disease of the respiratory organs, underlining the link between the upper and lower airways. The parameters which the ARIA guidelines use in the classification of rhinitis are the duration of the disease (intermittent and persistent) and the severity, measured not as a nasal symptom score, but as a short assessment of the impairment in the day-to-day life of the patient (mild and moderate/severe). This allows a stepwise, evidence-based treatment for rhinitis of different degrees of severity (5). Various reports underline that this new classification represents an improvement on the previous approach (9, 10).

The aim of this study was to determine which parameters of the ARIA classification most influence the prescription of medication for rhinitis. Moreover, in view of the link between the upper and lower airways, we investigated whether the severity and duration of rhinitis play a role in the prescription of drugs for asthma.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Study design

This was a multi-centre cross-sectional pharmaco-epidemiological survey carried out on a sample of 1610 allergic rhinitis patients referred by their general practitioner (GP) to an allergist. The study was conducted by 154 allergists selected from throughout Italy. The study period lasted from March 1 to June 30, 2002. Consistent with the protocol, a questionnaire was administered by each allergist to the first 12 consecutive patients who had been referred by their GP to evaluate rhinitis, asthma and pharmacological therapy of rhinitis and asthma. The ARIA classification should only be used in nontreated patients. However, if a patient was on medication at the time of his or her specialist visit the drug categories were recorded. The administration of specific immunotherapy was not recorded. The inclusion criteria were as follows:

  • 1
    Age 18 years or older.
  • 2
    Presence of rhinitis symptoms at the time of the hospital visit.
  • 3
    History of rhinitis ≥1 year.
  • 4
    Positive skin test for inhalant allergens.
  • 5
    Written informed consent.

If the patient had not performed a skin prick test (SPT) in the previous year, allergic sensitization was assessed during the visit, using SPTs with standardized extracts commercially available in Italy (Stallergenes-France, ALK-Abello Denmark, Lofarma, Italy). The allergens tested were: mites (Dermatophagoides pteronyssinus and D.farinae), animal dander (cat, dog, horse), pollens (grass, pellitory, olive, cypress, birch, hazelnut, mugwort, ragweed), fungal allergens (Alternaria, Cladosporium, Aspergillus) and latex. A negative and positive control was also included (histamine 10 mg/ml).

Patient characteristics

Patients were surveyed on socio-demographic data and on their rhinitic and asthmatic status. The clinical diagnosis of allergic rhinitis was obtained by matching the affirmative answer to the question: ‘In the last year, have you had a runny or stuffy nose or episodes of sneezing, apart from cold?’ and the results of the skin test.

The patients with allergic rhinitis were distributed according to the ARIA classification (5). In particular, according to the duration of the symptoms, the rhinitis was divided into intermittent (<4 days/week or <4 weeks/year) and persistent (>4 days/week and >4 weeks/year). The rhinitis was moderate/severe in those patients who replied ‘yes’ to one or more of the following items: abnormal sleep, impairment of daily work or school, impairment of leisure activities and presence of troublesome symptoms. The rhinitis was mild in those patients who replied ‘no’ to all previous items.

The clinical diagnosis of asthma was confirmed by the affirmative answers to a selection of questions from the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. A diagnosis of current asthma was made when patients gave affirmative answers to the following question: ‘Have you ever experienced asthma?’ and to at least one of the questions below:

  • 1
    In the past 12 months, have you experienced wheezing or whistling in your chest?
  • 2
    In the last 12 months, have you ever had an asthma attack during the day which occurred at least once a week?
  • 3
    In the last 12 months, have you had night time asthma symptoms more than twice a month?
  • 4
    In the last 12 months, have you taken asthma medication?

As the study was performed in a clinical setting, clinical judgement was involved to overcome possible misunderstandings between the clinical and questionnaire-related diagnoses. In particular, patients suffering from nasal or bronchial diseases, which are clearly different from allergic rhinitis and asthma (for instance nasal polyps or chronic obstructive pulmonary disease [COPD]), were excluded despite their affirmative answers to the questionnaire.

Statistical analysis

For all analyses, P-values < 0.05 were regarded as statistically significant. Fisher’s exact test was used to determine, if there were non-random associations between two dichotomous variables. The Cochran–Armitage test was used to test for trend in binomial proportions across ordered levels of the ARIA classification. All statistical analyses were performed using sas™ software (Release 8.2, SAS Institute Inc., Cary, NC, USA; Procedures: FREQ, MEANS).

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Clinical presentation of allergic rhinitis

One hundred and thirty-nine of the 154 allergists completed the study. Due to unavailable questionnaires and/or skin test data, out of the 1610 patients recruited only 1321 (84%) were eligible. The sample was made up of adults, slightly more females than males; the majority were non-smokers and was fairly well distributed throughout the country (Table 1). A majority of patients (73.4%) were polysensitive. Consistent with the ARIA classification, mild intermittent rhinitis was diagnosed in 102 patients (7.7%), moderate/severe intermittent in 226 patients (17.1%), mild persistent in 153 (11.6%), and moderate/severe persistent in 840 (63.6%) (Table 1).

Table 1.   Demographic characteristics, allergic sensitization and ARIA classification of rhinitic patients
  1. NR, not recorded.

Sample size1321
Male gender47.0%
Age (years)
 Mean (SD)34 (12)
 Range18–80
 Median32
Geographic area
 North43.9%
 Centre12.1%
 South/Islands43.9%
 NR28
Smoking status (%)
 Never smoked73.1
 Former9.0
 Current17.9
Number of sensitizations (%)
 One26.6
 Two or more 73.4
Allergens (%)
 Grass pollen57.6
 House dust mite47.2
 Pellitory41.3
 Olive26.6
 Birch24.6
 Cupressacee16.4
 Mugwort15.6
 Hazelnut15.6
 Cat14.7
 Dog9.4
 Ambrosia8.3
 Alternaria5.8
 Others4.1
Rhinitis classification (ARIA) (%)
 Mild intermittent7.7
 Moderate/severe intermittent17.1
 Mild persistent11.6
 Moderate/severe persistent63.6

A high prevalence of comorbidity between rhinitis and asthma (616/1321 = 46.6%) was documented in our survey. A majority of the patients [1060 (80.24%)] were on medication at the time of their specialist visit and the group of untreated patients showed an overall milder disease than treated patients (Table 2). Of these, 523 (49.33%) had been prescribed only one drug, 446 (42.07%) had been prescribed two different categories of drugs and 91 (8.58%) patients were taking more than two categories of drugs. The class of drugs taken by patients either as a single therapy or as treatment combinations is summarized in Table 3.

Table 2.   ARIA classification: untreated patients vs treated patients
ARIA classificationUntreatedTreated
Number of patients%Number of patients%
  1. Number of patients = 1321.

  2. P-value from Chi-square = 0.041.

Mild intermittent2710.3757.1
Moderate/severe intermittent4617.618017.0
Mild persistent3914.911410.7
Moderate/severe persistent14957.169165.2
Table 3.   Distributions of the classes of drugs taken by rhinitic patients on only one drug (number of patients = 523) and of the most common drug combinations
DrugsNumber of patients%
  1. anti-H1, H1 antihistamine.

  2. * The combinations, whose frequency is <1% and which group 31 patients, are not shown (number of patients = 537).

Single-drug therapy
Oral anti-H126149.90
Intranasal steroid14928.49
Decongestant5310.13
Intranasal anti-H1285.35
Chromones203.82
Oral steroid122.29
Total523 
Treatment combinations
Oral anti-H1 + intranasal steroid30356.42
Oral anti H1+ decongestant387.08
Oral anti-H1 + intranasal anti-H1264.84
Oral anti-H1 + intranasal anti-H1 + intranasal steroid264.84
Oral anti-H1 + chromones213.91
Oral anti-H1 + intranasal steroid + oral steroid162.98
Oral anti-H1 + chromones + intranasal steroid152.79
Oral anti-H1 + oral steroid152.79
Intranasal steroid + chromones132.42
Intranasal steroid + oral anti-H1 + decongestant112.05
Intranasal steroid + decongestant81.49
Intranasal steroid + intranasal anti-H181.49
Chromones + intranasal anti-H161.12
Total506 + 31* 

The ARIA parameters and rhinitis treatments

Different outcomes for duration and severity (each considered as a single parameter) on drug therapy for rhinitis were found. Oral antihistamines apart, no significant difference on drug prescriptions between patients with intermittent and persistent disease was found (Table 4). On the other hand, a significant percentage of patients with mild rhinitis, either did not seek medical treatment at all or were taking fewer oral antihistamines, topical nasal steroids and systemic steroids than those patients with moderate/severe rhinitis. The different outcomes of duration and severity of rhinitis were confirmed by the complete application of the ARIA classification (Table 5). If the ARIA classification was placed in order of the severity, the number and the strength of the associations were greater than, if the ARIA classification was placed in order of the duration (Table 5). In conclusion, the impairment of the patients’day-to-day life has a greater effect than duration on drug prescriptions for rhinitis.

Table 4.   Association between duration or severity of rhinitis (according ARIA classification) and rhinitis therapy
ClassificationRhinitis therapy
Any treatmentChromonesDecongestantIntranasal anti-H1Oral anti-H1Intranasal steroidOral steroid
  1. anti-H1, H1 antihistamine.

  2. Number of patients = 1321.

  3. P-values from Fisher’s Exact Test.

Intermittent (%)77.75.88.55.851.239.63.7
Persistent (%)81.16.710.29.458.743.54.4
P-value0.2010.6070.4530.0510.0210.2220.637
Mild (%)74.17.18.67.440.036.11.2
Moderate/severe (%)81.76.410.08.760.944.15.0
P-value0.0080.6730.5580.617<0.0010.0200.005
Table 5.   Association between complete ARIA classification of rhinitis and rhinitis therapy
ARIA classificationRhinitis therapy
Any treatmentChromonesDecongestantIntranasal anti-H1Oral anti-H1Intranasal steroidOral steroid
  1. anti-H1, H1 antihistamine.

  2. Number of patients = 1321.

  3. P-values from Cochran-Armitage Trend Test.

Arranged by duration
Mild intermittent (%)73.59.810.84.934.331.41.0
Moderate/severe intermittent (%)79.64.07.56.258.843.44.9
Mild persistent (%)74.55.27.29.143.839.21.3
Moderate/severe persistent (%)82.37.010.79.461.444.45.0
P-value0.0280.7150.3140.048<0.0010.0500.116
Arranged by severity
Mild intermittent (%)73.59.810.84.934.331.41.0
Mild persistent (%)74.55.27.29.143.839.21.3
Moderate/severe intermittent (%)79.64.07.56.258.843.44.9
Moderate/severe persistent (%)82.37.010.79.461.444.45.0
P-value0.0050.9590.3440.149<0.0010.0140.013

The ARIA parameters and asthma therapy

In the subgroup of patients who presented allergic rhinitis and asthma comorbidity (616 patients), the characteristics of rhinitis had a weak effect on the treatment for asthma. Both the percentage of nontreated patients (25%) and the distribution of asthma treatments in the remaining 75% of the patients undergoing therapy were homogeneous in all the ARIA categories. The only exceptions regarded the significant association between the severity of rhinitis and the use of antileukotrienes (= 0.026) and between the duration of rhinitis and the use of oral steroids (= 0.009) (Table 6). These different associations remained significant in the comparison of the complete ARIA classification arranged by duration and severity (data not shown). Even though no differences in the rhinitis ARIA profile were recorded between patients suffering from rhinitis as also rhinitis and asthma (Table 7), the presence of asthma comorbidity increases the intake of drugs for rhinitis, in particular, a significant greater intake of inhalant and oral steroids was documented (Table 8).

Table 6.   Association between duration or severity of rhinitis (according ARIA classification) and asthma therapy
ClassificationAsthma therapy
Any treatmentChromonesTheophyllineBeta 2 short actingBeta 2 long actingAnti-leukotrieneInhalant steroidOral steroid
  1. Number of patients = 616.

  2. P-values from Fisher’s Exact Test.

Intermittent (%)77.0%6.82.533.536.69.343.50.6
Persistent (%)75.44.01.136.342.011.951.05.3
P-value0.7480.1910.2500.5660.2630.4670.1190.009
Mild (%)74.37.60.037.136.24.851.42.9
Moderate/severe (%)76.14.11.835.241.512.548.54.3
P-value0.7080.1300.3700.7370.3280.0260.5940.785
Table 7.   Relationship between the presence of asthma and the rhinitis features consistent with the ARIA classification
ARIA ClassificationWithout asthmaWith asthma
Number of patients%Number of patients%
  1. Number of patients = 1321.

  2. P-value from Chi-square = 0.063.

Mild intermittent537.5497.9
Moderate/severe intermittent11416.211218.2
Mild persistent9713.8569.1
Moderate/severe persistent44162.539964.8
Table 8.   Association between the intake of drugs for rhinitis in patients without or with asthma
 Rhinitis therapy
Any treatmentChromonesDecongestantIntranasal anti-H1Oral anti-H1Intranasal steroidOral steroid
  1. anti-H1, H1 antihistamine.

  2. Number of patients = 1321.

  3. P-values from Chi-square Test.

Without asthma (%)76.66.59.48.555.238.33.0
With asthma (%)84.46.510.28.458.847.45.7
P-value<0.0010.9820.5970.9640.189<0.0010.015

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

The study was performed in the spring of 2002, when the ARIA guidelines had just been introduced in Italy, therefore, the aim of the study was not to assess the effect of the adoption of the new guideline on the prescribing habits of physicians, but to evaluate a methodological aspect, i.e. to identify which parameter of the new ARIA guidelines used to grade rhinitis plays a role in the prescription of drugs for allergic rhinitis and asthma. Our data demonstrate that the concise ARIA evaluation of the impact on quality of life had a more relevant effect than the duration of symptoms on the treatment of rhinitis.

A significant association between the severity of the rhinitis and the percentage of patients receiving treatment and between the severity of rhinitis and the percentage of patients on oral antihistamines, topical and systemic steroids was found (Tables 4–5). These findings are consistent with those of other investigators and suggest that the impact of the disease on quality of life forms the basic motivation for seeking medical assistance and is the driving factor for the type and amount of drug therapy prescribed (9, 11, 12).

A combination of topical steroids and antihistamines was the most widespread treatment, followed by the single use of antihistamines or of topical steroids (Table 3); these findings are consistent with results of other authors (11, 13). Another noteworthy finding of our study is that more than 80% of patients had moderate-to-severe symptoms despite therapy. Consistent with studies in other countries, our results confirm that a majority of the patients with allergic rhinitis were receiving treatment when they were referred to a specialist (13).

Our study was conducted in the springtime and over half the patients were allergic to pollens (Table 1), our results in particular underline the severe impairment of the pollination period in allergic patients. Both the rhinitis responsiveness to the available treatments and the methodological issues should be considered in this finding. Regarding the first point, numerous studies have proven drug efficacy in rhinitis (5, 14), but patients remain largely unsatisfied (15). Indeed, compared with placebo, the computed effect size of different common treatments for allergic rhinitis revealed rather modest beneficial effects (16, 17); furthermore, a recent study demonstrated that the addition of levocetirizine to the treatment with fluticasone for seasonal rhinitis failed to significantly improve symptoms (18). As regards the latter point, the methodological limitations include the absence of any data recording the dosage of medication administered and patient’s adherence to therapy.

Moreover, our results may have been affected by a selection bias – only those patients poorly responding to the usual treatments were referred to a specialist, even though, similar results were found in a survey performed in a general practice setting (9). However, the most important methodological objection concerns the use of the ARIA classification in treated patients. According to the guidelines, this classification should be used on nontreated patients to provide an evidence-based and stepwise treatment for rhinitis, but several studies, both in the specialist and the primary care setting, document that a majority of the patients were already being treated when they contacted the doctor (9, 13, 19).

The persistence of a significant impairment evaluated by the ARIA classification despite therapy in most of the patients consulting a GP has already been documented in another large survey (9). As the non-orthodox use of the ARIA classification in an epidemiological study is almost inevitable, the issue requires comment.

Currently, classification relies on a single dimension: the patient’s perspective (perceived symptoms). As our findings seem to suggest that the ARIA classification incorporates the effects of treatment, the assessment of a second dimension: the doctor’s perspective (therapy), should also be taken into account. This change shifts the classification from the simple measurement of the severity of the disease (in untreated patients), to a more complex measurement which takes into account the responsiveness to the therapy, i.e. the control of the disease (20).

The relevance of this issue was confirmed by the absence of any difference in rhinitis severity between patients with and without asthma comorbidity (Table 7), notwithstanding a significant greater intake of inhalant and oral steroids to treat rhinitis in the first group was found (Table 8). In order to extend the use of the ARIA guidelines to epidemiological or follow-up studies, this point should be examined at the next ARIA guidelines update. Also for the GINA guidelines for asthma, the role of treatment in the grading of the disease was added after the first version (1995), which has been proposed in untreated patients (21). An analysis of the relationship between rhinitis and asthma through the assessment of the ARIA categories and the drug treatments essentially produces two results:

  • 1
    An overall most severe rhinitis is associated with the asthma comorbidity (Table 7).
  • 2
    The ARIA categories of rhinitis have a weak effect on the treatment for asthma in the subgroup of patients with comorbidity (Table 6).

The first result is consistent with the hypothesis suggesting that rhinitis and asthma are manifestations of a single chronic inflammatory syndrome, in which the mildest and earliest forms primarily affect the upper airway (3). Indeed, in our survey, the interplay between the ARIA classification and the therapy demonstrates that rhinitis is milder in non-treated than in treated patients (Table 2). In treated patients, the interference of therapy prevents the ARIA classification from revealing any difference between patients with and without asthma, but a significant greater use of inhalant and oral steroids for rhinitis in the subgroup with comorbidity (Table 8) indirectly demonstrates that the most severe rhinitis is associated with the presence of asthma.

The second result could be related to two different interpretations: the first is that the asthma therapy was prescribed independently from the clinical features of rhinitis; such behaviour is consistent with the organ-related management of patients with comorbidities, which occurs when different specialists treat the same patient (22). On the other hand, the weak effect of the ARIA categories on asthma treatment could be caused by the complexity of the interference between the rhinitis therapy and the symptomatic features of the upper and the lower airways. This is particularly evident with drugs like oral steroids, which are able to treat acute asthma.

The significant association between oral steroids and persistent rhinitis suggests that the control of bronchial symptoms can be achieved much more easily in patients with intermittent, rather than persistent rhinitis. The involvement of the lower airways in patients with intermittent rhinitis has been reported (10, 23), but the bronchial impairment in these patients is milder than in patients with persistent rhinitis (23). The surprising absence of an association between the severity of rhinitis and the use of oral steroids to treat asthma (Table 6) could be related to a significant association between the use of oral steroids and severe rhinitis (Tables 4–5). The use of oral steroids for severe rhinitis can reduce the need of this therapy for asthma, thus undermining the association between the severity of rhinitis and the use of oral steroids for asthma. Indeed, worsening of the upper airway disease affects the lower airway (3), but numerous findings reveal that the treatment of rhinitis can improve asthma symptoms (24, 25). In our survey, the interplay between upper and lower airways treatment is less evident for the long lasting therapy of asthma. The significant association between the severity of rhinitis and prescription of antileukotrienes could be indicative of the intention to treat, with a single drug, patients with severe rhinitis and asthma (26), but the absence of further association weakens the strength of such a relationship. In this finding, a methodological issue, concerning the absence of a record of the therapeutic doses administered into the treatment of asthma played an important role. This was particularly relevant for the inhalant steroids, whose dosage is related to the severity of asthma.

In conclusion, our findings reveal certain methodological issues of the ARIA classification. A direct correlation between the severity of rhinitis and the amount and the type of drug prescribed for rhinitis was found, whereas the association between the ARIA categories of rhinitis and asthma therapy was weak. In epidemiological surveys, a vast majority of the patients are treated, and the ARIA classification is able to detect a relevant impairment notwithstanding therapy. Further studies will be necessary to better understand the interplay between the ARIA classification and the therapy of upper and lower airways.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

The authors wish to thank GlaxoSmithKline Italy for their logistical assistance and Paul Bowerbank for his help in reviewing the English of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References
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