Relationship between bronchial hyperreactivity and bronchodilation in patients with allergic rhinitis

Relationship between bronchial hyperreactivity and bronchodilation in patients with allergic rhinitis Giorgio Ciprandi, MD*; Alessio Signori, BS†; and Ignazio Cirillo, MD‡

Background: Allergic rhinitis (AR) may be considered a risk factor for the onset of asthma. Recently, it has been reported that forced expiratory flow between 25% and 75% of vital capacity (FEF25%⫺75%) may predict a positive response to bronchodilation test in asthmatic children. Moreover, bronchial hyperreactivity (BHR) is frequently detected in AR patients. Objective: To evaluate the possible relationship between the response to bronchodilation test and methacholine challenge, also considering the FEF25%⫺75% values in a large group of patients with persistent allergic rhinitis. Methods: Three hundred sixty-five consecutive AR patients were evaluated. Clinical examination, spirometry, methacholine bronchial challenge, and bronchodilation test were performed in all patients. Results: Two hundred forty-one patients (66%) had ”positive” results for bronchodilation test; FEF25%⫺75% was abnormal in 78 patients (21.4%), and 76 patients (20.8%) had severe BHR. An FEF25%⫺75% cutoff value of less than 58.5% of predicted may optimally (AUC 0.97) discriminate patients with both severe BHR and reversibility. Conclusion: This study confirms previous studies and increases the strength of the role of FEF25%⫺75% as a marker of early bronchial involvement in patients suffering from persistent allergic rhinitis. Moreover, an FEF25%⫺75% value less than 58.5% of predicted may suggest the co-existence of severe BHR and reversibility. Ann Allergy Asthma Immunol. 2011;106:460 – 466. INTRODUCTION Allergic rhinitis is frequently associated with asthma1,2 and may be considered a relevant risk factor for both the onset and the worsening of asthma.3 Both disorders are closely linked, as elegantly demonstrated by 2 studies showing that a nasal allergen challenge can induce bronchial inflammation, and a bronchial allergen challenge can cause nasal inflammation.4,5 Asthma is characterized by a chronic inflammation of the lower airways and by bronchial hyperreactivity (BHR) that in turn leads to recurrent typical asthmatic symptoms caused by airflow obstruction (www.ginasthma.com). Asthma diagnosis is based on clinical and functional evaluation. Spirometry is mandatory in asthmatic patients, and Global Strategy for Asthma Management and Prevention guidelines state that the forced expiratory volume/1 second (FEV1) is the gold standard lung function measurement to evaluate bronchial obstruction. Spirometric parameters are well standardized, and their interpretation is commonly recognized.6,7 In addition, reversibility of airflow obstruction is considered a main func* Affiliations: Department of Internal Medicine, Azienda Ospedaliera Universitaria San Martino, Genoa, Italy; † Department of Health Sciences, Genoa University, Italy; ‡ Navy Medical Corps, La Spezia, Italy. Funding Sources: Paste here. Disclosures: The authors have nothing to disclose. Received for publication January 9, 2011; Received in revised form February 27, 2011; Accepted for publication March 1, 2011. © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.anai.2011.03.001

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tional characteristic of asthma: the bronchodilation test is usually prescribed to demonstrate the reversibility of the bronchial obstruction, so a positive response (such as an increase of 12% or more of basal FEV1 values) would confirm the asthma diagnosis. However, forced expiratory flow between 25% and 75% of vital capacity (FEF25%⫺75%) may be a more sensitive indicator of chronic airflow obstruction than FEV1.8,9 In fact, subjects with mild asthma and normal FEV1 may show impaired FEF25%⫺75% only.10 In this regard, FEF25%⫺75% may be frequently impaired in patients suffering from allergic rhinitis and perceiving nasal symptoms alone.11 Moreover, the American guidelines on rhinitis report that an impaired FEF25%⫺75% may be a marker of early bronchial pathologic conditions in patients with allergic rhinitis.12 An impaired FEF25%⫺75% value (such as ⬍65% of predicted) might predict the presence of reversible airflow obstruction in children with asthma with normal FEV1.13 Conversely, BHR is a paramount feature of asthma. Moreover, BHR may be observed in a high proportion of patients with allergic rhinitis.14 In this regard, a positive bronchial challenge to methacholine could be considered as predictive, because those subjects with allergic rhinitis would progress to develop asthma.15 BHR was reported both in patients with perennial allergic rhinitis and in subjects with seasonal allergic rhinitis,16 and a seasonal variability in BHR was described in subjects sensitized to pollens.17 In addition, a large percentage of patients with allergic rhinitis may have a positive response to the methacholine bronchial challenge.11 A difference between FEV1 and FEF25%⫺75% predicted values of

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greater than 20 may suggest the presence of severe BHR in patients with respiratory allergy.18 A value of FEF25%⫺75% less than 65% of predicted might indicate BHR in patients with allergic rhinitis.19 To our knowledge, no study has investigated methacholine responsiveness and bronchodilation in allergic rhinitis at the same time. For these reasons, the current study aimed at evaluating the possible relationship between the response to a bronchodilation test and the methacholine challenge in a large group of patients with persistent allergic rhinitis. METHODS Patients This cross-sectional study included 365 patients with ages ranging between 19 and 48 years (mean, 24.0 years; standard deviation [SD], 3.8 years), suffering from persistent allergic rhinitis. They were Navy aspirants or soldiers who were referred to the Navy Medical Service for mandatory certification of their health status. The visit included skin prick test, spirometry, bronchodilation test, and methacholine challenge. The visits were performed during the spring immediately before the beginning of training courses. The Navy Review Board approved the study procedure, and written informed consent was obtained from each subject. Study Design and Setting A detailed clinical history was taken, and a complete physical examination was performed. The patients were enrolled in the study on the basis of a diagnosis of allergic rhinitis made by the concordance between positive skin prick test and presence of nasal symptoms after exposure to a sensitizing allergen, according to validated criteria.1 Exclusion criteria were any prior documented history of asthma or referral for asthma symptoms, including cough, wheezing, dyspnea, and shortness of breathing, impaired FEV1 values (such as ⬍80% of the predicted), and less than 0.75 FEV1/FVC ratio, presence of acute or chronic upper respiratory infections, anatomic nasal disorders (eg, nasal polyps, clinically relevant septum deviation), previous or current intensive smoking (screened by expired-CO assessment, such as analyzing carboxyhemoglobin and carbon monoxide levels in a single breath using the Bedfont Micro Smokerlyzer III, Bedfont Scientific Ltd & Decode, Maidstone, England), previous or current specific immunotherapy, and use of nasal or oral corticosteroids, nasal or oral vasoconstrictors, antileukotrienes, and antihistamines during the previous 4 weeks. Subjects receiving drug treatment or with acute upper respiratory airway infection returned after adequate time. Twenty-three subjects were excluded because they were intensive smokers or had FEV1 values less than 80%. Age, sex, duration of rhinitis, FEF25%⫺75%, FEV1 at baseline and after bronchodilation, and methacholine provocation concentration that caused a decrease in FEV1 of 20% (PC20) were registered for all patients in the analysis.

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Skin Prick Test The skin prick test was performed as stated by the European Academy of Allergy and Clinical Immunology.20 The panel consisted of house dust mites (Dermatophagoides farinae and pteronyssinus), cat, dog, grasses mix, Compositae mix, Parietaria officinalis, birch, hazel, olive tree, Alternaria tenuis, Cladosporium, and Aspergilli mix (Stallergenes, Milan, Italy). Spirometry Spirometry was performed by using a computer-assisted spirometer (Pulmolab 435-spiro 235, Morgan, England; predictive values ECCS 1993), with optoelectronic whirl flow meter. It was performed as stated by the European Respiratory Society.6,7 Bronchodilation Test The bronchodilation test was performed according to international guidelines and using a salbutamol metered dose of 400 ␮g. Reversibility was considered if an increase of at least 12% of FEV1 from baseline was achieved, according to international guidelines.6,7 Methacholine Bronchial Challenge Methacholine bronchial challenge was performed the day after the bronchodilation testing to evaluate BHR only if basal FEV1 was equal to or more than 80% of predicted. Aerosol was delivered using a dosimetric computerized supply (MEFAR MB3, Marcos, Italy). The test was performed following the American Thoracic Society guidelines for methacholine challenge.21 The threshold concentration causing a 20% fall of FEV1 (PC20) was calculated. Degree of BHR Severity Three categories of BHR were considered on the basis of PC20: severe PC20 less than 1 mg/mL; mild PC20 between 1 and 4 mg/mL; and borderline PC20 ranging from 4 to 16 mg/mL, according to the criteria of the American Thoracic Society guidelines for methacholine challenge.21 Subjects without response to the cumulative dose of 16 mg/mL were considered to have normal bronchial responsiveness.

Table 1. Clinical and Functional Characteristics of Evaluated Population Characteristic Age (years) Sex M F Duration of rhinitis (years) FEV1 (% predicted) FEF25%⫺75% (% predicted) FEV1 (% increment) FEF25%⫺75% (% increment) BHR (methacholine PC20) mg/mL

Mean(SD)/[median (25th–75th)] or N (%) 24 (3.8) 292 (80%) 73 (20%) 3 (2–6) 90.1 (5.9) 69 (6.5) 12.4 (4.1) 38.8 (8.8) 4.3 (1.1–9)

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Table 2. Distribution of Categorized Functional Characteristics Outcome

n (%)

Bronchodilation test ⬍12% (Negative) ⱖ12% (Positive) FEF25%⫺75% ⱕ65% (Abnormal) ⬎65% (Normal) BHR severity Negative Borderline Mild Severe

124 (34%) 241 (66%) 78 (21.4%) 287 (78.6%) 29 (7.9%) 172 (47.1%) 88 (24.1%) 76 (20.8%)

Statistical Analysis The FEF25%⫺75% at baseline was categorized as 65% or less (abnormal values) and greater than 65% (normal values). In addition, an increase of at least 12% of FEV1 after bronchodilation with respect to baseline FEV1 value was considered a positive test of bronchodilation. Age, duration of rhinitis, FEF25%⫺75%, and FEV1 pre and post bronchodilation values were described as mean and standard deviation if distribution was symmetrical or otherwise as median and 25th through 75th percentiles and as counts and percentages for sex, categorized FEF25%⫺75%, bronchodilation test, and BHR severity. The ␹2 test was used to evaluate the relationship between, separately, FEF25%⫺75%, bronchodilation, and categorized BHR. A multinomial logistic regression was implemented to evaluate the relationships among FEF25%⫺75%, BHR, and age, sex, and duration of rhinitis in the model. BHR was evaluated as an outcome, and the reference category was “negative.” A logistic regression model was implemented to evaluate the relationship between BHR and the bronchodilation test. The dependent variable was BHR expressed as a dichotomous variable, with all grades of severity considered together as “abnormal” responses. Regarding other covariates such as age, sex, and duration of rhinitis, a stepwise procedure was used and statistically significant covariates were added into the model. A box-plot and a bar diagram were created to represent median values of duration of rhinitis into BHR’s group of severity and for different response to bronchodilation.

A scatter-plot, with best linear fitting and Pearson correlation coefficient, showed the relationship between delta FEV1, represented by percentage variation in postbronchodilation FEV1 related to baseline values, and BHR. Moreover, a receiving operator characteristic curve was realized to test the validity of the bronchodilation test (negative, positive) as a diagnostic test for BHR. BHR was considered dichotomous (normal and abnormal bronchial responsiveness). Finally, another receiver operating characteristic curve, to test the validity of FEF25%⫺75% as a diagnostic test to detect patients with both a severe grade of BHR and positive bronchodilation, was assessed. The better cutoff of FEF25%⫺75% to differentiate patients with both a severe grade of BHR and positive bronchodilation from others was found. Best cutoff represented the value for which better classification of patients was achieved with high values for both sensitivity and specificity. Area under curve (AUC) and 95% confidence interval (CI) also were obtained. A value of P ⬍ .05 was considered statistically significant. SPSS (version 18.0; IBM Corporation; SPSS Inc., Chicago, Illinois) was used for statistical analysis. RESULTS Duration of rhinitis was lower than or equal to 3 years in 50% of patients; the mean FEV1 value was 90.1% of predicted, and the mean FEF25%⫺75% value was 69% of predicted; after bronchodilation, the mean increase was 12.4% and 38.8%, respectively; the median for MCH PC20 value was 4.3 mg/mL (Table 1). As for the distribution of categorized bronchodilation test, FEF25%⫺75% and BHR severity, 241 patients (66%) were classified as “positive” for the bronchodilation test; FEF25%⫺75% was abnormal in 78 patients (21.4%), and only 29 patients (7.9%) had no BHR, whereas 76 patients (20.8%) had severe BHR (Table 2). In the subgroup of patients with abnormal values of FEF25%⫺75%, 70.5% had a severe BHR, whereas none of them was negative to MCH challenge (Table 3). Conversely, 72.4% of patients with severe BHR had abnormal values of FEF25%⫺75%. Globally, a statistically significant association between FEF25%⫺75% and severity of BHR was revealed (P ⬍ .001). In addition, a negative relationship between FEF25%⫺75% and severity of BHR was demonstrated (r ⫽ ⫺0.33, P ⬍ .001). Furthermore, the multinomial logistic

Table 3. Joint Distribution of FEF25%⫺75% and BHR with Row and Column Percentages BHR FEF25%ⴚ75% ⬎65 (Normal) % ⬍65 (Abnormal) % Total

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Negative

Borderline

Mild

Severe

29 (100) 10.1 0 (0) 0 29

153 (89) 53.3 19 (11) 24.4 172

84 (95.5) 29.3 4 (4.5) 5.1 88

21 (27.6) 7.3 55 (72.4) 70.5 76

Total

P

287

⬍.001

78 365

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Table 4. Joint Distribution of Bronchodilation and BHR with Row and Column Percentages BHR Bronchodilation Negative % Positive % Total

Negative

Borderline

Mild

Severe

24 (82.8) 19.4 5 (17.2) 2.1 29

44 (25.6) 35.5 128 (74.4) 53.1 172

35 (39.8) 28.2 53 (60.2) 22 88

21 (27.6) 16.9 55 (72.4) 22.8 76

regression revealed an increased risk for severe BHR, considering the decrease of FEF25%⫺75% (odds ratio [OR] ⫽ 1.28; 95% CI, 1.02–1.60; P ⫽ .03). The FEF25%⫺75% was not statistically significant for borderline and mild grades of severity when compared with negative BHR. Regarding bronchodilation, almost all patients with reversibility had BHR, because only 2.1% of them did not respond to MCH challenge (Table 4). Conversely, 19.4% of patients with negative bronchodilation were negative to MCH test. Globally, a statistically significant association between bronchodilation and severity of BHR was revealed (P ⬍ .001). Furthermore, considering patients with severe grades of BHR: the 21 patients with normal values of FEF25%⫺75% had also negative responses to bronchodilation, whereas all of the 55 patients with abnormal FEF25%⫺75% values had positive responses to bronchodilation. Sex and duration of rhinitis resulted in statistical significance and were added into the model of logistic regression (Table 5). An increased and statistically significant probability of having positive (OR ⫽ 9.34; P ⬍ .001; 95% CI, 3.23–26.98) MCH challenge was revealed for patients with positive bronchodilation in comparison with patients with negative bronchodilation. In addition, an increased risk for a 1-year increment of time from diagnosis of rhinitis (OR ⫽ 1.49; P ⫽ .04; 95% CI, 1.01–2.20) was revealed. In fact, duration of rhinitis (Fig 1) had a rising trend at increasing BHR’s grade of severity; and in patients with severe BHR and positive bronchodilation (Fig 2), the median of duration was higher than in other patients. A statistically significant inverse correlation (Pearson ⫽ -0.39; P ⬍ .001) between delta FEV1 (%) and BHR was found (Fig 3). The response to bronchodilation testing fairly allowed discrimination between BHR-positive and BHR-negative patients: AUC ⫽ 0.76 (95% CI, 0.68 – 0.85), sensitivity ⫽ 70%, and specificity ⫽ 82.8%. The FEF25%⫺75% measurement did optimally (AUC ⫽ 0.97) identify patients with both severe

Total

P

124

⬍.001

241 365

grade of BHR and positive bronchodilation: they were 55 (15% of total) (Fig 4). For all of these patients, the baseline FEF25%⫺75% values were 57% or less of predicted; thus, the best cutoff of FEF25%⫺75% resulted in 58.5, with a sensitivity of 100% (patients with a FEF25%⫺75% lower than or equal to 58.5 and positive bronchodilation combined with severe grade of BHR) and a specificity of 94.5%. DISCUSSION Allergic rhinitis may precede asthma onset; indeed, allergic rhinitis may be considered a relevant risk factor for it.22,23 In this regard, patients with allergic rhinitis alone may frequently show impaired FEF25%⫺75% values,24 even in patients with recent onset25: in fact, this parameter has been considered an early marker of bronchial impairment in allergic rhinitis.24 Therefore, impaired FEF25%⫺75% values might be considered a reliable marker of precocious bronchial involvement in patients with allergic rhinitis as reported also by international guidelines on rhinitis.12 In addition, the duration of allergic rhinitis is per se a risk factor for inducing spirometric impairment,26 BHR,27 and positive response to a bronchodilation test.28 Particularly, reversibility to a bronchodilation test might be an early marker of bronchial function deterioration in patients with allergic rhinitis.

Table 5. Results of Multivariate Logistic Regression for BHR OR

P

95% CI for OR Lower Upper

Male vs female 5.75 ⬍.001 Duration of rhinitis (1-year increment) 1.49 .04 Bronchodilation 9.34 ⬍.001

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2.30 1.01 3.23

14.42 2.20 26.98

Figure 1. Boxplot for duration of rhinitis grouped by grade of severity of BHR.

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Figure 4. ROC Curve with FEF25%⫺75% as diagnostic test and BHR severe plus positive bronchodilation as true outcome.

Figure 2. Histogram for median duration of rhinitis grouped by grade of severity of BHR and response to bronchodilation.

Therefore, the current study was designed to correlate the response to bronchodilation test with the response to methacholine bronchial challenge in patients with persistent allergic rhinitis, perceiving nasal symptoms alone, and with normal FEV1 values and normal FEV1/FVC ratio. This study demonstrated that many subjects had impaired bronchial function: more than 60% of them had reversibility to bronchodilation (though with normal FEV1 values and

Figure 3. Scatter-plot of delta FEV1 and BHR.

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FEV1/FVC ratio), approximately 20% had severe BHR, and approximately 20% had impaired FEF25%⫺75% values. Therefore, these findings show that patients with allergic rhinitis may frequently present with functional impairment, also without perceiving overt bronchial symptoms. Second, FEF25%⫺75% values were well associated with BHR: in fact, no patient with abnormal values was negative to the methacholine challenge, whereas approximately 70% of patients with impaired FEF25%⫺75% values had severe BHR. Conversely, only 7% of patients with normal FEF25%⫺75% values had severe BHR. These data thus underline the possible role of FEF25%⫺75% as a predicting factor for BHR in patients with persistent allergic rhinitis as evidenced by previous studies.18,19 Third, the response to the bronchodilation test was also associated with BHR severity: in fact, only 2% of patients with reversibility were negative to a methacholine challenge, whereas approximately 20% of patients without reversibility were negative to methacholine challenge. In this regard, a significant inverse relationship occurred between the methacholine PC20 and the percentage increase of FEV1 after the bronchodilation test. This finding may have clinical relevance, because a positive response to a bronchodilation test might suggest the presence of BHR in patients with allergic rhinitis. Fourth, 2 main risk factors for BHR may be identified: reversibility and duration of rhinitis. The reversibility to the bronchodilation test is the most relevant: in fact, it is characterized by an OR of 9.34. Therefore, a bronchial airflow limitation, documented by reversibility, may suggest with fair reliability the co-existence of BHR in patients with persistent allergic rhinitis. These subjects did not perceive bronchial symptoms. In addition, duration of rhinitis is another relevant risk factor for the development of impaired lung function. This finding might highlight the role of the minimally per-

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sistent inflammation that might allow the development of structural bronchial remodeling. Indeed, continuous exposure to an allergen induces the persistence of inflammatory phenomena that might consequently suggest the hypothesis of a worsening of respiratory function.29 Moreover, this study showed that patients with severe BHR had the longest duration of rhinitis, mainly the patients with reversibility. This last finding underlines the close association among BHR, bronchodilation, and duration of allergic inflammation. In other words, longer rhinitis and severe BHR may concur to determine an initial airflow obstruction detected by reversibility to bronchodilation. However, a longitudinal study should confirm this hypothesis and resolve the open question of whether reversibility can predict progressively worsening obstruction. From a clinical point of view, one must consider in each patient with allergic rhinitis the duration of nasal symptoms. This study underlines the concept that allergic rhinitis may frequently precede asthma onset by impairing bronchial physiology, such as BHR and reversibility. In this regard, an FEF25%⫺75% value of 58.5% or less of predicted may represent an optimal marker to identify patients with both severe grade of BHR and positive response to a bronchodilation test; in fact, the AUC was very high (0.97) as were sensitivity and specificity (100% and 94.5%, respectively). Conceivably, these subjects are at great risk of developing asthma. Thus, a patient with allergic rhinitis who presents with FEF25%⫺75% values up to 58.5% of predicted should be carefully followed up and possibly adequately treated. However, this study had some limitations: The design was cross-sectional without follow-up, and the subjects studied were not completely representative of the general population of patients with allergic rhinitis on the basis of the study design and the subject selection process. In particular, there was predominance of male sex and younger age. Another criticism was the possibility that subjects could be withholding certain data about their health status to obtain certification or its renewal. In addition, a control group of subjects without rhinitis was missing. Moreover, an FEV1 value of 80% or more of predicted is not necessarily normal, and this fact may reflect the results in this study. All of these aspects should be considered as potential limits of this study. Conversely, the strength of this study is the large number of evaluated patients. Of course, further studies should be conducted to confirm these preliminary findings. In conclusion, this study confirms previous studies and increases the strength of the role of FEF25%⫺75% as a marker of early bronchial involvement in patients suffering from persistent allergic rhinitis. Moreover, an FEF25%⫺75% value of 58.5% or less may suggest the co-existence of severe BHR and reversibility, so it may identify early asthmatic bronchial impairment in patients with persistent allergic rhinitis, especially when the rhinitis has been of longer duration.

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Requests for reprints should be addressed to: Giorgio Ciprandi, MD Semeiotica e Metodologia Medica I Viale Benedetto XV 6, 16132 Genoa, Italy E-mail: [email protected]

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