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First published online on February 22, 2007
Chest, doi:10.1378/chest.06-2618
doi:10.1378/chest.06-2618
(Chest. 2007; 131:1345-1352)
© 2007 American College of Chest Physicians
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Diagnostic Classification of Persistent Rhinitis and Its Relationship to Exhaled Nitric Oxide and Asthma*

A Clinical Study of a Consecutive Series of Patients

Giovanni Rolla, MD, FCCP; Giuseppe Guida, MD; Enrico Heffler, MD; Iuliana Badiu, MD; Luisa Bommarito, MD; Antonella De Stefani, MD; Antonio Usai, MD; Domenico Cosseddu, MD; Franco Nebiolo, MD and Caterina Bucca, MD

* From Allergologia e Immunologia Clinica (Drs. Rolla, Guida, Heffler, Badiu, Bommarito, and Nebiolo), University of Torino; Otorinolaringoiatria (Drs. De Stefani and Usai), Ospedale Mauriziano Umberto I; Laboratorio Analisi (Dr. Cosseddu), Ospedale Mauriziano Umberto I; and Dipartimento di Scienze Biomediche ed Oncologia Umana (Dr. Bucca), Università di Torino, Torino, Italy.

Correspondence to: Giovanni Rolla, MD, FCCP, Allergologia e Immunologia Clinica, Ospedale Mauriziano Umberto I, Largo Turati 62-10128 Torino, Italy; e-mail: grolla{at}mauriziano.it

Abstract

Background: Rhinitis and asthma represent the manifestation of one syndrome. Our hypothesis is that in patients with symptoms of persistent rhinitis, lower airway inflammation, lower respiratory symptoms, and lung function abnormalities compatible with asthma are more frequently associated with the diagnosis of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) than with nonallergic rhinitis (NAR).

Methods: One hundred eight of 590 consecutive patients referred in 1 year for rhinitis were enrolled on the basis of nasal symptoms lasting > 4 weeks. Asthma was diagnosed on the basis of symptoms and a positive bronchodilation testing result and/or methacholine hyperresponsiveness. Exhaled nitric oxide (FENO) was measured with the single exhalation method at 50 mL/s.

Results: AR was diagnosed in 39%, NAR in 21%, and CRS in 40%. The prevalence of asthma was significantly higher in AR patients (33%) and CRS patients (42%) than in NAR patients (8.7%) [p = 0.036 and p = 0.005, respectively]. FENO was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34 to 54 ppb; and 53 ppb; 95% CI, 42 to 64 ppb; vs 22 ppb; 95% CI, 18 to 27 ppb; p = 0.002 and p = 0.001, respectively). Patients with asthma had FENO values significantly higher than patients without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001).

Conclusions: The diagnostic classification of persistent rhinitis helps to predict lower airway inflammation (increased FENO) and prevalence of asthma: AR and CRS are associated with higher mean FENO values and higher prevalence of asthma than NAR.

Key Words: allergy • asthma • chronic rhinosinusitis • exhaled breath analysis • exhaled nitric oxide • rhinitis

Epidemiologic, clinical and experimental data have accumulated in the last years indicating that rhinitis and asthma represent the manifestation of one syndrome with a wide spectrum of severity.1 Most data supporting the extensive inflammatory process from the nose to the lower airways come from studies2 on allergic airway disease, even if the same relationship between nasal and bronchial inflammation may also be found in nonallergic inflammatory airway disease. For example, rhinitis is a stronger risk factor for asthma in the nonatopic, compared with the atopic population.3 Nonallergic rhinitis (NAR), which accounts for a quarter of patients with rhinitis,34 may overlap with chronic rhinosinusitis (CRS),5 which is considered a strong risk factor for asthma, independent from allergic sensitization.6 Large epidemiologic studies789 on respiratory health of the general population have either not been designed to identify patients with NAR or have included the risk factor for asthma due to NAR into the risk due to CRS. Finally, duration (persistent vs intermittent) and severity of rhinitis seem to be important factors in determining the association with asthma, both in atopic10 and in nonatopic subjects.3

These considerations suggest that the association between nasal and airway inflammation and between rhinitis and asthma may be different, depending on the precise diagnostic classification of rhinitis (allergic or nonallergic) and its association with sinusitis. In other words, looking in depth into the nose may help to predict lower airway involvement, reinforcing the Allergic Rhinitis and Its Impact on Asthma (ARIA) recommendation2 of testing for asthma patients with allergic rhinitis (AR) and asthma-like symptoms. We expected to find, in clinical practice, that airway inflammation and diagnosis of asthma were most frequently associated with AR and CRS than with NAR. To this aim, we evaluated the prevalence of lower airway symptoms, associated or not with respiratory function abnormalities, and exhaled nitric oxide (FENO) as a marker of airway inflammation11 in a series of consecutive patients referred to our clinic for symptoms of persistent rhinitis. All the patients underwent a stepwise diagnostic approach of rhinitis, according to the ARIA document2 and the European Academy of Allergology and Clinical Immunology position paper12 on CRS, resulting in the following four possible diagnoses: AR, NAR, allergic CRS, and nonallergic CRS.

Materials and Methods

Patients
Consecutive patients referred to Outpatients Allergy Clinic in the period October 2004 to September 2005 for symptoms of chronic persistent rhinitis (sneezing, watery rhinorrhea, nasal itching, nasal obstruction, present > 4 days a week for > 4 consecutive weeks; Fig 1 ) were asked to participate in the study if they had not previously received a diagnosis of asthma. Exclusion criteria were the use of corticosteroids in the last 2 months, antiasthma medications, smoking, and respiratory infections during the last 6 weeks. The study was approved by the local ethics committee, and all subjects gave their informed consent. Thirty healthy subjects (mean age, 41 years; range, 13 to 65 years) served as control group.


Figure 1
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  		Figure 1.. Clinical classification of patients depending on rhinitic symptoms. aIndicates when allergen sensitization and exposure are related to symptoms. bIndicates evaluated also by nasal cytology in order to identify patients affected by NARES.

 
Classification of Rhinitis and Diagnosis of Comorbidities
The flow chart of study design is reported in Figure 1. AR was diagnosed in patients with at least one sensitization clearly related to the actual symptomatic period of the year. Allergic sensitization was assessed using skin-prick tests (SPTs) with a panel of 14 inhalant standard allergens (ALK-Abelló; Hørsholm, Denmark). NAR was diagnosed in patients with no sensitization or with positive SPT results clinically irrelevant.

All the patients complaining of nasal blockage/obstruction and discolored discharge or reduction of smell or facial pain/pressure for > 3 months were referred to an ear, nose, and throat specialist for nasal endoscopy and/or CT scan of the sinuses. CRS was confirmed by the presence of two of the above-mentioned symptoms and endoscopic signs (polyps, mucopurulent discharge from middle meatus, edema/mucosal obstruction primarily in middle meatus) and/or CT signs of mucosal changes within ostiomeatal complex and/or sinuses.12 The severity of rhinitis and rhinosinusitis (mild vs moderate/severe) was assessed respectively according to ARIA document,2 and to the visual analog scale as suggested by the European Academy of Allergology and Clinical Immunology position paper12 on rhinosinusitis.

At the end of combined allergologic and ear, nose, and throat evaluation, each patient could receive one of the following four diagnoses: AR, NAR, allergic CRS, and nonallergic CRS. In all NAR patients, a nasal specimen was obtained by scraping (Rhinoprobe; Arlington Scientific; Springville, UT) and fixing the material on a slide. After staining (Diff-Quick; Medion Diagnostics GmbH; Düdingen, Switzerland) differential cell count was obtained and the diagnosis of NAR with eosinophilia syndrome (NARES) was defined on the basis of the presence of eosinophils > 20% of 400 nonsquamous cells in the nasal smear.13

Airway Involvement and Diagnosis of Comorbidities
The flow chart of study design is reported in Figure 2 . All subjects were inquired about lower respiratory symptoms through a standardized questionnaire,14 and in all of them spirometry and FENO measurements were also obtained. All symptomatic patients (cough, dyspnea, chest tightness, and wheezing) during the last 3 months were further investigated by methacholine inhalation challenge and/or bronchodilation testing. The diagnosis of asthma was based on typical symptoms and on at least a 12% improvement in FEV1 in response to salbutamol (200 + 200 µg metered-dose inhaler) or provocative dose of methacholine producing a 20% fall in FEV1 (PD20) ≤ 800 µg in agreement with current international guidelines.15 Severity of asthma has been classified according to Global Initiative for Asthma.16 Induced sputum obtained by a standardized method17 was examined in all the subjects reporting lower airway symptoms who did not fulfil the respiratory function criteria of asthma. Eosinophilic bronchitis was defined as cough for > 2 months, a sputum eosinophil count > 3%, normal FEV1 and FEV1/FVC ratio (> 80% predicted and > 70%, respectively), an increase of < 12% in FEV1 following inhalation of salbutamol, and PD20 > 1,600 µg.18


Figure 2
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  		Figure 2.. Clinical classification of patients depending on airway involvement. aWhen PD20 was < 800 µg or FEV1 after bronchodilation testing with salbutamol was > 12% compared to the basal FEV1 value. bEosinophilic bronchitis if eosinophils > 3% of differential cell count.

 
Measurements
FEV1 and FVC were measured using a water-sealed spirometer (Biomedin; Padua, Italy). The methacholine inhalation challenge method has been described in details elsewhere.14 Methacholine was delivered via a dosimeter (Mefar; Bovezzo, Italy), and the test was stopped if the FEV1 fell by ≥ 20%, or if the maximum cumulative dose of 2 mg was reached.

Induced sputum was obtained using 4% saline solution administered via an ultrasonic nebulizer and processed as previously described.17 A sputum sample was considered to be adequate when the percentage of squamous cells was < 20% and viability > 70%. Sputum eosinophil differential counts were expressed as a percentage of 400 nonsquamous cells.

Measurements of FENO were obtained 2 h after breakfast, immediately after mouthwash. FENO was measured using a chemiluminescence analyzer (NiOX; Aerocrine AB; Solna, Sweden) calibrated with a certified nitric oxide calibration gas mixture. The online single exhalation technique with exhalation rate 50 mL/s and positive expiratory mouth pressure of 10 cm H2O was applied according to recommendations.19 The mean FENO of three acceptable last 3-s end-expiratory plateau measurements was calculated.

Statistical Analysis
Variables were summarized by descriptive statistics and compared by the analysis of variance or Mann-Whitney test, depending on the distribution of the variables. Categorical variables were compared with the Fisher exact test.20 Data were analyzed with the statistical software (SPSS version 13.0 for Window; SPSS; Chicago, IL). All p values were two tailed, and p values < 0.05 were considered significant.

Results

Among 590 subjects evaluated for nasal symptoms in the period October 2004 to September 2005, 152 subjects had persistent nasal symptoms, but 44 subjects were excluded because of recent airway infection (n = 15), current smoking (n = 32), therapy with corticosteroids (n = 28), or with antiasthma medication (n = 12), leaving 108 patients (49 male; mean age, 39 ± 3.3 years [± SEM]; range, 11 to 75 years) for the present study.

Classification of Rhinitis and Comorbidities
According to the proposed diagnostic algorithm (Fig 1), symptoms suggestive of CRS were present in 60 of 108 patients, eventually resulting in 43 patients (39.8%) receiving a diagnosis of CRS; 17 of them (39.5%) were also sensitized to allergens. Nasal polyps were present in 30 of 43 CRS patients (69.7%); 11 of them had a history of aspirin sensitivity. AR was diagnosed in 42 patients (38.9%), and NAR was diagnosed in 23 patients (21.3%), 7 of them (30.4%) with NARES. The prevalence of lower respiratory symptoms, diagnosis of asthma, spirometric data, and demographic characteristics for each group of patients are reported in Table 1 . Lower respiratory symptoms were more frequent in AR and CRS than in NAR (71.4% and 67.4% vs 39.1%; p = 0.017 and p = 0.037, respectively), with no difference in cough and chest tightness and with a significant increased prevalence in dyspnea (55% and 56% in AR and CRS, respectively, compared to 22% in NAR; p < 0.02) and in wheezing (59.5% and 60.5% in AR and CRS, respectively, compared to 21.7% in NAR, p = 0.004) [Table 1]. The prevalence of asthma was higher in AR (14 of 42 patients, 33.3%) and CRS (18 of 43 patients, 41.9%) than in NAR (2 of 23 patients, 8.7%) [p = 0.036 and p = 0.005, respectively]. Of the 12 of 34 patients with moderate/severe asthma, 8 of them had concomitant CRS (Table 2 ). In patients with CRS, no significant difference in lower respiratory symptoms and prevalence of asthma was found among patients with or without nasal polyps and with or without allergic sensitization (Table 3 ). The severity of nasal disease was associated with a not significantly higher prevalence of asthma (37.1% with moderate/severe symptoms vs 21.0% with mild symptoms, p = 0.128).


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  		Table 1.. Clinical and Demographic Characteristics, Symptoms, Spirometric Data, Diagnosis of Asthma, and FENO in Patients With AR, NAR, and CRS*

 

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  		Table 2.. Characteristics of the Asthmatic Patients (n = 34) Depending on the Severity of the Disease

 

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  		Table 3.. Clinical and Demographic Characteristics, Symptoms, Diagnosis of Asthma, and FENO in Patients With CRS With or Without Nasal Polyps, and With or Without Allergenic Sensitizations

 
Eosinophilic bronchitis was diagnosed in 6 of 26 nonasthmatic patients complaining of lower airway respiratory symptoms who provided an adequate sputum sample. Five of them had CRS with nasal polyps, while one had NARES.

FENO
FENO was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34.2 to 54.4 ppb; and 52.7 ppb; 95% CI, 41.9 to 63.6 ppb; vs 22.2 ppb; 95% CI, 17.7 to 26.6; p = 0.002 and p < 0.001, respectively) [Table 1]. All three groups of patients had mean FENO higher than control subjects (13.5 ppb; 95% CI, 8.2 to 18.8 ppb; p < 0.001 compared both to AR and CRS, and p = 0.002 compared to NAR) [Fig 3 ]. Among patients with NAR, those with NARES had the higher mean FENO (27.8 ppb; 95% CI, 16.4 to 39.2 ppb; vs 19.7 ppb; 95% CI, 10.7 to 28.7 ppb, respectively; p = 0.038). The FENO of patients with NAR, excluding patients with NARES and the two patients with asthma, was not significantly different from healthy control subjects. Among patients with CRS, there was no difference in FENO between allergic CRS and nonallergic CRS (49.9 ppb; 95% CI, 30.9 to 68.9 ppb; vs 54.6 ppb; 95% CI, 40.5 to 68.6 ppb; p = 0.679) and between those with or without nasal polyps (55.6 ppb; 95% CI, 41.9 to 69.2 ppb; vs 46.2 ppb; 95% CI, 26.6 to 65.8 ppb; p = 0.43) [Table 3].


Figure 3
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  		Figure 3.. Mean (95% CI) FENO values in patients with NAR, AR, and CRS depending on respiratory symptoms and diagnosis of asthma. *p = 0.015, comparing AR with asthma to AR with respiratory symptoms without asthma. {dagger}p < 0.05, comparing AR with asthma and AR with respiratory symptoms without asthma to AR with rhinitis only. {ddagger}p < 0.01, comparing CRS with asthma and CRS with respiratory symptoms without asthma to CRS with rhinitis only. There were no significant differences in FENO values in all subgroups of NAR patients. Mean FENO values of AR, CRS (both p < 0.001), and NAR (p = 0.002) are significantly higher than healthy subjects (HS).

 
In all the patients, those with asthma had FENO values significantly higher than those without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001). When looking at the relationship between lower respiratory symptoms and FENO, in AR there was a significantly progressive increase of FENO starting from patients without lower respiratory symptoms (24.5 ppb; 95% CI, 18 to 31 ppb) to patients with lower respiratory symptoms without functional criteria of asthma (38 ppb; 95% CI, 27 to 49 ppb), to patients with asthma (68 ppb; 95% CI, 45 to 92 ppb) [Fig 3]. However, CRS patients with lower respiratory symptoms, whether or not they received the diagnosis of asthma, had similar mean FENO values, significantly increased compared to patients without lower respiratory symptoms (Fig 3).

Allergenic Sensitization
Data on allergic sensitization are reported in Table 4 showing no difference between AR and allergic CRS patients.


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  		Table 4.. Prevalence of Sensitizations to Common Inhalant Allergens and Distribution of Monosensitizations and Multisensitizations in AR and in the Atopic Group of CRS Patients*

 
Discussion

In a consecutive series of patients referred to an allergy clinic for chronic persistent rhinitis symptoms, airway inflammation, evaluated by increased values of FENO, and diagnosis of asthma were significantly more prevalent in patients with AR and CRS compared to patients with NAR. The prevalence of AR and NAR observed in our selected population (39% and 22%, respectively) was similar to that reported by the retrospective survey conducted by the National Rhinitis Classification Task Force.4 The near-40% prevalence of CRS observed in our patients is not surprising because they had chronic persistent rhinitis symptoms and it is well known that sinusitis is often preceded by and rarely occurs without rhinitis.21 The prevalence of allergic sensitization in our CRS subjects, near 40%, is in the range of 40 to 80% reported in the literature.52223 Our study confirms the close relationship between upper and lower airway diseases. Particularly, as far as AR is concerned, asthma was found in 21% of patients with mild rhinitis and in 37% of patients with moderate/severe rhinitis, a prevalence quite similar to near 24% reported in DREAMS study.10 The near-40% asthma prevalence we found in CRS patients was comparable to that reported in studies2224 involving large series of selected patients with CRS and nasal polyps, in which asthma was found in 20 to 70%. The high prevalence of asthma in patients with AR and CRS is not surprising considering that > 70% of asthmatic patients report either AR or CRS according to a recent study.9 Compared to patients with NAR, AR, and CRS patients had significantly increased values of FENO, reflecting the more frequent asthma comorbidity, which is recognized as the most important condition associated with high levels of FENO. Recently, we found that in patients with rhinitis and asthma-like symptoms, the presence of asthma was associated with higher FENO values.25 FENO was actually significantly increased also in subjects with lower respiratory symptoms who failed to demonstrate lung function changes diagnostic for asthma.

Eosinophilic airway inflammation, even in the absence of a diagnosis of asthma, has been previously reported in patients with asthma-like symptoms and elevated FENO.2627 Sputum examination of our patients with lower airway symptoms demonstrated massive eosinophilia in six patients, who received the diagnosis of eosinophilic bronchitis, and mild eosinophilia (1 to 3%) in other seven subjects, four of them with CRS with polyps (data not shown). Peripheral, as well bronchial, eosinophilia has been frequently observed in patients with CRS with polyps.28 In patients with CRS, possible contribution of inflamed pharynx to the increased values of FENO cannot be excluded because chronic pharyngitis has been reported to be commonly associated with CRS,29 even if the demonstration of nitric oxide production by inflammatory pharynx is presently lacking.

The lower prevalence of asthma we have found in NAR is in disagreement with the first European Community Respiratory Health Survey (ECRHS), in which the prevalence of perennial rhinitis was a major risk factor for asthma, with odds ratios of 11 for the atopic population and 17 for the nonatopic population.3 We suspect that in the ECRHS nonatopic individuals with CRS and NAR may have been "lumped" under the single category of NAR, explaining the discrepancy with our results. Many disorders may be included in nonallergic noninfectious rhinitis.5 Most of them were excluded in our patients with NAR; 30% of them received the diagnosis of NARES, the others probably having idiopathic rhinitis. It is interesting that FENO was significantly higher in the subgroup of patients with NARES compared to the subgroup without NARES, who had values not different from healthy control subjects. Idiopathic rhinitis seems to be a noninflammatory rhinopathy,30 so that is not surprising that lower airway inflammation and asthma are not particularly prevalent in patients with this disorder. In conclusion, our findings confirm the strict relationship between upper and lower airway inflammation in CRS28 and AR.31 In particular, we have found that a precise diagnosis of chronic persistent rhinitis, that is AR or CRS vs NAR, helps to predict lower airway involvement, reinforcing and extending the ARIA recommendation of testing for asthma patients with AR2 and asthma-like symptoms with the suggestion of testing for asthma also the patients with chronic rhinosinusitis and lower respiratory symptoms.

Acknowledgements

The authors thank Ms. Luisa Verda and Mr. Marco Pelà for technical help.

Footnotes

Abbreviations: ANOVA = analysis of variance; AR = allergic rhinitis; ARIA = Allergic Rhinitis and Its Impact on Asthma; CI = confidence interval; CRS = chronic rhinosinusitis; ECRHS = European Community Respiratory Health Survey; FENO = exhaled nitric oxide; NAR = nonallergic rhinitis; NARES = nonallergic rhinitis with eosinophilia syndrome; PD20 = provocative dose of methacholine producing a 20% fall in FEV1; ppb = parts per billion; SPT = skin-prick test

This work was supported by a grant of Regione Piemonte Ricerca Scientifica Applicata 2004.

The authors have no conflicts of interest to declare.

Received for publication October 25, 2006. Accepted for publication January 3, 2007.

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