Nasal hyper-reactivity is a common feature in both allergic and nonallergic rhinitis

Authors


  • Edited by: Pascal Demoly

Abstract

Background

Nasal hyper-reactivity is an increased sensitivity of the nasal mucosa to various nonspecific stimuli. Both allergic rhinitis (AR) and nonallergic rhinitis (NAR) patients can elicit nasal hyper-reactivity symptoms. Differences in the prevalence or type of nasal hyper-reactivity in AR and NAR patients are largely unknown. In this study, we quantitatively and qualitatively assessed nasal hyper-reactivity in AR and NAR.

Methods

In the first part, an analysis of a prospectively collected database was performed to reveal patient-reported symptoms of hyper-reactivity. In the second part, cold dry air provocation (CDA) was performed as a hyper-reactivity measure in AR and NAR patients and healthy controls, and symptoms scores, nasal secretions and peak nasal inspiratory flow were measured. Comparisons were made between AR and NAR patients in both studies.

Results

The database analysis revealed high hyper-reactivity prevalence in AR (63.4%) and NAR (66.9%). There were no differences between AR and NAR in terms of the number or type of hyper-reactivity stimuli. Hyper-reactivity to physical stimuli did not exclude a response to chemical stimuli, or vice versa. CDA provocation resulted in a significant increase in rhinitis symptoms and the amount of nasal secretions in AR and NAR patients, but not in controls.

Conclusions

We found no quantitative or qualitative differences in nasal hyper-reactivity between AR and NAR patients. It is not possible to differentiate NAR subpopulations based on physical or chemical stimuli.

Nasal hyper-reactivity is an increased sensitivity of the nasal mucosa to everyday nonspecific stimuli, both physical and chemical, such as sudden temperature changes, cigarette smoke or chemical pollutants [1, 2]. Nasal hyper-reactivity can be found in different types of rhinitis, varying from common cold to both allergic and nonallergic chronic rhinitis [3, 4]. However, specific data on prevalence and type of nasal hyper-reactivity in different types of rhinitis are very limited. There is only one small epidemiological study by Shusterman et al. [5], which evaluated self-reported nasal hyper-reactivity in allergic rhinitis (AR) (31 patients) and nonallergic rhinitis (NAR) (29 patients). The only study with patient groups of sufficient size that compared nasal hyper-reactivity of AR with that of NAR is the study of Lindberg et al. [6]. In this study, however, they reported only symptoms after the chemical exposure to cigarette smoke and perfumes to be similar in both groups, and hyper-reactivity to other physical stimuli was not investigated. Another limitation of this study was the lack of a control group.

The lack of assessment of physical stimuli is relevant because in recent years, the Food and Drug Association (FDA) imposed to differentiate NAR patients based on hyper-reactivity to chemical and physical sensitivity only [7]. Bronchial hyper-reactivity is a common and aspecific symptom of diseased lower airway mucosa without exclusive sensitivity to chemical or physical stimuli only. It seems likely that the same applies to nasal hyper-reactivity in the upper airways. This would assume no differences in nasal hyper-reactivity between types of rhinitis or in sensitivity to types of aspecific stimuli between patients.

In this study, we investigated quantitative and qualitative aspects of nasal hyper-reactivity in AR and NAR by means of patient-reported responses to different forms of nasal hyper-reactivity. We also addressed whether it is possible to identify subtypes of hyper-reactivity based on responses to physical or chemical stimuli only. To further validate the patient-reported outcomes, we performed cold dry air (CDA) provocation in a random selection of AR and NAR patients and healthy controls.

Methods

Study design

We performed a prospectively collected database analysis of chronic rhinitis patients (Database study) to elucidate the rate of hyper-reactivity based on patient-reported symptoms. To validate these results, we performed a CDA provocation study to measure hyper-reactivity in AR and NAR patients and healthy controls (Figs 1 and 2).

Figure 1.

Subjective report of rhinorrhea (A) and objective amount of nasal secretion (B) in healthy controls, AR and NAR patients before and after CDA provocation.

Figure 2.

Subjective report of nasal congestion (A) and objective PNIF values (B) in healthy controls, AR and NAR patients before and after CDA provocation. Individual patient results are shown in small circles; median results for each group are shown in large squares.

Database study

Patient characteristics

The patients were prospectively recruited from the outpatient clinic of the Department of Otorhinolaryngology of the Academic Medical Centre, Amsterdam, the Netherlands. All patients had a positive history of rhinitis symptoms and were referred to our tertiary care outpatient clinic by their general practitioner or another otorhinolaryngology clinic. AR patients had at least one positive skin prick test result and clinical symptoms relevant to their sensitization. NAR was defined as clinically relevant symptoms of rhinitis without positive skin prick test results. Severity of symptoms was assessed according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines [8]. We excluded patients with chronic rhinosinusitis (CRS) with or without nasal polyposis, nasal surgery within the previous 3 months, a serious and/or unstable disease and history of immunotherapy and patients with other causes of rhinitis (infectious or anatomic). Patients were not allowed to use antihistamines 14 days before inclusion, and patients using medication affecting nasal function were excluded. All patients in whom symptoms could not be explained by sensitization only were excluded, leaving only those with classic AR and NAR.

Skin prick test

To assess allergic sensitization, we used the Global Allergy and Asthma European Network's (GA2LEN) standardized method of skin prick test (SPT) [9]. Patients were asked to stop their antihistamine medication 14 days before SPT. A positive reaction to SPT was defined as a skin reaction >3 mm for one or more of the 18 tested allergens and no reaction to the negative control.

Patient-reported outcomes

All rhinitis patients were routinely asked to fill in a questionnaire regarding symptoms of rhinitis, allergy and nasal hyper-reactivity. In regard to nasal hyper-reactivity, patients were asked to report sensitivity to temperature change, tobacco smoke or scents, exercise, emotional stress and humidity. Patients were allowed to choose more than one option. Patients were asked to report number and type of rhinitis symptoms, duration and periods of symptoms and severity according to ARIA classification [8].

CDA provocation study

Patient characteristics

Cold dry air provocation was performed in a random selection of the database patients (AR and NAR) as well as in healthy volunteers. Patients were classified according to ARIA guidelines [8]. Patients were asked to stop antihistamine medication 4 weeks before CDA provocation and any medication possibly influencing nasal function, including all nasal medication, 2 weeks before provocation. A healthy control group consisted of individuals, recruited via advertisement, who had no medical history of rhinitis and a negative skin prick test to allergens. All subjects signed an informed consent form. This study was approved by the institutional Medical Ethics Committee.

Dose escalation CDA provocation

Patients were first provoked with a vehicle, that is, air at room temperature and humidity for 1 min. Following this, patients were provoked with CDA at a temperature of at least −10°C and humidity of around 20% in 5 dose-escalating steps as described in the validated protocol of CDA provocation by Braat et al. [10].

Questionnaires during the CDA provocation

At 1, 5 and 10 min after each provocation (including with the vehicle), patients were asked to assess their symptoms of rhinorrhea, nasal congestion, burning, itching and sneezing on visual analogue scale (VAS, 0–100 mm).

Nasal secretion during the CDA provocation

To assess the amount of nasal secretions, 2 min after each provocation, a 3.5-cm Ivalon® Post-Op Sinus Packing (Endovision BVBA, Holsbeek, Belgium) was placed anteriorly in the same nostril for 3 min. The nasal dressing, placed in a 3-ml BD Falcon™ tube (BD Biosciences, San Jose, CA, USA), was weighed before and after provocation to measure the amount (in mg) of nasal secretions.

Peak nasal inspiratory flow (PNIF) during the CDA provocation

To measure nasal inspiratory flow, we used PNIF 5 min after each provocation. Patients were instructed to exhale through their mouth, place the mask over their nose and mouth in a way that the nose would not be compressed and inspire air through their nose with their mouth closed. Patients were allowed to perform the PNIF exercise three times. The highest recorded value (ml) was used for analysis.

Statistical analyses

In both studies, all statistical analyses were performed using SPSS, version 19.0 for Windows (IBM Corporation, New York, NY, USA). Despite multiple testing, the cut-off value of statistically significance was kept at P values of <0.05. Bonferroni correction was not performed because we did not want to underestimate potential differences between the groups.

Database study

The Fisher's exact test was used to compare hyper-reactivity between NAR and AR based on total prevalence and type of different provoking stimuli.

CDA provocation study

Due to data being not normally distributed, nonparametric statistics was used. The Wilcoxon signed rank test was used to compare rhinitis symptoms before and after CDA provocation measured by means of VAS (0–100 mm), PNIF (ml) and amount of nasal secretions (mg). Median values were used.

Results

Database study

Patient characteristics

Table 1 demonstrates patient characteristics, the use of medication and ARIA classification in the database study. There were no significant differences between both patient groups for age, gender, smoking and ARIA classification, with an exception of asthma, which was more prevalent in the AR group (P < 0.0001, Fisher's exact test). Table 1 also demonstrates the type and frequency of medication use in the previous 4 weeks.

Table 1. Patient characteristics, the use of medication and ARIA classification in the database study
Total, n = 993AR, n = 585NAR, n = 408
  1. AR, allergic rhinitis; ARIA, Allergic Rhinitis and its Impact on Asthma; NAR, nonallergic rhinitis.

  2. a

    Antihistamines were stopped 14 days before inclusion.

Male (%) 45.634.3
Mean age (years)39.043.3
Smoking N (%)122 (20.9)93 (22.8)
Asthma N (%) 100 (17.1)34 (8.3)
Sensitizations (skin prick test) N (%)585 (100.0)0 (0)
Medication use (per patient) N (%)
Medication 292 (49.9)225 (55.1)
No medication 122 (20.9)88 (21.6)
Unknown 171 (29.2)95 (23.3)
Type of medication last 4 weeks N (%)
Nasal corticosteroids 243 (41.5)217 (53.1)
Oral antihistaminesa54 (9.2)8 (2.0)
Xylometazoline (intermittent use) 5 (0.9)2 (0.5)
Nasal sodium cromoglicate2 (0.3)0 (0.0)
Other medication3 (0.5)0 (0.0)
ARIA grading N (%)
Mild intermittent10 (1.7)15 (3.7)
Moderate-to-severe intermittent112 (19.1)64 (15.7)
Mild persistent13 (2.2)12 (2.9)
Moderate-to-severe persistent403 (68.9)281 (68.9)
Undefined47 (8.0)36 (8.8)

Skin prick test

The five most frequent sensitizations (not exclusive of each other) were grass mix (61.9%), house dust mites (56.6%), birch (46.8%), dog (46.5%) and hazel (41.5%).

Patient-reported outcomes

Nasal hyper-reactivity is a common feature in AR and NAR

Table 2 demonstrates the number and type of hyper-reactivity provoking stimuli in AR and NAR patients. There were no differences between AR and NAR patients.

Table 2. Prevalence of the number and type of hyper-reactivity provoking stimuli per AR or NAR patient based on questionnaire reports in the database study
 AR, N (%)NAR, N (%)AR vs NAR (P, Fisher's exact test)
  1. AR, allergic rhinitis; NAR, nonallergic rhinitis.

  2. NS: not significant, P > 0.05.

  3. Italic values denote P = 0.2798 (comparing AR and NAR for responding to at least 1 stimulus).

Number of hyper-reactivity stimuli per patient
None214 (36.6)135 (33.1)NS
At least one 371 (63.4) 273 (66.9) NS
One129 (22.1)87 (21.3)NS
Two 138 (23.6)91 (22.3)NS
Three 68 (11.6)58 (14.2)NS
Four 24 (4.1)26 (6.4)NS
Five12 (2.1)11 (2.7)NS
Total585 408  
Types of hyper-reactivity provoking stimuli
Temperature changes246 (42.1)195 (47.8)NS
Smoke, smells228 (39.0)160 (39.2)NS
Exercise127 (21.7)110 (27.0)NS
Emotional stress101 (1.7)85 (20.8)NS
Humidity63 (10.8)52 (12.7)NS
Total765 602  
No specificity in the reaction to individual stimuli or to classes of stimuli

No significant differences were seen in the type of provoking stimuli reported by AR and NAR patients, with the highest prevalence in both groups being for ‘temperature changes’ and ‘smoke/scents’ (Table 2). We selected individuals who reported ‘temperature change’ and determined whether this would exclude a response to ‘smoke/scents’ [7]. In both AR and NAR, a majority of those reporting sensitivity to ‘temperature change’ also reported sensitivity to ‘smoke/scents’ (58.9% in AR and 53.8% in NAR). As expected in the reciprocal analysis of individuals responding to smoke/scents, we saw no indication of this precluding a response to temperature changes (63.6% in AR and 65.6% in NAR responded to both smoke/scents and temperature stimuli).

Hyper-reactivity is not different between individuals suffering from intermittent or persistent rhinitis

We investigated whether individuals diagnosed with either intermittent or persistent rhinitis (AR or NAR) would demonstrate a different pattern of responsiveness in terms of the number and type of stimuli causing hyper-reactivity (Table 3). There were no significant differences in the number or type of provoking stimuli between intermittent or persistent rhinitis patients. The exclusion was the significantly higher frequency of a single hyper-reactivity stimulus per patient in intermittent vs persistent NAR.

Table 3. Prevalence of the number and type of hyper-reactivity provoking stimuli per patient as a function of rhinitis duration (intermittent or persistent) in the database studya
Number of stimuli per patientIntermittent AR N (%)Persistent AR N (%)Intermittent vs persistent AR P (Fisher's Exact test)Intermittent NAR, N (%)Persistent NAR, N (%)Intermittent vs persistent NAR P (Fisher's Exact test)
  1. AR, allergic rhinitis; ARIA, Allergic Rhinitis and its Impact on Asthma; NAR, nonallergic rhinitis.

  2. NS: not significant, P > 0.05.

  3. a

    ARIA classification (intermittent or persistent) is missing on 47 patients with AR and 36 patients with NAR.

  4. Italic values denote P = 0.9147 (comparing intermittent AR and persistent AR for responding to at least 1 stimulus); P = 0.1802 (comparing intermittent NAR and persistent NAR for responding to at least 1 stimulus).

  5. Bold values denote P = 0.0025 (comparing intermittent NAR and persistent NAR for responding to 1 stimulus only).

Number of hyper-reactivity stimuli per patient
None43 (35.2) 150 (36.1)NS 21 (26.6) 102 (34.8) NS
At least one 79 (64.8) 266 (63.9) NS58 (73.4) 191 (65.2) NS
One27 (20.0) 91 (22.9)NS26 (32.9) 49 (16.7) NS
Two37 (30.0) 90 (21.6) NS21 (26.6) 64 (218) NS
Three13 (10.0) 52 (12.5) NS6 (7.6) 49 (16.7) P  = 0.049
Four2 (0) 21 (5.0) NS4 (5.1) 20 (6.8) NS
Five0 (0) 12 (2.9) NS1 (1.3) 9 (3.1) NS
Total 122 (100)416 (100) 79 (100)293 (100) 
Types of hyper-reactivity provoking stimuli
Temperature changes50 (33.8)180 (31.5)NS40 (37.4)140 (31.2)NS
Smoke, smells52 (35.1)165 (28.9)NS26 (24.3)121 (26.9)NS
Exercise22 (14.9)96 (16.8)NS18 (16.8)84 (18.7)NS
Emotional stress13 (8.8)80 (14.0)NS13 (12.1)64 (14.3)NS
Humidity11 (7.4)50 (8.8)NS10 (9.3)40 (8.9)NS
Total 148 (100)571 (100) 107 (100)449 (100) 

CDA provocation study

Patient characteristics

We performed CDA provocation as a reliable measure of nasal hyper-reactivity in a subpopulation of rhinitis patients [18 patients with AR (mean age 40.3) and 21 with NAR (mean age 47.0)], as well as 17 healthy controls (mean age 31.8). There were no significant differences for gender ratio (AR: NAR, NAR: healthy: P = 0.2753, AR: healthy: P = 1.000, Fisher's exact test). There were no significant differences in age in AR and NAR between the database and the CDA provocation studies (AR: P = 0.682, Mann–Whitney U-test; NAR: P = 0.213, Mann–Whitney U-test).

In AR and NAR, respectively, 83.3% and 72.6% of patients were classified as moderate-to-severe persistent according to ARIA classification, and 5.6% of AR and 14.3% of NAR classified as moderate-to-severe intermittent and 5.6% of AR mild intermittent [8].

Skin prick test

The five most frequent sensitizations were grass mix (94.1%), hazel (47.1%), alder (47.1%), birch (47.1%) and house dust mites (35.3%).

Results of CDA provocation

In contrast to controls, patients with AR and NAR react to CDA provocation

Patient with both AR and NAR demonstrated a significant response to CDA provocation, while the control population did not (Table 4). Specifically, both patient groups demonstrated a significant increase in rhinitis symptoms after CDA provocation (rhinorrhea, congestion and burning, with a trend of congestion in NAR and sneezing in AR) and a significant increase in the amount of secretion. This was in contrast with the control group that did not demonstrate any significant reaction to CDA.

Table 4. Response to CDA provocation in AR patients
Outcome parameterMedian pre-CDA (25-75th interquartiles)Median post-CDA (25-75th interquartiles)Median DeltaPre- vs post-CDA (P, Wilcoxon signed rank test)
  1. CDA, cold dry air; PNIF, peak nasal inspiratory flow; VAS, visual analogue scale.

  2. NS: not significant; bold denotes significant value (P < 0.05).

Allergic rhinitis
Rhinorrhea (VAS, mm) 0 (0.00–1.75) 4 (0.00–0.20) 2.5 P  = 0.008
Congestion (VAS, mm) 0 (0.00–6.75) 7.5 (0.00–36.50) 6.5 P  = 0.04
Burning (VAS, mm) 0 (0.00–3.00) 6 (0.00–25.00) 6 P  = 0.013
Sneezing (VAS, mm) 0 (0.00–1.50)0 (0.00–0.50)0NS
Itching (VAS, mm) 0 (0.00–4.50)0 (0.00–8.00)0NS
Nasal secretion (mg) 30 (30.00–50.00) 65 (30.00–170.00) 40 P  = 0.003
PNIF (ml)150 (117.50–172.50)135 (100.0–170.00)−15NS
Nonallergic rhinitis
Rhinorrhea (VAS, mm)0 (0.004.50)3 (0.0015.00) 1 P  = 0.020
Congestion (VAS, mm) 0 (0.00–10.00)4 (1.00–32.50)2NS
Burning (VAS, mm) 0 (0.00–0.00) 0 (0.00–1.00) 0 P  = 0.039
Sneezing (VAS, mm) 0 (0.00–0.00)0 (0.00–0.00)0NS
Itching (VAS, mm) 0 (0.00–4.00)0 (0.00–1.00)46NS
Nasal secretion (mg) 30 (10.00–50.00) 40 (30.00–80.00) 20 P   =  0.021
PNIF (ml)140 (95.00–180.00)120 (100.00–155.00)−10NS
Healthy
Rhinorrhea (VAS, mm) 1 (0.00–3.50)2 (0.00–8.50)0NS
Congestion (VAS, mm) 0 (0.00–0.00)0 (0.00–3.00)0NS
Burning (VAS, mm) 0 (0.00–0.00)0 (0.00–2.00)0NS
Sneezing (VAS, mm) 0 (0.00–0.00)0 (0.00–0.00)0NS
Itching (VAS, mm) 0 (0.00–0.00)0 (0.00–0.00)0NS
Nasal secretion (mg)40 (30.00–100.00)55 (20.00–90.00)0NS
PNIF (ml)150 (110.00–185.0)140 (125.00–140.00)0NS

The median PNIF after CDA provocation decreased in AR and NAR, with a trend in NAR and not reaching significance in AR. There was no change in PNIF in control patients.

Discussion

In accordance with the concept of nasal hyper-reactivity being a general outcome of disturbed nasal mucosa of the upper airways, our patient-reported outcomes demonstrated no differences in quantitative or qualitative aspects of nasal hyper-reactivity between AR and NAR [11]. Within NAR, the higher frequency of a single hyper-reactivity stimulus per patient in patients with intermittent vs persistent symptoms could be explained by less severe rhinitis symptoms in the former. Hyper-reactivity has been shown to be a phenomenon of uncontrolled disease in rhinitis, conjunctivitis and asthma [12-14].

As we did not perform nasal provocation tests, it is possible that some of the NAR patients had local allergic rhinitis (LAR) causing confounding of patient groups [15]. However, in the past, several studies were performed in our clinic assessing inflammatory cells and cytokines in nasal secretions of NAR patients, and no sign of inflammation was demonstrated in these patients [16-18].

The FDA recently imposed a distinction between nasal hyper-reactivity symptoms exclusively elicited to either physical or chemical stimuli [7]. This distinction, however, was not confirmed in our database analysis. Most AR and NAR patients responded to both physical and chemical stimuli.

To validate the patient-reported outcomes, a CDA provocation was performed. Hyper-reactivity can be objectively determined with either direct (histamine, methacholine, capsaicin) or indirect (CDA provocation) stimuli. CDA provocation, contrary to histamine, is able to distinguish patients with hyper-reactivity from healthy controls [8, 10, 19-21]. In bronchial hyper-reactivity, indirect stimuli, such as CDA, exercise and adenosine monophosphate, also appear to be more clinically relevant and better correlate with eosinophilic inflammation than direct stimuli [22-26]. For this purpose, we randomly selected 25 patients per group from the database study. Unfortunately, not all patients who originally indicated that they were willing to participate did so, because of time and other practical constraints. As we aimed to perform the provocation outside pollen season, we decided to stop further inclusion. This resulted in smaller and unequal sized patient groups for CDA provocation than originally planned. As a result of relatively small group sizes in the latter, there were some differences between patient groups. ARIA classification in the CDA provocation study showed a higher proportion of moderate-to-severe persistent rhinitis compared with the database patient group. Therefore comparisons based on severity of symptoms cannot be performed.

Reactions to CDA were significant for symptoms of rhinorrhea, congestion and burning. This was accompanied by a significant increase in nasal secretions in both AR and NAR, but not in healthy patients. PNIF decreased in both groups; however, it did not reach a statistically significant level. Most likely, this was caused by the large variation in PNIF values and relatively small groups sizes. These results are in agreement with a recent study by Hellings et al., [27] demonstrating a significant response to CDA in both AR and NAR patients compared with controls.

As our results demonstrate that nasal hyper-reactivity is as common in NAR, as in AR, while no inflammatory cells or markers are present in NAR (according to previous studies), the question of the underlying mechanism causing nasal hyper-reactivity remains unknown [16-18, 28]. Possible explanations of nasal hyper-responsiveness can be an upregulation of the nervous system with a (para)sympathetic dysbalance or neurogenic inflammation with release of neuropeptides as part of an antidromic reflex in the nose. Another hypothesis refers to the release of substance P from the trigeminal nerve [28-30]. Substance P is suggested to induce hyper-reactivity in allergic and nonallergic airway disease by directly and indirectly (via histamine and mast cell degranulation) affecting smooth muscle tissue and vasculature [31, 32]. While hyper-reactivity is the result of smooth muscle contraction in lower airway disease, the absence of muscle tissue in the upper airways suggests another pathogenic mechanism, that is, vasodilation and increased vascular permeability. Another interesting aspect of airway hyper-reactivity is a (dysfunctional) role of the mucosal membrane barrier and its phospholipid composition [11, 33].

In conclusion, nasal hyper-reactivity seems to be an indistinctive feature of upper airway disease, irrespective of inflammation.

Conflicts of interest

C. M. van Drunen and W. J. Fokkens receive private sector support for research and/or clinical trials related to the treatment of allergic and nonallergic rhinitis from Allergopharma, ALK-Abello, GlaxoSmithKline, HAL Allergy, MSD, Optinose UK, as well as public sector research support from InterUniveristy Attraction Poles (Belgium), ZonMW (the Netherlands), and Global Allergy and Asthma European Network (EU). C. M. van Drunen has received royalties for legal consultation/expert witness testimony from Stallergens; W. J. Fokkens has received royalties for legal consultation/expert witness testimony for Stallergens, GSK, MSD. Other authors have no potential conflict of interest. Peter W. Hellings is the recipient of unrestricted research grants of GlaxoSmithKline, MSD, and Stallergens and participated in clinical trials on allergic rhinitis of HAL and GlaxoSmithKline.

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