Local allergic rhinitis: entopy or spontaneous response?
© Gelardi et al. 2016
Received: 27 July 2016
Accepted: 10 October 2016
Published: 6 December 2016
The existence of a local allergic rhintis was proposed on the basis of the detection of nasal IgE in the absence of a systemic sensitization. Nevertheless, the significance of this phenomenon remains still unclear.
We assessed the presence of mucosal nasal IgE in patients with ascertained allergic rhinitis, nonallergic rhinitis with inflammation and in healthy controls.
Consecutive patients with a well ascertained diagnosis (clinical history, skin prick test, specific IgE assay, nasal endoscopy, nasal cytology) underwent an immunoenzymatic measurement of specific IgE to grass, cypress, parietaria and olive in nasal scrapings.
Fifteen patients with allergic rhinitis, 12 with non allergic rhinitis and 14 healthy subjects were studied. The patients with allergic and nonallergic rhinitis had higher nasal symptoms as compared to control subjects. Systemic sensitizatition (assessed by skin test and CAP-RAST) was obviously more frequent in allergic rhinitis, than in the other two groups. Allergen-specific nasal IgE could be detected in all groups (86,7, 33,3, and 50 % positive, respectively), even more frequently in the control group than in nonallergic rhinitis patients. No difference among allergens was identified. Out of the 26 non-allergic patients (non allergic rhinitis + controls) nasal IgE were positive in 11(42 %).
According to the results, the presence of nasal IgE against allergens seems to be a non-specific phenomenon, since they can be detected also in non allergic rhinitis and in healthy subjects.
It can be hypothesized that the nasal IgE production represents a form of spontaneous immune response.
KeywordsAllergic rhinitis Nonallergic rhinitis Sensitization Nasal IgE Local allergic rhinitis Entopy
Rhinitis is defined as an inflammation of the nasal mucosa, usually characterized by rhinorrhoea, sneezing, nasal blockage and itching, variably associated. Those symptoms can be accompanied, expecially in the allergic form, by ocular symptoms such as lacrimation, eye itching, conjunctival hyperemia . Allergic rhinitis (AR) is the most common form of non-infectious rhinitis, and it is triggered by an IgE-mediated immune response to allergens. Its prevalence reaches about 35 %  within the general population, and continues to increase .
Also non-allergic conditions can cause symptoms of rhinitis: infections, hormonal imbalance, physical/irritant agents, anatomical abnormalities or drugs . Also the non-allergic form of rhinitis (NAR) are of clinical relevance. These are characterized essentially by an intense inflammatory infiltration, in the absence of a systemic IgE-sensitization. According to the predominant cell types, NAR can be distinguished into NARES (non-allergic rhinitis with eosinophils), NARMA (non-allergic rhinitis with mast cells), NARNE (non-allergic rhinitis with neutrophils) and NARESMA (non-allergic rhinitis with eosinophils and mast cells) [5–8].
Since 1975, another pathophysiological type of rhinitis was proposed, characterized by the presence of allergen-specific IgE only in the nose, without any evidence of systemic sensitisation detectable by skin prick test (SPT) or specific IgE serum assays (CAP-RAST) . This observation suggested the term of “entopy” and, subsequently, of “local allergic rhinitis” (LAR) . These definitions are still a matter of debate, since LAR has not been yet clearly identified as an independent nosographic entity. With the aim of exploring more in depth the local aspects of IgE response, we evaluated the presence of nasal IgE, in two groups of patients with well identified forms of rhinitis, and in healthy controls.
Adult patients were assessed for the presence of allergen-specific nasal IgE, after the type of rhinitis was classified in detail according to the diagnostic procedure. Patients were subdivided into AR (positive SPT and CAP-RAST), and NAR (negative SPT and CAP-RAST, with nasal inflammation). A control group of healthy subjects (no rhinitis symptoms and negative SPT/CAP-RAST) was also included for comparison. The study took place between November 2014 and January 2015 at the Rhinology Unit of the University of Bari. All subjects provided an informed consent for the management of their anonymous clinical data. The inner ethical committee was simply notified, since this was not an interventional study, no placebo was used, and the procedures were part of the standard diagnostic practice. According to the existing laws, also the healthy volunteers could be admitted, after written informed consent. The diagnostic work-up for rhinitis involved: personal clinical history, family history, symptoms (scores and visual analog scale), SPT, CAP-RAST assay, nasal endoscopy, nasal scraping for cytology, and assay for nasal mucosal IgE (see below). Those patients with symptoms of chronic rhinosinusitis, anatomical abnormalities (septal deviation, turbinate hyperthrophy), unilateral symptoms/signs or malignancies were excluded from the assessment of nasal IgE. We also excluded those patients reporting symptoms of possible acute infectious diseases (e.g. common cold) in the last month. All patients were medication-free (local/systemic antihistamines, local/systemic corticosteroids) in the past 2 weeks.
Obstruction and itching were assessed by a 10-cm visual analog scale (0 = totally obstructed to 10 = absent; 0 = absent to 10 = intense, respectively) . Rhinorrhea and sneezing were simply assessed as present/absent. Positive family history was defined as the presence of rhinitis and/or asthma in at least one parent.
Skin prick test
It was performed using a panel of the most common aeroallergens (Stallergenes, Milan, Italy) according to the recommendations of the European Academy of Allergy and Clinical Immunology: house dust mite, grass mix, Parietaria, olive, cypress, mugwort, alternaria, ragweed, cat and dog dander .
Serum IgE assay (CAP-RAST)
Allergen-specific IgE antibodies against the same allergens assayed with skin test were measured by a quantitative immunoassay (Immunocap® Thermo Fisher Scientific Inc. Uppsala, Sweden). The measure range of the test varies from 0.1 to 100 kU/L, and in clinical practice, 0.35 kU/L is commonly used as a the optimal lower cut-off.
It was carried out by a 3,4 mm diameter flexibile-fibroscope (Vision-Sciences® ENT-2000), to assess the presence of major abnormalities, such as septal deviation, polyposis, turbinate hypertrophy, or exudation from the ostiomeatal complex.
This procedure was performed by scraping the middle part of the inferior turbinate with a Rhino-Probe® device (Arlington Scientific). The sample was smeared on a slide, air-dried, then stained with the May-Grünwald Giemsa preparation. The type and cell number were examined using microscopy (Nikon® E600). Cell types were identified, and intracellular components were studied at x1000 in oil immersion. The mean number per 50 fields was calculated and reported [14, 15]. This noninvasive method allows to obtain representative samples of the nasal mucosa and its cellular components .
Samples for nasal IgE assay were collected by Rhino-probe® scraping, as for nasal cytology. Samples were diluted in 0.5 mL physiological solution, then stored at 4 °C. Measurement of nasal specific IgE was carried out by the Immunocap® Specific IgE tests (Thermo Fisher Scientific Inc, Uppsala, Sweden) by a quantitative immunoassay. The test is the same routinely used on serum or plasma samples. In order to establish a lower threshold limit of detection we tested 10 negative controls (healthy, negative SPT and CAP-RAST), and the limit resulted to be 0.17 kU/L. Specific IgE to parietaria, olive, dust mite, cypress and grasses were assayed.
Demographic and clinical characteristics were analyzed by descriptive statistics (% or mean and SD). Continuous variables were analyzed by the t test for independent samples, whereas the Chi-square test was used for qualitative measures. The 3 groups were compared by the ANOVA test. P values for the null hypothesis was set at 0.05. The dedicated software SPSS22 was employed.
Demographic, clinical and sensitization characteristics of the patients
(n = 14)
(n = 12)
(n = 15)
Age, mean ± SD
37.6 ± 16.3
32.4 ± 15.2
37.8 ± 17.7
ASTHMA n (%)
Family history, n (%)
ASA sensitivity, n
SPT positive, n (%)
CAP-RAST positive n(%)
N and % of positive patients to SPT, CAP-RAST and nasal IgE assay in AR patients (N = 15)
Results of nasal cytology in the three studied groups
(n = 14)
NONALLERGIC RHINITIS (n = 12)
ALLERGIC RHINITIS (n = 15)
P value a
23,5 ± 5,8
303,4 ± 19,3
502,5 ± 24,4
82,5 ± 10,4
59,4 ± 7,9
7,3 ± 2,3
8,7 ± 3,9
34,5 ± 5,9
28,5 ± 6,3
10,3 ± 3,7
In general, more than 60 % of patients with NAR receive a generic diagnosis of “idiopathic” rhinitis, that is based on an exclusion criterion . Although the pathophysiology of those forms of rhinitis remains poorly defined, an infiltration of eosinophils, mast-cells and T-lymphoctyes can be frequently evidenced, this supporting the presence of an active inflammation. Based on this, the hypothesis of a “local” allergic reaction has been suggested.
In 1975 Huggings demonstrated, in a qualitative way, the presence of house dust mite-specific IgE in the nose of subjects with symptoms of rhinitis but no evidence of systemic IgE , whereas in 2003 Powe introduced the concept of “entopy” . He assessed 32 patients [11 with AR, 10 with idiopathic rhinitis and 12 controls), and found nasal grass-specific IgE in 3 of the patients with idiopathic rhinitis. Thus the term entopy was used to indicate an allergy confined to the nasal mucosa, in the absence of the evidence of systemic sensitization. Subsequently, in 2004, the strict immunological interaction between T lymphocytes and mast cells in entopy were described [17, 18]. Other authors, evaluating relatively large groups of patients, introduced the term of “local allergic rhinitis” (LAR), to describe the isolated presence of specific IgE in the nasal mucosa. In this regard, the specific nasal provocation test was used to diagnose the disease [11, 19].
Our results confirmed the presence of nasal IgE in AR subjects, usually in agreement with the systemic sensitization profile, revealed by IgE serum assay and SPT. Interestingly, nasal specific IgE could be detected also in a relevant percentage of patients with NAR. More importantly, as unexpected finding, nasal allergen-specific IgE could be found also in 50 % of the healthy control subjects. Although the number of patients studied is small, the percentage remains highly significant. This latter aspect would suggest, as an hypothesis, that a local secretion of IgE could be part of a spontaneous immune response to environmental agents. The identification of nasal allergen-specific IgE also in healthy subjects and in patients with non allergic rhinitis suggest that the concept of LAR should be reconsidered and re-evaluated. These observations also suggest that a more detailed diagnostic approach, involving nasal endoscopy and nasal cytology, should be carried out when the diagnosis is uncertain. In fact, nasal cytology can better define and refine the details of nasal inflammation. The technique is not invasive, does not alter the cellular profile and it is also used in electron microscopy studies for other diseaes [16, 20]. According to this, in the presence of symptoms of rhinitis, without a clear evidence of an allergic sensitization, the detection of mucosal nasal IgE should not be considered as a certain demonstration of LAR. In addition, NAR cannot be immediately defined as LAR, even in the presence of local IgE, because of both severity, cytological pattern and, possibly, the association with polyposis . It can be argued that the aforementioned studies on LAR suffered from a relatively low specificity. The allergen nasal provocation test implies the administration of allergens at high concentration, that can provoke a non specific response expecially in NAR where the nasal mucosa is already inflamed . Also, acoustic rhinometry is now considered poorly reproducible and difficult to standardize . In this regard, the active anterior rhinomanometry after decongestion would be preferable from a functional point of view [24, 25]. To better define the pathophysiological picture, an incremental-concentration nasal specific challenge with each allergen should be performed in NAR and controls, but this was not part of the aims of the present work.
Indeed, the postivity of allergen-specific nasal IgE in the absence of a detectable systemic sensitization remains unclear, needs more experimental proof [26, 27], and is anyway not explained by this experimental study. In fact the main limitation of the present study is the absence of specific nasal provocation tests. On the other hand, the presence of nasal allergen specific IgE in heathy subjects (without symptoms, but exposed to allergens) would not justify the use of a challenge. We can only hypothesize that the nasal mucosa, exposed since birth to allergens, can evoke an IgE synthesis in the context of the immune response, independently of the atopic sensitization . This is indirectly confirmed by the fact that in allergic patients the presence of local nasal and systemic IgE to allergens are consistent, expecially for perennial allergens (parietaria 34,6 % and mites 26 %. Finally, to date there is no formal evidence that LAR can evolve into an AR with a systemic IgE production .
The detectable presence of allergen-specific IgE on the nasal mucosa of subjects with nonallergic rhinitis and healthy subjects suggests that this phenomenon could be the expression of an innate response, rather than a specific local reactivity.
Local allergic rhinitis, SPT, Skin Prick Test
Non-allergic rhinitis with eosinophils
Non-allergic rhinitis with eosinophils and mast cells
Non-allergic rhinitis with mast cells
Non-allergic rhinitis with neutrophils
Availability of data
All the clinical and laboratory data are available, on request, at email@example.com in the respect of patients’ anonimity.
All the signing Authors equally contributed in the clinical work, collection of the data and drafting of the MS. MG, GP and GWC designed the study and prepared the final version of the article. All the Authors have read and approved the present submission.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the Ethical Committee of the University of Bari. All participants signed an informed consent for the treatment of personal and sensible data.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Wheatley LM, Togias A. Allergic Rhinitis. N Engl J Med 2015;372:456–63.View ArticlePubMedPubMed CentralGoogle Scholar
- Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–43.View ArticlePubMedGoogle Scholar
- Cruz AA, Popov T, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, et al. Common characteristics of upper and lower airways in rhinitis and asthma: 460 ARIA update, in collaboration with GA(2)LEN. Allergy. 2007;62:1–41.View ArticlePubMedGoogle Scholar
- Bousquet J, Fokkens W, Burney P, Durham SR, Bachert C, Akdis C, et al. Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper. Allergy. 2008;63:842–53.View ArticlePubMedGoogle Scholar
- Jacobs RL, Freedman PM, Boswell RN. Non allergic rhinitis with eosinophilia (NARES syndrome): clinical and immunologic presentation. J Allergy Clin Immunol. 1981;67:253–7.View ArticlePubMedGoogle Scholar
- Gelardi M, Maselli del Giudice A, Fiorella ML, Fiorella R, Russo C, Soleti P, Di Gioacchino M, et al. Non-allergic rhinitis with eosinophils and mast cells constitutes a new severe nasal disorder. Int J Immunopathol Pharmacol. 2008;21:325–31.PubMedGoogle Scholar
- Pattanaik D. Nonallergic rhinitis. Curr Allergy Asthma Rep. 2014;14:439.View ArticlePubMedGoogle Scholar
- Settipane RA, Kaliner MA. Chapter 14: Nonallergic rhinitis. Am J Rhinol Allergy. 2013;27 Suppl 1:S48–51.View ArticlePubMedGoogle Scholar
- Huggins KG, Brostoff J. Local production of specific IgE antibodies in allergic-rhinitis patients with negative skin tests. Lancet. 1975;2:148–50.View ArticlePubMedGoogle Scholar
- Powe DG, Jagger C, Kleinjan A, Carney AS, Jenkins D, Jones NS. ‘Entopy’: localized mucosal allergic disease in the absence of systemic responses for atopy. Clin Exp Allergy. 2003;33:1374–9.View ArticlePubMedGoogle Scholar
- Rondon C, Romero JJ, Lopez S, Antúnez C, Martín-Casañez E, Torres MJ, et al. Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis. J Allergy Clin Immunol. 2007;119:899–905.View ArticlePubMedGoogle Scholar
- Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126:466–76.View ArticlePubMedGoogle Scholar
- Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, et al. Practical guide to skin prick tests in allergy to aeroallergens. Allergy. 2012;67:18–24.View ArticlePubMedGoogle Scholar
- Gelardi M, Fiorella ML, Russo C, Fiorella R, Ciprandi G. Role of nasal cytology. Int J Immunopathol Pharm. 2010;23:45–9.Google Scholar
- Gelardi M. Atlas of nasal cytology. 2nd ed. Milan: Edi Ermes; 2012.Google Scholar
- Gelardi M, Iannuzzi L, Quaranta N, Landi M, Passalacqua G. NASAL cytology: practical aspects and clinical relevance. Clin Exp Allergy. 2016;46(6):785–92.View ArticlePubMedGoogle Scholar
- Froese A. The presence of two kinds of receptors for IgE on rat mast cells. J Immunol. 1980;139:600.Google Scholar
- Powe DG, Huskisson RS, Carney AS, Jenkins D, McEuen AR, Walls AF, et al. Mucosal T-cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells. Allergy. 2004;59:204–12.View ArticlePubMedGoogle Scholar
- Rondón C, Fernández J, López S, Campo P, Doña I, Torres MJ, et al. Nasal inflammatory mediators and specific IgE production after nasal challenge with grass pollen in local allergic rhinitis. J Allergy Clin Immunol. 2009;124:1005–11.View ArticlePubMedGoogle Scholar
- Caruso G, Gelardi M, Passali GC, de Santi MM. Nasal scraping in diagnosing ciliary dyskinesia. Am J Rhinol. 2007;21:702–5.View ArticlePubMedGoogle Scholar
- Gelardi M, Iannuzzi L, Tafuri S, Passalacqua G, Quaranta N. Allergic and non-allergic rhinitis: relationship with nasal polyposis, asthma and family history. Acta Otorhinolaryngol Ital. 2014;34:36–41.PubMedPubMed CentralGoogle Scholar
- Gelardi M, Quaranta N, Passalacqua G. When sneezing indicates the cell type. Int Forum Allergy Rhinol. 2013;3:393–8.View ArticlePubMedGoogle Scholar
- Clement PA, Gordts F. Standardisation Committee on Objective Assessment of the Nasal Airway, IRS, and ERS. Consensus report on acoustic rhinometry and rhinomanometry. Rhinology. 2005;43:169–79.PubMedGoogle Scholar
- Merkle J, Kohlhas L, Zadoyan G, Mösges R, Hellmich M. Rhinomanometric reference intervals for normal total nasal airflow resistance. Rhinology. 2014;52:292–9.PubMedGoogle Scholar
- Scadding G, Hellings P, Alobid I, Bachert C, Fokkens W, van Wijk RG, et al. Diagnostic tools in Rhinology EAACI position paper. Clin Transl Allergy. 2011;1(1):2. doi:10.1186/2045-7022-1-2.View ArticlePubMedPubMed CentralGoogle Scholar
- Rondón C, Campo P, Blanca-López N, Torres MJ, Blanca M. More research is needed for local allergic rhinitis. Int Arch Allergy Immunol. 2015;167(2):99–100.View ArticlePubMedGoogle Scholar
- Lee KS, Yu J, Shim D, Choi H, Jang MY, Kim KR, Choi JH. Cho SH local immune responses in children and adults with allergic and nonallergic rhinitis. PLoS One. 2016;9:11(6).Google Scholar
- De Schryver E, Devuyst L, Dericke L, Dullaers M, Van Zele T, Bachert C, Gevaert P. Local immunoglobulin E in the nasal mucosa; clinical implications. Allergy Asthma Immunol Res. 2015;7:321–31.View ArticlePubMedPubMed CentralGoogle Scholar
- Rondón C, Campo P, Zambonino MA, Blanca-Lopez N, Torres MJ, Melendez L, et al. Follow-up study in local allergic rhinitis shows a consistent entity not evolving to systemic allergic rhinitis. J Allergy Clin Immunol. 2014;133:1026–31.View ArticlePubMedGoogle Scholar