Carlos E Mijares, MD Former Allergy / Immunology Fellow, pediatrics. University of Kansas. School of Medicine. Kansas City Kansas . Kansas City Missouri. USA. VENEZUELA.
Allergic Rhinitis / Rhinosinuconjuctivitis
ALLERGY has nothing to do with Religion, Herbal remedies, Accupuncture and Probiotics.
. GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • A detailed history is useful in helping distinguish between allergic rhinitis from different types of non-allergic rhinitis, but allergy testing is needed to make a reliable diagnosis, particularly when year round nasal symptoms are present • Demonstration of sensitisation by testing is not sufficient alone to make the diagnosis of allergic rhinitis and must be correlated with clinical history • Differential considerations for allergic rhinitis include various types of non-allergic rhinitis, rhinosinusitis and anatomic problems To correctly diagnose allergic and non-allergic rhinitis, rhinosinusitis and other conditions that may affect the nose and sinuses, history, physical exam and when appropriate, testing should be performed. Some symptoms of allergic rhinitis (nasal drainage, nasal congestion, sneezing, and nasal itching) overlap with some symptoms associated with non-allergic rhinitis, rhinosinusitis, (Table 1) or with other disorders that may involve the nose and sinuses. (Table 2). By history, allergic rhinitis (AR) is more likely than non-allergic rhinitis if there are nasal itching and sneezing, associated eye symptoms (itchy, watery eyes), and nasal symptoms that develop or worsen with exposure to furry pets or seasonally in association with regional allergy pollen seasons (Table 1). Year round symptoms make it more difficult to distinguish AR from non-AR, or even chronic rhinosinusitis, on the basis of history alone. Allergy testing then is needed for a correct diagnosis. However, the mere presence of sensitisation as identified by skin testing or blood testing is not sufficient and must be correlated with the clinical history. Unilateral nasal symptoms ALLERGIC RHINITIS DIAGNOSTIC WORK-UP OVERVIEW 1 KEY MESSAGES suggest that an anatomic issue is present (Table 2). Physical examination of the nose should be performed, in part to identify complicating or alternative nasal conditions (e.g, nasal polyps, septal deviation). In AR, inflamed mucosa classically has a bluish/ pale hue, but appearance may vary and may not reliably differentiate between AR and non-AR. Rhinosinusitis (including nasal polyps) is characterized by two or more symptoms, one of which should be either a) nasal blockage/ obstruction/congestion or b) nasal discharge (anterior/posterior nasal drip). Other symptoms may be c) facial pain/pressure, and/or d) reduction or loss of smell. Discolored nasal drainage may occur in AR and some types of non-AR, so its presence does not necessarily indicate bacterial rhinosinusitis. The common cold from respiratory viruses has an acute onset of rhinosinusitis symptoms typically lasting for less than 10 days or getting better after 5 days. The common cold and rhinosinusitis are not typically associated with nasal itching or ocular symptoms that may be seen in AR. KEY REFERENCES 1. Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW, Naclerio RM, et al. Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the AmerAllergic rhinitis diagnostic work-up overview Mark S. Dykewicz Saint Louis University School of Medicine Saint Louis, Missouri, USA 151 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Allergic rhinitis diagnostic work-up overview TABLE 1 Differential Diagnostic Features of History, Physical Exam, Testing Medical History Physical examination In vitro - in vivo tests Allergic rhinitis • Symptoms: obstruction/congestion, nasal drainage, sneezing, itching • Seasonal symptoms may be present with prominent nasal itching and sneezing • Concurrent allergic conjunctivitis (itchy, watery eyes) common • Early onset (age <20 years) common • May be associated with atopic dermatitis, asthma, food allergy, obstructive sleep apnea syndrome • Variable appearance of mucosa: mucosal pallor, edema, hyperemia • Allergic shiners: dark discolorations of the periorbital skin • Dennie–Morgan lines: folds of the low––er eyelid in children • Allergic crease: horizontal wrinkle near the tip of the nose • Skin-prick tests (SPTs) with allergen • Serum allergen-specific IgE tests • Nasal smears for eosinophils (>10%) (not routinely employed clinically) Nonallergic rhinitis & infectious rhinosinusitis • Idiopathic rhinitis (IR: sneezing, pruritus and ocular involvement uncommon • NARES,C RSwNP, and atrophic rhinitis: Hyposmia/anosmia common • Rhinosinusitis: headache and facial pain common • NARES, CRSwNP, and IR: usually adult onset • Gustatory rhinitis: food related symptoms at any age, but more likely with increasing age. Sneezing, pruritus, ocular involvement uncommon. • Rhinitis of pregnancy: mainly congestion during the last 6 weeks of pregnancy and up to 2 weeks post-partum • Atrophic rhinitis: mucosal atrophy, foetor, crusts and perceived congestion inconsistent with observed nasal patency • Rhinosinusitis: Endoscopic findings of polyps and/or mucopurulent discharge, edema, mucosal obstruction primarily in middle meatus, are prerequisite for diagnosis • CRS: CT findings are a prerequisite for the diagnosis if endoscopic findings inconclusive • NARES: Nasal smears for eosinophils (any amount from >5% to >20%) (not routinely employed) • NARES, atrophic rhinitis and rhinoshinusitis: Objective and subjective olfactory evaluation to demonstrate hypoosmia/ anosmia. • AERD: Oral aspirin challenges to demonstrate sensitivity AERD (aspirin exacerbated respiratory disease); CRSwNP (chronic rhinosinusitis with nasal polyps); IR (idiopathic rhinitis), NARES (nonallergic rhinitis and eosinophilia syndrome) Modified from Papadopoulos NG, Bernstein JA, Demoly P, Dykewicz M, Fokkens W, Hellings PW, et al. Phenotypes and Endotypes of Rhinitis and Their Impact on Management: A PRACTALL Report. Allergy 2015;70:474-494. ican Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2013;131:1479-1490. 2. 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;126:466-476. 3. Papadopoulos NG, Bernstein JA, Demoly P, Dykewicz M, Fokkens W, Hellings PW, et al. Phenotypes and Endotypes of Rhinitis and Their Impact on Management: A PRACTALL Report. Allergy 2015;70:474-494. 4. Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008;122:S1-84. 5. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50:1-12. 152 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Allergic rhinitis diagnostic work-up overview TABLE 2 Rhinitis differential diagnosis: other disorders Structural/Mechanical abnormalities Systemic disease • Septal deviation Unilateral obstruction, sleep apnea, epistaxis • Primary ciliary dyskinesia (PCD) Recurrent respiratory infections; Kartageners syndrome (situs inversus, chronic rhinosinusitis and bronchiectasis), low nasal and tidally exhaled NO, diagnosis through biopsy and electron microscopy examination of cilia • Turbinate hypertrophy Often contralateral to septal deviation • Nasal tumors Epistaxis, hypoosmia/anosmia, facial pain, otalgia, recurrent ear infections, unilateral obstruction • Cystic fibrosis Thick, viscous secretions, recurrent infection, often radiologic evidence of sinus disease and concurrent nasal polyps. Diagnosis through genetic and sweat testing • Adenoidal hypertrophy congestion, mouth breathing, nasal speech and sleep apneic episodes/snoring • Pharyngonasal reflux apneic spells, secondary rhinitis (caused by return of ingested liquids) and recurrent pneumonia due to aspiration • Churg–Strauss syndrome Asthma, blood eosinophilia, mononeuropathy/polyneuropathy, migratory pulmonary infiltrates, paranasal sinus disease, tissue eosinophilia • Choanal atresia Mild symptoms if unilateral, severe symptoms if bilateral (often involving generalized cyanosis • Granulomatosis with polyangiitis Obstruction, rhinorrhea, crusting, ulcerations and epistaxis, often secondary bacterial sinusitis • Nasal trauma/foreign object May present with unilateral obstruction, epistaxis, olfactory impairment • Sarcoidosis Obstruction, nasal crusting, anosmia, epistaxis, lymphadenopathy, malaise • Cerebrospinal fluid rhinorhea Clear watery secretion – often unilateral, headaches and olfactory impairment, β-2 transferrin protein elevated in nasal discharge • Amyloidosis Obstruction, nasal discharge, epistaxis and post nasal drip • Relapsing polychondritis Chondritis (auricular, nasal, and laryngotracheal, including ocular inflammation, audio vestibular damage, or seronegative inflammatory arthritis. Modified from Papadopoulos NG, Bernstein JA, Demoly P, Dykewicz M, Fokkens W, Hellings PW, et al. Phenotypes and Endotypes of Rhinitis and Their Impact on Management: A PRACTALL Report. Allergy 2015;70:474-494. 153 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • Visualizing the nasal cavity is an important evaluation in patients with nasal symptoms • There are no definitive signs of allergic rhinitis • Rhinoscopy visualizes the anterior third of the nasal cavity • Nasal endoscopy visualizes the entire nasal cavity, and allows the differential diagnosis of mucosal vs structural endonasal pathology One of the great advances in diagnosing and understanding nasal and sinus diseases has been the ability to visualize the entire nasal cavity. The advances primarily relate to the development of ritig and flexible endoscopes. Traditional approaches of using a nasal speculum and a light source or an otoscope, referred to as rhinoscopy, investigate the anterior part of the nose prior to the level of the middle turbinates. Although the experienced examiner might be able to visualize the middle turbinate with this technique, the view is limited. The anterior part of the nose contains the nasal vestibule, where the epithelium transitions from squamous to pseudostratified columnar ciliated. One can also easily visualize the anterior septum, inferior turbinates, and nasal valve. The nasal valve is formed by the junction between the anterior nasal septum medially and the most caudal margin of the upper lateral cartilage of the nose superiorly and laterally. This valve is the narrowest portion of the airway between the external environment and the alveoli. Deflections of the anterior septum have a marked impact on airflow and can be diagnosed by anterior rhinoscopy. DIAGNOSIS OF ALLERGIC RHINITIS - RHINOSCOPY AND ENDOSCOPY 2 KEY MESSAGES Other salient findings that can be visualized by rhinoscopy are hypertrophia (Figure 1) or congestion of the inferior turbinates. Most septal perforations involve this area. Large nasal polyps (NP) can also be seen, but novice clinicians often mistake the anterior tip of the middle turbinate or a large inferior turbinate for a polyp. Eighty-five percent of nose bleeds occur in the anterior septum in the area that is the confluence of the anterior ethmoid artery, the facial artery, and the septal artery, which form a rich plexus of vessels, called the Keisselbach’s plexus. There are no definitive signs of allergic rhinitis (AR) on anterior rhinoscopy; however, visualization by rhinoscopy helps to rule out other causes of similar symptoms such as nasal congestion due to anatomic causes. Although anterior rhinoscopy is helpful, it does not provide visualization of the entire nasal cavity. Specifically it does not provide a good view of the middle meatus, where the sinuses (which are commonly involved in patients with AR) drain. Adenoid hypertrophy, NP, tumors, posterior epistaxis, septal deviations obstructing the sinus ostia, and sinus infections are common and form part of the differential diagnosis of rhinopathy. Nasal endoscopy provides not only visualization to enhance diagnostic abilities (Figures 2, 3 and 4), but also the opportunity to work inside the nose under direct visualization. Nasal endoscopy can be performed with a rigid or a flexible endoscope. Both can be attached to cameras for educating observers and patients and documenting Diagnosis of allergic rhinitis - rhinoscopy and endoscopy Robert Naclerio Fuad Baroody University of Chicago Chicago, USA 154 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis the examination. Both examinations are usually performed after the administration of a topical decongestant and anesthetic. The response to the nasal decongestant sometimes provides clues to the underlying problem. Patients with AR often decongest well with oxymetazoline because the congestion of the inferior turbinates is caused by inflammatory mediators released during an allergic reaction that subsequently dilate the cavernous veins in the inferior turbinates. Flexible endoscopy is easier to perform and can also be used for visualizing the nasopharynx and larynx. Rigid endoscopy provides better image definition, and the endoscope can be held with one hand, freeing the other hand to intervene in the nasal cavity. Such interventions include lysis of adhesions, obtaining guided cultures (Figure 5), performing biopsies, and cauterizing nosebleeds. Directed middle meatal cultures correlate highly with maxillary sinus Figure 1 Left panel: Endoscopic view of an antrochoanal polyp (originating from the maxillary sinus and protruding into the nasal cavity) of the right nostril in a teenage male who presented with a unilateral nasal obstruction. Right panel: closeup view. One can see the nasal septum (*), the middle turbinate (#), and the polyp (arrowhead). Figure 2 Anterior rhinoscopy with use of a nasal speculum and headlight showing a hypertrophied right inferior turbinate. Figure 3 Endoscopic view showing a small polyp (*) in the osteomeatal unit. ∗ # ∗ # ∗ Diagnosis of allergic rhinitis - rhinoscopy and endoscopy 155 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Figure 4 Left panel shows an endoscopic view of a posterior septal deviation impacting the inferior turbinate and heading to the osteomeatal unit. Right panel is an intraoperative photo following removal of the septal deviation showing multiple accessory ostia believed to be secondary to prior acute infections. puncture cultures in patients with acute bacterial rhinosinusitis. When should nasal endoscopy be performed in a patient who has a nasal complaint? One could argue that it should be done in everyone, but that would be too costly. A more reasonable approach is to perform endoscopy in subjects who have symptoms that are not explained by rhinoscopy and who did not respond to initial treatment. Figure 5 View of the right middle turbinate (#) and the right osteomeatal unit (arrowhead) with some purulent drainage. This view was obtained with the use of a rigid scope, allowing the introduction of a Calgae swab (*) to obtain a culture. ∗ # KEY REFERENCES 1. Stammberger H. Functional Endoscopic Sinus Surgery. Decker. Philadelphia, Pennsylvania, 1991. 2. Benninger MS, Appelbaum PC, Denneny JC, Osguthorpe DJ, Stankiewicz JA. Maxillary sinus puncture and culture in the diagnosis of acute rhinosinusitis: the case for pursuing alternative culture methods. Otolaryngol Head Neck Surg 2002;127:7-12. 3. Psaltis AJ, Li G, Vaezeafshar R, Cho KS, Hwang PH. Modification of the Lund-Kennedy endoscopic scoring system improves its reliability and correlation with patient-reported outcome measures. Laryngoscope 2014;124:2216-2223. 4. Stankiewicz JA, Chow JM. Nasal endoscopy and the definition and diagnosis of chronic rhinosinusitis. Otolaryngol Head Neck Surg 2002;126:623-627. Diagnosis of allergic rhinitis - rhinoscopy and endoscopy 156 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • Allergic rhinitis (AR) is a complex allergen-driven mucosal inflammation caused by the interplay between local and infiltrating inflammatory cells and many vasoactive and inflammatory mediators • Increased Nasal Nitric Oxide (nNO) levels are associated with nasal inflammation; however, results should be interpreted with caution in patients with severe or persistent AR, which may reduce nNO levels • Nasal cytology is performed to help differentiate AR (predominantly) from infectious rhinitis (predominantly neutrophils), although it is relatively nonspecific and insensitive • Non-invasive sampling of mediators by nasal lavage is an emerging method to monitor AR In allergic rhinitis (AR), the early-phase reaction due to IgE-mediated mast cell degranulation and mediator release is rapid and leads to sneezing and rhinorrhea. The late-phase reaction involves an eosinophilic infiltrate, leading to nasal inflammation. Nasal nitric oxide (nNO) is produced continuously in the paranasal sinuses without inflammatory stimuli and plays a role in airway homeostasis. AR may be associated with elevated nNO levels, by the increase in inducible nitric oxide synthase (iNOS) expression in respiratory epithelial cells. While the level of nNO may be increased by nasal inflammation, nasal swelling and secretions may occlude the ostia of the paranasal sinuses thereby lowering nNO levels. A high nNO may be a useful marker of eosinophilic inflammation of the nasal cavity and indicate open sinus ostia. nNO measurements may be an alternative to diagnose AR in patients who are not able to undergo allergic tests or invasive procedures. Infiltrating eosinophils are the hallmark of nasal inflammation in AR. Nasal smears for eosinophils are not recommended for routine use in diagnosing AR when NON-INVASIVE EVALUATION OF NASAL INFLAMMATION (NO, NASAL 3 CYTOLOGY AND MEDIATORS) KEY MESSAGES the diagnosis is clearly supported, but may be a useful adjunct when there remains a high clinical suspicion of allergy in a history-positive, skin test-negative patient. Nasal cytology can not only be utilized to establish the diagnosis of AR, but is also useful in the follow-up of treated patients with this condition. The technique allows clinicians to detect the cellular modifications of the nasal epithelium during allergen exposure (Figure 1) and by subsequent treatment with corticosteroids. Many different mediators, cytokines, and chemokines have been measured in nasal lavage (NL) studies (Figure 2). Certain proinflammatory mediators including eosinophilic major basic protein and neutrophil elastase have been identified in allergic mucin. Eosinophil cationic protein (ECP) is one of the most studied inflammatory markers and is considered a general marker of mucosal inflammation, both in processes of eosinophil and neutrophil activation. Another key feature of mucosal inflammation is the exudation of plasma proteins such as albumin, a2-macroglobulin, and others, which can be monitored by analysis of plasma proteins in NL. While histamine is rapidly degraded by Non-invasive evaluation of nasal inflammation (NO, nasal cytology and mediators) Stephanie Kubala Elina Toskala Temple University School of Medicine Philadelphia, USA 157 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Non-invasive evaluation of nasal inflammation (NO, nasal cytology and mediators) histaminases and N-methyl transferase, the more stable mast cell degranulation products, tryptase and prostaglandin PGD2 are recommended as markers of mast cell activation. The choice of which inflammatory marker to probe in AR depends on the purpose of the investigation and the manner of monitoring therapy. KEY REFERENCES 1. Lee KJ, Cho SH, Lee SH, Tae K, Yoon HJ, Kim SH, et al. Nasal and exhaled nitric oxide in allergic rhinitis. Clin Exp Otorhinolaryngol 2012;5:228-233. 2. Quirce S, Lemière C, de Blay F, del Pozo V, Gerth Van Wijk R, Maestrelli P, et al. Noninvasive methods for assessment of airway inflammation in occupational settings. Allergy 2010;65:445–458. 3. Suojalehto H, Vehmas T, Lindström I, Kennedy DW, Kilpeläinen M, Plosila T, et al. Nasal nitric oxide is dependent on sinus obstruction in allergic rhinitis. Laryngoscope 2014;124:E213-218. 4. Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008;122:S1-S84. 5. Gelardi M, Luigi Marseglia G, Licari A, Landi M, Dell'Albani I, Incorvaia C, et al. Nasal cytology in children: recent advances. Ital J Pediatr 2012;25;38:51. 6. Diamant Z, Boot JD, Mantzouranis E, Flohr R, Sterk PJ, Gerth van Wijk R. Biomarkers in asthma and allergic rhinitis. Pulm Pharmacol Ther 2010;23:468-481. Figure 2 Biomarkers of allergic rhinitis. (Reprinted from Pulm Pharmacol Ther, 23/6, Diamant Z, Boot JD, Mantzouranis E, Flohr R, Sterk PJ, Gerth van Wijk R. Biomarkers in asthma and allergic rhinitis, 468-481, Copyright 2010, with permission from Elsevier.) Figure 1 Nasal inflammation occurring in seasonal allergic rhinitis. (From Gelardi M, Luigi Marseglia G, Licari A, Landi M, Dell'Albani I, Incorvaia C, et al. Nasal cytology in children: recent advances. Ital J Pediatr 2012;25;38:51.) 158 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • Skin testing with allergen extracts or small molecules is well established in the diagnostic work-up of allergic rhinitis (AR) to demonstrate IgE mediated sensitizations • The quality of allergen extracts is critical. False negative results can occur if minor allergens or instable allergenic proteins are underrepresented in an extract • Well-standardized allergen extracts are available for many inhalant allergens • The best established skin test is the skin prick test (SPT). The more sensitive intradermal tests are recommended after negative SPT in some situations, but can lead to false positive reactions and are associated with a higher risk of systemic side effects Skin testing is well established in the diagnostic work-up of allergic rhinitis (AR) to demonstrate IgE mediated sensitizations. It is mainly performed with protein allergens and only rarely with small molecules. A positive skin test usually indicates sensitization but not necessarily clinically relevant allergy. The latter has to be proven either by a very convincing history or with further steps in the algorithm of in vivo diagnosis (i.e. nasal challenge tests). SKIN PRICK TEST The skin prick test (SPT) is the best established skin test and recommended as first diagnostic test in patients with AR. SPT can be performed in patients of any age although the reactivity may possibly be lower in the elderly. The quality of allergen extracts used for SPT is critical. False negative results can occur if minor allergens or instable allergenic proteins are underrepresented in an extract. However, well-standardized allergen extracts are available for many inhalant allergens. EU legislation makes it currently difficult to have new and optimized diagnostic products approved due to very high standard requirements. SKIN TESTING IN THE DIAGNOSTIC WORKUP OF RHINITIS 4 KEY MESSAGES The major advantage of SPT as compared to an in vitro measurement of specific IgE antibodies is the fact that the test can be interpreted within 15 to 20 minutes (Figure 1). A further advantage is that the test gives a visual indication of the sensitivity to the patient which may have impact on the patient’s behavior. Usually prick tests are performed with panels of allergens of interest; a standard set is proposed for inhalant allergens (Table 1). Some studies show discordances between serum-specific IgE and SPT results. In a recent meta-analysis on studies with SPT with inhalant allergens, every fourth sensitized patient would have been misdiagnosed as non-sensitized for a particular allergen if only serum specific IgE testing had been done. This has leads to the suggestion that the two methods complement each other and cannot be used interchangeably. OTHER SKIN TESTS Intradermal tests are recommended after negative SPT in some clinical situations. They are considered to be more sensitive than the SPT but can lead to false positive reactions and they are associated with a higher risk of sysSkin testing in the diagnostic workup of rhinitis Thomas Werfel Hannover Medical School Hannover, Germany 159 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis temic side effects. Therefore extracts utilized for intradermal skin testing are less concentrated than those utilized for SPT. Patch testing is the mainstay in the diagnosis of allergic contact dermatitis – it is not recommended for the diagnosis of AR. KEY REFERENCES 1. Anon. Position Paper: allergen standardization and skin tests. The European Academy of Allergology and Clinical Immunology. Allergy 1993;48:48-82. 2. 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. 3. de Vos G. Skin testing versus serum-specific IgE testing: which is better for diagnosing aeroallergen sensitization and predicting clinical allergy? Curr Allergy Asthma Rep 2014;14:430. 4. Heinzerling LM, Burbach GJ, Edenharter G, Bachert C, Bindslev-Jensen C, Bonini S, et al. GA(2) LEN skin test study I: GA(2)LEN harmonization of skin prick testing: novel sensitization patterns for inhalant allergens in Europe. Allergy 2009;64:1498-1506. 5. Heinzerling L, Mari A, Bergmann KC, Bresciani M, Burbach G, Darsow U, et al. The skin prick test - European standards. Clin Transl Allergy 2013;3:3. 6. Konstantinou GN, Bousquet PJ, Zuberbier T, Papadopoulos NG, et al. The longest wheal diameter is the optimal measurement for the evaluation of skin prick tests. Int Arch Allergy Immunol 2010;151:343- 345. 7. Zuberbier T, Werfel T. Is European legislation killing allergy diagnostics? Curr Opin Allergy Clin Immunol 2012;12:475-476. Figure 1 SPT is usually performed on the forearm with a negative (saline 0.9%) and positive (histamine 10mg/ml) control. A reaction is considered to be positive with a wheal diameter ≥ 3mm after 15 minutes. TABLE 1 Proposal for a standard prick test panel for Europe for inhalants Hazel Corylus avellana Alder Alnus incana Birch Betula alba Plane Platanus vulgaris Cypress Cupressus sempervirens Grass mix Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense Olive Olea europaea Mugwort Artemisia vulgaris Ragweed Ambrosia artemisiifolia Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus Parietaria Cat Dog Dermatophagoides pteronyssinus, Dermatophagoides farinae, Cockroach Blatella germanica Skin testing in the diagnostic workup of rhinitis 160 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • Nasal provocation involves a controlled exposure of the nasal mucosa to allergen(s) or non-specific triggers in order to elicit a measurable response • Provocations have been essential in delineating pathomechanisms of (allergic) rhinitis • Applications in clinical practice include identification of predominant allergens in polysensitised patients, proof of causation of symptoms for novel or occupational allergens, and investigation of local allergic rhinitis • Several different approaches to provocation exist, universal consensus on optimal methods is lacking Nasal provocation testing is the use of various stimuli – typically specific allergen(s), but also non-specific triggers including irritants, chemicals and physical stressors – to elicit a measurable response from the nose. Outcomes include symptom scores, measures of nasal airway patency, cellular influx and inflammatory mediators in nasal fluid. Applications of provocation tests are outlined in Table 1. In clinical practice, provocations may help differentiate between sensitisation and allergy, and identify individuals with local allergic rhinitis (AR). In research settings, provocations have demonstrated the efficacy of pharmacotherapies including anti-histamines and intranasal corticosteroids, and identified basic immunological and neural mechanisms. A reliable, reproducible means of delivering allergen to the nasal mucosa is required. Various delivery systems used are outlined in Table 2, alongside different provocation protocols. The latter include up-dosing/titration provocations, providing dose-response profiles and allowing tailoring of future doses to each individual. Repeat challenges, usually every 24 hours 5 PROVOCATION TESTS KEY MESSAGES for several days, may provide an approximation to real-life allergen exposures and allow investigation of ‘priming’ of the mucosa. For research, participants are selected on the basis of typical allergic symptoms and evidence of systemic sensitisation to the allergen in question. Allergen provocations are usually performed outside of usual seasonal exposure and in the absence of symptoms induced by alternative/perennial allergens, infection, nasal polyps or structural pathologies. Whilst provocations are extremely safe, individuals with poorly controlled asthma or FEV1 <70% predicted should be excluded; other contraindications include pregnancy or a history of anaphylaxis to the allergen in question. Anti-allergic medications need to be stopped for a sufficient wash-out period prior to provocations. Clinical and laboratory outcomes of nasal provocations are given in Table 3. Typically, provocation is preceded by nasal lavage to provide a clean baseline. An example of the time-course of symptom and peak nasal inspiratory flow responses to a single dose nasal allergen challenge is given in Figure 1. In contrast to bronchial allergen provocation, a distinct late phase response is seldom seen, although nasal obstruction typically persists for some hours after provocation. Conversely, clear immunological Provocation tests Guy Scadding Imperial College London, UK Glenis Scadding Royal National TNE Hospital London, UK 161 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis TABLE 1 Clinical and research uses of nasal provocations Clinical Practice Research Confirmation of clinical relevance in cases of polysensitisation to aeroallergens Assessment of mechanisms of (allergic) rhinitis: • Cellular influx • Early and late phase mediators • Neural pathways • Gene expression • Naso-ocular, naso-bronchial interaction Selection of patients for allergen immunotherapy (e.g. for house dust mite) Investigation of symptoms in the absence of evidence of systemic allergen sensitisation (local allergic rhinitis) Proof of symptom causation for novel and occupational allergens Assessment of therapeutic interventions: • Efficacy • Onset • Duration Investigation of aspirin hypersensitivity Assessment of non-specific nasal hyperreactivity TABLE 2 Methods of nasal allergen provocation Delivery System Challenge Protocol Allergen in aqueous solution, administered by nasal spray, drops, pipette Up-dosing/titration protocol - half-log increments, every 10 minutes, ending at maximum dose or threshold response Filter discs with adsorbed allergen, placed directly onto nasal mucosa Allergen as dry powder insufflated or nebulised Single fixed dose challenge (standard or determined by titration challenge) Allergen administered in high volume nasal lavage Repeat dosing, usually daily, to mimic seasonal priming effect TABLE 3 Clinical and laboratory outcome measures of nasal provocation. Clinical Outcomes Laboratory Outcomes Total nasal symptom score: 0-3 for each of sneezing, rhinorrhoea, itching, blocking/ congestion; maximum score 12. Nasal mucosal fluid, collected by lavage or direct absorption (synthetic filters, polyurethane sponges), immunoassay for: • Early phase mediators, e.g. tryptase, histamine, leukotrienes • Cytokines and chemokines • Allergen-specific antibodies • Eosinophil products, e.g. ECP • Neuropeptides • Vascular, glandular proteins Visual analogue scale (0-100mm; none – maximal symptoms) Collected secretion weight Nasal airflow/patency: • Peak inspiratory flow • rhinomanometry Nasal cross-sectional area: • acoustic rhinometry Nasal brushings for cytology, mRNA Eosinophilic inflammation: • nasal FeNO Nasal (turbinate) biopsy for immunohistochemistry, in situ hybridisation Nasal lavage for cytology Provocation tests 162 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis late phase responses are seen for both cellular influx (eosinophilic) and nasal fluid cytokines/chemokines (Th2 predominant). Whilst allergen provocations are more frequently used, non-specific provocations, described in Table 4, have also been used to identify nasal hyperreactivity, investigate the effect of environmental pollutants, and elucidate basic mechanisms of rhinitis. KEY REFERENCES 1. Naclerio RM, Proud D, Togias AG, Adkinson NF Jr, Meyers DA, Kagey-Sobotka A, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 1985;313:65-70. 2. Creticos PS, Peters SP, Adkinson NF Jr, Naclerio RM, Hayes EC, Norman PS, et al. Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med 1984;310:1626-1630. 3. Wagenmann M, Baroody FM, Cheng CC, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Bilateral increases in histamine after unilateral nasal allergen challenge. Am J Respir Crit Care Med 1997;155:426-431. 4. Castells M, Schwartz LB. Tryptase levels in nasal-lavage fluid as an indicator of the immediate allergic response. J Allergy Clin Immunol 1988;82:348-355. 5. Soliman M, North M, Steacy LM, Thiele J, Adams DE, Ellis AK. Nasal allergen challenge studies of allergic rhinitis: a guide for the practicing clinician. Ann Allergy Asthma Immunol 2014;113:250-256. 6. Litvyakova LI, Baraniuk JN. Nasal provocation testing: a review. Ann Allergy Asthma Immunol 2001;86:355-364. TABLE 4 Non specific nasal challenges Biochemical Irritant/inflammatory Physical Histamine – ipsilateral and contralateral effects Capsaicin - Activates TRPV-1 receptors on sensory nerve endings; increased response in allergic rhinitics Cold dry air - rhinorrhoea and congestion in susceptible individuals, associated with increased histamine, PGD2 and kinins. Superior to histamine in identifying patients with non-allergic rhinitis from controls. Methacholine – ipsilateral effect only AMP – non-specific mast cell activation Environmental tobacco smoke - rhinitis in susceptible individuals Neuropeptides – stimulation of sensory nerves Diesel exhaust particles – may augment response to allergen Bradykinin, leukotrienes – investigation of effects of individual components of mast cell granules Ozone (in challenge chamber) - neutrophilic inflammation Hyperosmolar solutions, e.g. mannitol, hypertonic saline - induces fluid shift into the nasal lumen and increases in mediators including mast cell, epithelial and neuronal factors. Aspirin – diagnosis of hyperreactivity and desensitisation Chlorine – increases in nasal resistance 0 1 2 3 4 5 6 7 8 9 10 Total nasal symptom score : time course Allergen Diluent -140 -120 -100 -80 -60 -40 -20 0 20 40 Δpeak nasal inspiratory flow: time-course Figure 1 Time course of total nasal symptom score (0-12) and change from baseline peak nasal inspiratory flow (L/min) in 19 cat-allergic individuals after single dose cat allergen challenge and diluent-only challenge. (Adapted from Scadding GW, Eifan A, Penagos M, et al. Local and systemic effects of cat allergen nasal provocation. Clin Exp Allergy 2015;45:613-623.) Provocation tests 163 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • Elevated allergen-specific IgE serum levels are indicative for an allergy • Determination of allergen-specific IgE in serum allows rapid screening of the sensitization spectrum of a patient • Screening panels of allergen-specific IgE without previous consideration of the history of the patient is not recommended • A negative skin prick or serum IgE test does not entirely exclude a diagnosis of AR especially if they are in contrast with a convincing clinical history • The diagnosis of AR with discordant clinical history and elevated allergen-specific serum IgE levels needs to be confirmed by provocation tests Allergic rhinitis (AR) is a very common inflammatory chronic condition affecting the upper airways. It occurs in predisposed individuals when allergens such as pollens, dust, or animal dander are inhaled. Its incidence is rising in parallel with other IgE-mediated diseases, affecting 10 to 30% of adults and up to 40% of children in industrialised countries. Seasonal AR is mainly elicited by exposure to pollens during the pollination period, while perennial AR is elicited by allergens present in the environment throughout the year like those from house dust mite allergens or fungal spores. The disease is often associated with other IgE-mediated diseases like allergic asthma, or atopic dermatitis. The characteristic symptoms of AR are excess nasal secretion, itching, sneezing, nasal congestion and obstruction associated with eosinophilic inflammation of the mucosa. To confirm the diagnosis of AR, sensitisation (specific IgE reactivity) needs to be recorded and should be concordant with the clinical history. The prototype for the in vitro detection of serum IgE (the radioallergosorbent test, RAST) first described in 1967 used a paper SPECIFIC IgE AND DIAGNOSIS 6 OF ALLERGIC RHINITIS KEY MESSAGES disc as a solid phase to covalently immobilize the allergen followed by the addition of patient’s serum. After different washing procedures to remove unbound serum proteins and antibodies, bounded IgE was detected with 125I-labelled polyclonal anti-human IgE (Figure 1). Modern assays for the detection of allergen-specific IgE have undergone impressive improvements including the calibration against the WHO Standard 72/502, allowing quantitative determinations, and the implementation of fully automated devices (Figure 2). To date the most commonly used system to determine allergen-specific IgE is the ImmunoCAP system (Thermo Fisher Scientific, Uppsala) considered as the “gold standard” for the in vitro diagnosis of allergic conditions. More recently, novel diagnostic tests based on allergen microarrays have been introduced both in research and clinical practice. Multiplex-based in vitro tools for allergy diagnosis allow a component resolved diagnostics of the atopy status of a patient in a cost effective way. In vitro tests for allergen-specific serum IgE are excellent for identifying a sensitization state of a patient and can be recommended at any age and without wash-out for antiallergic medication. HowSpecific IgE and diagnosis of allergic rhinitis Reto Crameri Swiss Institute of Allergy and Asthma Research Davos, Switzerland 164 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis ever, a positive in vitro test for allergen-specific IgE in serum does not always equate with clinical allergy, and a negative test does not completely exclude the disease. For a clinical manifestation of any allergy the only biologically relevant allergen-specific IgE is those immobilized on the surface of effector cells through the high affinity FcεRI receptors. This can, through cross-linking of the IgE molecules after allergen exposure and the resulting mediator release from effector cells, elicit local symptoms of AR also in the absence of soluble allergen-specific IgE in serum. Therefore, the best tool for the diagnosis of AR is by correlating the patient’s history and physical exam with the presence of aeroallergen specific IgE determined by skin testing or by in vitro assays. Like skin testing, limitations of in vitro specific IgE measurement include the availability of fully standardized allergenic extracts, particularly for foods, drugs, and occupational agents. New perspectives for the diagnosis of AR have been opened by in vitro diagnostic tests based on molecular approaches, which allow a component resolved diagnosis of hundreds of the offending allergens. Multiplex measurement platforms like the Immuno-Solid phase Allergen Chip (ISAC) allows discrimination between genuine and cross-reactive sensitization thereby reducing unnecessary allergen challenges, and facilitating the identification of patients with a good prognosis for a successful allergen immunotherapy. KEY REFERENCES 1. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet 2011;378:2112-2122. 2. Sicherer SH, Wood RA; American Academy of Pediatrics Section On Allergy And Immunology. Allergy testing in childhood: using allergen-specific IgE tests. Pediatrics 2012;129:193-197. 3. Pawankar R, Yamagishi S, Yagi T. Revisiting the roles of mast cells in allergic rhinitis and its relation to local IgE synthesis. Am J Rhinol 2000;14:309-317. 4. Bousquet J, Anto JM, Bachert C, Bousquet PJ, Colombo P, Crameri R et al. Factors responsible for differences between asymptomatic subjects and patients presenting and IgE sensitization to allergens: a GA2LEN project. Allergy 2006;61:671-680. 5. Canonica GW, Ansotegui IJ, Pawankar R, Schmid-Grendelmeier P, van Hage M, Baena-Cagnani CE, et al. A WAO – ARIA GA2LEN consensus document on molecular-based allergy diagnosis. World Allergy Organ J 2013;6:17. 6. Crameri R. The crux with a reliable in vitro and in vivo diagnosis of allergy. Allergy 2013;68:393-394. Figure 1 Mechanism of the first radioallergosorbent assay (RAST). Figure 2 Example of a fully automated device for the determination of allergen-specific IgE (PhadiaTM Immunoassay Analyzer). Specific IgE and diagnosis of allergic rhinitis 165 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis • The IgE response usually evolves from a monomolecular to an oligo- and poly-molecular stage (“molecular spreading” phenomenon) and can involve both, highly specific and highly cross-reactive molecules • Allergic patients reacting to the same allergenic source (e.g. grass pollen) can be highly different in their molecular profile of IgE sensitization to that allergenic source • Component resolved diagnosis (based on single or multiplex assays) allows discriminating whether a patient is truly or only apparently sensitized to an allergenic source (e.g. pollen) • Component resolved diagnosis has a strong impact on the precision of allergen immunotherapy (AIT) prescription, which might imply to a better AIT efficacy and cost-effectiveness. Ad hoc Diagnostic Algorithms have been proposed The number of allergenic molecules cloned and available for diagnostic tests grows year after year. We can nowadays precisely define the patient’s IgE repertoire and distinguish, in polysensitized patients, true sensitization (IgE to major, “species-specific” allergenic molecules) from apparent sensitization, due to cross-reactive molecules (e.g. profilin, serum albumin, tropomyosin, CCD) shared by many allergenic sources. This molecular approach, also called ‘component-resolved diagnosis’ (CRD), can rely upon classical ‘singleplex’ or newer ‘multiplex’ methods. By the singleplex method, single molecules are separately analyzed and the operator can select, with an inductive approach, those to be tested in the individual patient. By the multiplex method, fixed arrays of molecules are tested in the same assay and the response is interpreted with a deductive approach. CRD applies to all IgE-mediated allergic diseases and it is of paramount importance in the correct diagnosis of pollen-food syndromes. In patients with seasonal allergic rhinitis (SAR), CRD may influence therapeutic decisions, by helping the selection of sources COMPONENT 7 RESOLVED DIAGNOSIS KEY MESSAGES for allergen immunotherapy (AIT). Indeed, the IgE response against grass pollen (e.g. Phleum pratense) usually evolves from a simple, monomolecular stage to an oligomolecular stage and eventually to a polymolecular sensitization stage. This phenomenon has been defined as ‘molecular spreading’, that is, “The sequential development of antibody (IgE) response to distinct non-cross-reacting molecules from the same antigenic (allergenic) source, starting with an “initiator” (allergenic) molecule.” Phl p 1 is the probable ‘initiator’ molecule in most patients, and the response involves then Phl p 4 or Phl p 5, thereafter also Phl p 2 and Phl p 11 and at a later stage Phl p 12 or Phl p 7 (Figure 1). Interestingly, the molecular spreading process follows different sequences in different children: some patients remain sensitized only to the “initiator” molecule while a few patients become sensitized to most or all allergenic molecules. Consequently, a population of grass-pollen allergic patients “apparently” homogeneous if examined with an allergen extract, is Component resolved diagnosis Paolo Maria Matricardi Charité Medical University Berlin, Germany 166 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Component resolved diagnosis Figure 1 IgE to Phleum pratense allergenic molecules from the onset of grass-related seasonal allergic rhinitis (SAR). Lines show the prevalence of IgE sensitization (ISAC class >_1) to the 8 Pheum pratense allergenic molecules in children whose sera were available at each time point. The number of children examined at each time point is indicated under the x-axis. Clinical stages of SAR are also indicated. (Adapted from J Allergy Clin Immunol 130/4, Hatzler L, Panetta V, Lau S, et al. Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever. 894-901. e5, Copyright 2012, with permission from Elsevier.) remarkably heterogeneous when examined with allergenic molecules (Figure 2). A consistent proportion of pollen allergic patients are sensitized to profilin and other highly cross-reacting molecules. When tested with extracts-based skin prick tests or IgE assays, these patients with SAR appear sensitized to many different pollens which often share, especially at warmer latitudes (e.g. Mediterranean countries), overlapping season. In vitro molecular assays can discriminate true IgE sensitization from co-recognition and allow refining the diagnosis made with extract-based SPT or IgE assays. Not surprisingly, a precise molecular diagnosis can play a strong influence on AIT prescription in Mediterranean countries (Figure 3) and this might imply a better AIT efficacy and cost-effectiveness. Accordingly, new diagnostic algorithms for an improved prescription of AIT in patients with pollen-related allergic rhinitis have been recently proposed (Figure 4). KEY REFERENCES 1. Valenta R. The future of antigen-specific immunotherapy of allergy. Nat Rev Immunol 2002;2:446-453. 2. Hatzler L, Panetta V, Lau S, Wagner P, Bergmann RL, Illi S, et al. Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever. J Allergy Clin Immunol 2012;130:894–901.e5. 3. Matricardi PM. Allergen-specific immunoprophylaxis: toward secondary prevention of allergic rhinitis? Pediatr Allergy Immunol 2014;25:15–18. 4. Tripodi S, Frediani T, Lucarellli S, Macrì F, Pingitore G, Di Rienzo Businco A, et al. Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implicationsfor specific immunotherapy. J Allergy Clin Immu- 167 GLOBAL ATLAS OF ALLERGIC RHINITIS AND CHRONIC RHINOSINUSITIS SECTION D - Allergic rhinitis - diagnosis Figure 3 The impact of CRD on AIT prescription. CRD impact on AIT prescription based on SPT with extract, by SPT cut-point and prescription model. (Reprinted from J Allergy Clin Immunol, 134/1, Stringari G, Tripodi S, Caffarelli C, et al. The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever. 75-81, Copyright 2014, with permission from Elsevier.) Figure 2 Profiles of IgE sensitization to eight Phleum pratense molecules in 176 sensitized children. Profiles of IgE sensitization to eight Phleum pratense molecules in 176 children with an IgE reaction to Phleum pratense and complete data-set. The APCS code and the absolute and cumulative frequency are shown. The profiles are ordered by declining frequency and the point at which the arbitrary threshold of 80% of the patient population has been reached is marked in red. (Reprinted from J Allergy Clin Immunol, 129/3, Tripodi S, Frediani T, Lucarelli S, et al. Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implications for specific immunotherapy. 834-839.e8, Copyright 2012, with permission from Elsevier.) Component resolved diagnosis 168 G
