Marek L. Kowalski

EAACI Position Paper on Rhinosinusitis and Nasal Polyps Executive Summary

OS document, initated by the Academy ofAllergology and Clinical Immunology (EAACI) andapproved by the European Rhinologic Society (ERS), isintended to be state-of-the art for the specialist as well asfor the general practitioner:• to update their knowledge of rhinosinusitis and nasalpolyposis;• to provide an evidence-based documented revision ofthe diagnostic methods;• to provide an evidence-based revision of the availabletreatments;• to propose a stepwise approach to the management ofthe disease;• to propose guidance for definitions and outcomemeasurements in research in different settings.This executive summary focuses on definitions, diagnosisand treatment and the relation to allergy and lowerairway disease. The whole document is published at theEAACI website (http://www.eaaci.org) and in the JournalRhinology (Supplement 18, March 2005).Definition of rhinosinusitis/nasal polypsRhinitis and sinusitis usually coexist and are concurrentin most individuals; thus, the correct terminology is nowrhinosinusitis.In 2001 the WHO put together a working group onrhinitis and its impact on asthma (ARIA) (9). In thisgroup rhinitis was classified according to duration andseverity. Because rhinitis and sinusitis are so closelylinked the definition of CRS/NP in the EPOS document isdeveloped from the ARIA classification of rhinitis andbased on symptomatology, duration and severity ofdisease.The diagnosis of rhinosinusitis is made by a widevariety of practitioners, including allergologists, otolar-yngologists, pulmonologists, primary care physicians andmany others. Due to the large differences in technicalpossibilities to diagnose and treat rhinosinusitis/nasalpolyps by various professions, definitions of CRS/NPshould be tailored to the individual group.Clinical definition of rhinosinusitis/nasal polypsRhinosinusitis (including nasal polyps) is defined as:• Inflammation of the nose and the paranasal sinusescharacterised by two or more symptoms:– blockage/congestion– discharge: anterior/post nasal drip– facial pain/pressure– reduction or loss of smelland either• Endoscopic signs:– polyps– mucopurulent discharge from middle meatus– oedema/mucosal obstruction primarily in middlemeatusand/or• CT changes:– mucosal changes within ostiomeatal complex and/or sinusesSeverity of disease. The disease can be divided intoMILD and MODERATE/SEVERE based on total visualanalogue scale (VAS) score (0–10 cm): MILD ¼ VAS0–4, MODERATE/SEVERE ¼ VAS 5–10.To evaluate the total severity the patient is asked toindicate on a VAS the question:How troublesome are your symptoms of rhinosinusitis?Not troublesome Most troublesome

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe

To cite this article: Jarvis D, Newson R, Lotvall J, Hastan D, Tomassen P, Keil T, Gjomarkaj M, Forsberg B, Gunnbjornsdottir M, Minov J, Brozek G, Dahlen SE, Toskala E, Kowalski ML, Olze H, Howarth P, Krämer U, Baelum J, Loureiro C, Kasper L, Bousquet PJ, Bousquet J, Bachert C, Fokkens W, Burney P. Asthma in adults and its association with chronic rhinosinusitis: The GA2LEN survey in Europe. Allergy 2012; 67: 91–98.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine

To cite this article: Bousquet J, Anto J, Auffray C, Akdis M, Cambon‐Thomsen A, Keil T, Haahtela T, Lambrecht BN, Postma DS, Sunyer J, Valenta R, Akdis CA, Annesi‐Maesano I, Arno A, Bachert C, Ballester F, Basagana X, Baumgartner U, Bindslev‐Jensen C, Brunekreef B, Carlsen KH, Chatzi L, Crameri R, Eveno E, Forastiere F, Garcia‐Aymerich J, Guerra S, Hammad H, Heinrich J, Hirsch D, Jacquemin B, Kauffmann F, Kerkhof M, Kogevinas M, Koppelman GH, Kowalski ML, Lau S, Lodrup‐Carlsen KC, Lopez‐Botet M, Lotvall J, Lupinek C, Maier D, Makela MJ, Martinez FD, Mestres J, Momas I, Nawijn MC, Neubauer A, Oddie S, Palkonen S, Pin I, Pison C, Rancé F, Reitamo S, Rial‐Sebbag E, Salapatas M, Siroux V, Smagghe D, Torrent M, Toskala E, van Cauwenberge P, van Oosterhout AJM, Varraso R, von Hertzen L, Wickman M, Wijmenga C, Worm M, Wright J, Zuberbier T. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011; 66: 596–604.

Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.

BACKGROUND The role of IgE in patients with severe asthma is not fully understood. OBJECTIVE We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease severity in adult asthmatic patients. METHODS Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids. RESULTS Enterotoxin IgE positivity was significantly greater in patients with severe asthma (59.6%) than in healthy control subjects (13%, P< .001). Twenty-one percent of patients with severe asthma with enterotoxin IgE were considered nonatopic. Logistic regression analyses demonstrated significantly increased risks for enterotoxin IgE-positive subjects to have any asthma (OR, 7.25; 95% CI, 2.7-19.1) or severe asthma (OR, 11.09; 95% CI, 4.1-29.6) versus enterotoxin IgE-negative subjects. The presence of GP or house dust mite IgE antibodies was not associated with either significantly increased risk for asthma or severity. Oral steroid use and hospitalizations were significantly increased in patients with enterotoxin IgE and nonatopic asthma. GP IgE was associated with a higher FEV(1) percent predicted value, and enterotoxin IgE was associated with a lower FEV(1) percent predicted value. CONCLUSIONS Staphylococcal enterotoxin IgE antibodies, but not IgE against inhalant allergens, are risk factors for asthma severity. We hypothesize that the presence of enterotoxin IgE in serum indicates the involvement of staphylococcal superantigens in the pathophysiology of patients with severe asthma.

Prevalence of allergy, patterns of allergic sensitization and allergy risk factors in rural and urban children

Background:  We aimed to compare the prevalence of allergic diseases and sensitization in children living in urban and rural areas and to identify potential risk/protection factors associated with allergy.

Anaphylaxis in children and adolescents: The European Anaphylaxis Registry.

BACKGROUND Anaphylaxis in children and adolescents is a potentially life-threatening condition. Its heterogeneous clinical presentation and sudden occurrence in virtually any setting without warning have impeded a comprehensive description. OBJECTIVE We sought to characterize severe allergic reactions in terms of elicitors, symptoms, emergency treatment, and long-term management in European children and adolescents. METHODS The European Anaphylaxis Registry recorded details of anaphylaxis after referral for in-depth diagnosis and counseling to 1 of 90 tertiary allergy centers in 10 European countries, aiming to oversample the most severe reactions. Data were retrieved from medical records by using a multilanguage online form. RESULTS Between July 2007 and March 2015, anaphylaxis was identified in 1970 patients younger than 18 years. Most incidents occurred in private homes (46%) and outdoors (19%). One third of the patients had experienced anaphylaxis previously. Food items were the most frequent trigger (66%), followed by insect venom (19%). Cows milk and hens egg were prevalent elicitors in the first 2 years, hazelnut and cashew in preschool-aged children, and peanut at all ages. There was a continuous shift from food- to insect venom- and drug-induced anaphylaxis up to age 10 years, and there were few changes thereafter. Vomiting and cough were prevalent symptoms in the first decade of life, and subjective symptoms (nausea, throat tightness, and dizziness) were prevalent later in life. Thirty percent of cases were lay treated, of which 10% were treated with an epinephrine autoinjector. The fraction of intramuscular epinephrine in professional emergency treatment increased from 12% in 2011 to 25% in 2014. Twenty-six (1.3%) patients were either admitted to the intensive care unit or had grade IV/fatal reactions. CONCLUSIONS The European Anaphylaxis Registry confirmed food as the major elicitor of anaphylaxis in children, specifically hens egg, cows milk, and nuts. Reactions to insect venom were seen more in young adulthood. Intensive care unit admissions and grade IV/fatal reactions were rare. The registry will serve as a systematic foundation for a continuous description of this multiform condition.

Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients

BACKGROUND Although the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated. OBJECTIVE The aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E(1) analogue (misoprostol). METHODS Twenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays. RESULTS Unstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE(2), leukotriene C(4), and 15-HETE, but lipoxin A(4) release was significantly less in aspirin-sensitive patients (300 +/- 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 +/- 100 pg/mL, P <.05). Cell incubation with 2, 20, or 200 micromol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE(1) analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A(4) in both groups. CONCLUSION PBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.

Aspirin Sensitivity and IgE Antibodies to Staphylococcus aureus Enterotoxins in Nasal Polyposis: Studies on the Relationship

Background: Nasal polyposis is a multifactorial disease characterized by a chronic eosinophilic inflammation of the sinus mucosa, often associated with asthma and aspirin sensitivity. We have recently shown that the presence of IgE antibodies to Staphylococcus aureus enterotoxins (SAEs) was related to the severity of eosinophilic inflammation in nasal polyp tissue. In this study, we therefore aimed to determine, whether aspirin sensitivity was related to an immune response to SAEs, and how both criteria would be related to eosinophilic inflammation. Methods: 40 subjects with nasal polyposis (NP) were classified as aspirin-sensitive (n = 13, ASNP) or aspirin-tolerant (n = 27, ATNP) based on a bronchial aspirin challenge test. Homogenates prepared from nasal polyp tissue and inferior nasal turbinates from healthy subjects (n = 12) were analyzed for concentrations of IL-5 by enzyme immunoassay and for ECP, total and IgE to a mix of SAEs (A, C, TSST-1) using the ImmunoCAP system. Results: Concentrations of IL-5, ECP, total IgE, and IgE to an SAE mix were significantly increased in ASNP compared with ATNP patients and controls. In addition, a subgroup analysis showed an increase in eosinophilic markers in ATNP-SAE(+) compared to ATNP-SAE(–). This relationship, however, was not found in ATNP-SAE(+) and ATNP-SAE(–) subjects, indicating that SAE immune response is overlapped or not relevant in this condition. Conclusions: Aspirin sensitivity was associated with increased concentrations of eosinophil-related mediators, as well as IgE antibodies to SAEs in nasal polyp tissue. However, a direct impact of S. aureus could not be established. It seems that aspirin sensitivity and immune reactions to SAEs are independently related to eosinophilic inflammation.

Nasal secretions in response to acetylsalicylic acid

BACKGROUND Acetylsalicylic acid (ASA) induces rhinorrhea in a subset of patients with asthma or chronic rhinosinusitis or both and nasal polyps. The underlying mechanism of the reaction is obscure. METHODS To assess the nasal response to ASA challenge, four groups of patients were challenged orally with ASA: group A (10 ASA-sensitive patients); group B (nine patients with nasal polyps and histories of tolerance to ASA); group C (nine ASA-tolerant patients with chronic allergic rhinitis); and group D (eight healthy nonatopic subjects). RESULTS Nasal lavages obtained before and after ASA challenge were assayed for proteins (total protein, lactoferrin, lysozyme, albumin) and inflammatory mediators (histamine, prostaglandin D2, and leukotriene C4). ASA challenges induced severe rhinorrhea and congestion and significant increases in mean concentrations of all measured nasal proteins in group A. Histamine and prostaglandin D2 rose, but not significantly. In the two control groups with chronic rhinitis, ASA induced increases in the concentration of proteins and histamine. Leukotriene C4 concentrations were significantly elevated in nasal lavages after ASA challenge in groups A and C only. In group D no symptoms or changes in nasal proteins were observed after aspirin challenge. CONCLUSIONS These observations suggest that production of lipoxygenase products of arachidonate may induce glandular secretions that may participate in the clinical changes associated with ASA sensitivity.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Isam Alobid, MD, PhD1, Nithin D. Adappa, MD2, Henry P. Barham, MD3, Thiago Bezerra, MD4, Nadieska Caballero, MD5, Eugene G. Chang, MD6, Gaurav Chawdhary, MD7, Philip Chen, MD8, John P. Dahl, MD, PhD9, Anthony Del Signore, MD10, Carrie Flanagan, MD11, Daniel N. Frank, PhD12, Kai Fruth, MD, PhD13, Anne Getz, MD14, Samuel Greig, MD15, Elisa A. Illing, MD16, David W. Jang, MD17, Yong Gi Jung, MD18, Sammy Khalili, MD, MSc19, Cristobal Langdon, MD20, Kent Lam, MD21, Stella Lee, MD22, Seth Lieberman, MD23, Patricia Loftus, MD24, Luis Macias‐Valle, MD25, R. Peter Manes, MD26, Jill Mazza, MD27, Leandra Mfuna, MD28, David Morrissey, MD29, Sue Jean Mun, MD30, Jonathan B. Overdevest, MD, PhD31, Jayant M. Pinto, MD32, Jain Ravi, MD33, Douglas Reh, MD34, Peta L. Sacks, MD35, Michael H. Saste, MD36, John Schneider, MD, MA37, Ahmad R. Sedaghat, MD, PhD38, Zachary M. Soler, MD39, Neville Teo, MD40, Kota Wada, MD41, Kevin Welch, MD42, Troy D. Woodard, MD43, Alan Workman44, Yi Chen Zhao, MD45, David Zopf, MD46