Nasal hyperreactivity and inflammation in perennial allergic rhinitis Nasale hyperreactiviteit en ontsteking in chronische allergische rhinitis In 't Veld, Catharina & Garrelds, Ingrid Martine. Nasal hyperreactivity and inflanunation in perennial allergy I C. in 't Veld & I.M. Garrelds. Thesis Erasmus University Rotterdam. - With ref. - With summary in Dutch. Subject headings: nasal hyperreactivity / inflammation / perennial allergic rhinitis. © C. in 't Veld & I.M. Garrelds 1995 All rights reserved, Save exceptions stated by the law, no part of this publication may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or by means, electronic, mechanical, photocopying, recording or otherwise, included a complete or partial transcription, without the prior written permission of the authors, Nasal hyperreactivity and inflammation in perennial allergic rhinitis Nasale hyperreactiviteit en ontsteking in chronische allergische rhinitis PROEFSCHRlFT Tel' verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof. Dr. P.W.C. Akkermans M.A. en volgens besluit van het college voor promoties. De openbare verdediging zal plaatsvinden op woensdag 22 november 1995 om 13.45 Ullt'. door CATHARINA IN 'T VELD geboren te Rotterdam De openbare verdediging zal plaatsvinden op woensdag 22 november 1995 om 15.00 Ullt'. door INGRID MARTINE GARRELDS geboren te Dordrecht PROMOTIE COMMISSIE: C. IN 'T VELD: PROMOTOR: Prof. Dr. C.D.A. Verwoerd OVERIGE LEDEN: Prof. Dr. P.R. Saxena Prof. Dr. F.P. Nijkamp Prof. Dr. J.G.R. de Monchy CO-PROMOTOR: Dr. R. Gerth van Wijk I.M. GARRELDS: PROMOTOR: Prof. Dr. P.R. Saxena OVERIGE LEDEN: Prof. Dr. C.D.A. Verwoerd Prof. Dr. F.P. Nijkamp Prof. Dr. J.G.R. de Monchy CO-PROMOTOR: Dr. F.J. Zijlstra Acknowledgement - Financial supp0l1 by the Netherlands Asthma Foundation (research grant 92,74); Janssen-Cilag B.Y.; Glaxo B.Y.; Pharmachcmie B.V" Haarlem; ARTU Biologicals N.V.; ASTA Medica B.V.; A.C.M. Ooms Allergie B.V.; Bolidt Kunststof­ toepassing B.V.; ALK Benelux B.V.; Schering-Plough B.V.; UCB Pharma B.V.; Cara C'nir; Bio-RAD for this study and the pUblication of this thesis is gratefully acknowledged. vaal' Erik en Jeroen Contents Contents vii Preface xi PART ONE: General introduction Chapter 1. Allergic rhinitis 3 c. de Graa/-il1" Veld, l Ai GOl'l'elds 1.1 Historical review of allergy 3 1.2 Allergic rhinitis 4 1.2.1 Epidemiology 4 1.2.2 Clinical aspects of allergic rhinitis 4 1.2.3 Impact on daily activities and quality of life 4 1.3 Reactions of nasal mucosa on allergen exposure 5 1.3.1 Immediate allergic reaction 6 1.3.2 Late allergic reaetion 6 1.3.3 Nasal priming 6 1.4 Allergen-induced nasal hyperrcactivity 7 1.5 Allergic rhinitis. A model to study airway inflammation 9 Chapter 2. Allergic inflammation II I.M. Garre/ds, C. de Graaf-in't Veld 2.l Introduction II 2.2 Cells in allergic rhinitis II 2.2.1 Primary effector cells II Mast cells II Antigen-presenting cells 12 Epithelial cells 13 2.2.2 Secondary effcclor cells 14 Basophils 14 Eosinophils 15 Neulrophils 16 Monocytes/macrophages 17 Lymphocytes 17 Platelets 19 2.3 Products of allergic inflammation 20 Histamine 20 Tryptase 21 Eicosanoids 22 Platelet activating factor 24 Eosinophil-derived granule proteins 25 Cytokines 26 Nitric oxide 28 2.4 Concluding remarks 29 vii Chapter 3. Aim of the study 31 PART TWO: Hypel'l'eactivity and inflammation 33 Chapter 4. Nasal responsiveness to allergen and histamine are associated 35 in patients with perennial allergic rhinitis c. de Graafill', Veld, 1.M. Garrelds, A. rl~ vall Toorenenbergen, R. Gerth van Wijk Chapter 5. Relationships between nasal hyperreactivity, mediators and eosinophils 45 in paticnts with perennial allergic rhinitis and controls c. de Graafin't Veld, I.M. Garrelds, S. Koenders, R. Gerth vall fVijk PART THREE: Thel'apeutic inten'ention 53 Chapter 6. Glucocorticosteroid intervention 55 Chapter 7. Effect of intranasal fluticasone propionate on the immediate and 57 late allergic nasal reaction and nasal hyperreactivity in patients with a house dust mite allergy c. de Graaf-in" Veld, I.M. Garrelds, A.P.H. Jansen, A.IV. van Toorenenbergen, P.G.H. Mlilder, J Meellwis, R. Gerth van H'ijk Chapter 8. Effect of fluticasone propionate aqueous nasal spray treatment on 67 platelet activating factor and eicosanoid production by nasal mucosa in patients with a hOllse dust mite allergy I.M. Garrelds, C. de Graaf-in't Vehl, A.P.!f. Jansen, R. Gel'th van Wijk, F.J. Zijlstra Chapter 9. Interleukin-5 and eosinophil cationic protein in nasal lavages of 75 rhinitis patients J.A!. Garrelds, C. de Graafin't Vehl, AI-A Nahor;, B.B. Vargaflig, R. Gerth van Wijk, F.J. Zijlstra Chapter 10. Nitric oxide metabolites in nasal lavage fluid of patients with 85 hOllse dust mite aJIergy U.l. Gal'relds, J.G.c. vall Amsterdam, C. de Graafin't Vehl, R. Gerth van Wijk, F.J. Zijlstra Chapter 11. The reduction of symptoms to the corticoid fluticasone propionate of 93 patients with perennial allergic rhinitis is not associated with glucoc0l1icoid receptor binding characteristics of peripheral blood mononuclear cells I.M. Gan'e/ds, C. de Graafin" Veld, P.G.!/. Alulder, R. Gerth van Wijk, F.J. Zijlstra Chapter 12. Antihistaminic intervention 103 viii Contents Chapter 13. Effect of topicallevocabastine on nasal response to allergen challenge 105 and nasal hyperreactivity in perclUlial rhinitis C. de Graafill't Veld, l.M Garrelds, A. W. van Toorenenbergen, P.G.H. Mllider, R. Gerth van Wijk, J.P.J. Boegheim Chapter 14. Selective effect of levocabastine on histamine receptor and 115 histamine release from human leukocytes and guinea-pig isolated tissue 1.M. Garrelds, C. de Graafin't Veld, A.H~ van Toorenenbergen, R. Gerth van Wijk, J.P.J. Boegheim, P.R. Sm:ena, F.J. Zijlslra PART FOUR: Hyperreactivity and quality of life 129 Chapter 15. The relationships between nasal hyperreactivity, quality of life 131 and nasal symptoms in perennial allergic rhinitis c. de Graafin't Veld, S. Koenders, l.A!. Garrelds, R. Gerth van Wijk PART FIVE: General discussion and summary 139 Chapter 16. General discussion 141 Chapter 17. Summary 149 Samenvatting 152 References 156 Abbreviations 186 Dankwoord 189 Curriculum vitae 190 Publications 191 ix Preface Allergic rhinitis is a conunon disease resulting in a high morbidity. It is defined as an inflammation of the nasal mucosa and is characterised by symptoms such as itchy nose, sneezing, rhinorrhoea and nasal blockage. Repetitive allergen exposure gives rise to increased sensitivity to allergens (priming) and nonspecific stimuli. This nonspecific nasal hyperreactivily can be measured by history and by nasal challenge tests with methacholine or histamine. However, the pathogenesis of nasal hyperreactivity is still not clear. In asthmatic patients bronchial hyperreactivity seems to be associated with the latc phase response and allergic inflammation, suggesting that inflammation is involved in the pathogenesis of hyperreactivity. In analogy with the bronchial situation these associations were also studied in the nose. Until now, most studies investigating the relationship between nasal response to allergen and nasal hyperreactivity have been performed in patients with pollinosis. In these studies no relationship could be found between nasal hyperreactivity, nasal priming, the late phase response and nasal inflammation, Only a few studies have been performed in patients allcrgic to house dust mites (BDM). In this subgroup it has becn demonstrated that pre-existent nasal hyperreactivity can predict nasal response to allergen challenge, a finding more in agreement with the lower airways. In this thesis we further want to investigate the relationship between nasal hyperreactivity, nasal response to allergen and nasal inflammation in perennial rhinitis. Hereto, we evaluated the effects of therapeutic intervention on nasal response to allergen and hyperreactivity and data obtained during the placebo treatment. Nasal response to HDM challenge was monitored by symptoms and mediators in nasal lavage fluid. Allergen-induced nasal hyperreactivity was determined 24 hours later by nasal challenge with histamine or methacholine. It is expected that non-specific nasal hyperreactivity is particularly important in patients with perennial allergic rhinitis, since they are continuously exposed to allergen. However, the importance of routine histamine challenges in daily practice is not clear. Hereto, we studied nasal response to histamine and daily nasal symptoms. Inflammatory mediators in lavage fluid and eosinophils in cytospins were also determined in order to evaluate the involvement of inflammation in the ongoing allergic reaction. In addition, we investigated the impact of rhinitis symptoms on day-to-day life. By means of a rhinitis quality of life (QOL) questiOlUlaire, the relationship between nasal response to histamine, QOL and daily nasal symptoms was estimated in patients allergic to HDM. Part one presents the definitions and clinical aspects of allergic rhinitis (chapter one), the cells and mediators involved in the allergic reaction (chapter two) and the aims of the study (chapter 3). In part two the relationship between nasal hyperreactivity and inflammation is studied. Chapter 4 describes a nasal challenge study in patients with perennial rhinitis. Inflammatory mediators and nasal hyperreactivity were compared between patients with an early and late phase response and individuals expressing an isolated early response only. In chapter 5, inflammatory mediators in nasal lavage, eosinophils in nasal blUshes and responsiveness to histamine were studied in non-challenged patients with perennial rhinitis xi Preface and healthy subjects. Part three concerns the therapeutic intervention on nasal response to allergen challenge and hyperreactivity with a c0l1icosteroid (fluticasonc propionate) and an antihistamine (levocabastine). In chapter 7-10 the effect of two weeks topical fluticasone propionate on the immediate and late nasal symptoms, inflammatory mediators and nasal response to histamine is described.