M.D. Thesis

Evaluation of the medical and surgical treatment of chronic rhinosinusitis and its effect upon the lower airways

Sameh Mostafa Ragab MBBCh., MSc., FRCSEd. University College London

University of London 2002

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ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract

Evaluation of the medical and surgical treatment of chronic rhinosinusitis and its effect upon the lower airways

Sameh Mostafa Ragab University College London M.D. Thesis 2002

1. Chronic rhinosinusitis (CRS) is a prevalent disease that has marked effects on the society. Its definition, pathophysiology, microbiology and treatment are still a source of debate. Likewise, there is still considerable confusion in the literature concerning the relationship and the effect of therapy of CRS upon the concomitant asthma. The aims of the thesis were: To conduct the first prospective randomised controlled trial, evaluating and comparing the medical and surgical treatment of CRS and its subgroups; to study whether the presence of nasal polyps serves as a poor prognostic factor for the efficacy of CRS therapy; to study whether asthma serves as a poor prognostic factor for the efficacy of CRS therapy; to elucidate the relationship between upper and lower airway diseases, considering specifically the relationship between CRS and asthma; to conduct the first prospective randomised study evaluating and comparing the effect of the medical and surgical treatment of CRS and its subgroups upon asthma, applying a range of subjective and objective parameters, and including exhaled NO as an easy and sensitive detector of inflammation; to study whether the presence of nasal polyps serves as a poor prognostic factor for asthma control in CRS patients; to study the effect of medical and surgical therapy of CRS upon nasal NO levels; to investigate the value of nasal NO as an objective indicator of the effect of therapy on CRS.

2. Subjects were 90 patients with CRS, of whom 43 were asthmatics. Patients were randomised either to medical or surgical therapy of CRS. All patients underwent pre and post-treatment assessments of visual analogue score (VAS), chest score, overall asthma control score, use of anti-asthma medication, hospitalisation for asthma, the Sinonasal Outcome Test-20, the Short Form 36 Health Survey (SF-36), nitric oxide (NO), acoustic rhinometry, saccharine clearance time, spirometry, and nasal examination including anterior rhinoscopy and endoscopy.

3. Both the medical and surgical treatment of CRS significantly improved almost all the subjective and objective parameters of CRS (P<0.01), with no significant difference being found between the medical and surgical groups (P>0.05) except for total nasal volume in CRS (P<0.01) and CRS without polyposis (P<0.01) groups in which the surgical treatment demonstrated greater changes..

4. Both the medical and surgical treatment significantly improved almost all the subjective and objective parameters of CRS in asthmatic patients (P<0.01 in total groups and <0.05 in subgroups), with no significant difference being found between the surgical and medical groups.

5. The asthmatic surgical groups showed a general trend for improvement in the subjective and objective lower airway measurements. However, this did not reach a statistical significance except for use of broncho dilator inhalers (P<0.05), use of oral corticosteroids (P<0.05), hospitalisation (P<0.05), overall asthma control score (P<0.05), exhaled NO (P<0.05) and FEV1% (P<0.05) in the total surgical group of CRS. The medical groups showed higher significance values than the corresponding surgical groups. However, the difference between the medical and surgical groups did not reach a statistical significance except for exhaled NO (P<0.05) and FEV1% (P<0.05) measurements in CRS with polyposis. On the other hand, no significant difference was found between the surgical groups of CRS without and with polyposis, although CRS without polyposis tended to show higher improvement percentage values in the subjective and objective lower airway measurements.

6. Nasal NO increased significantly with medical (P<0.01) and surgical (P<0.01) treatment of CRS. The surgical groups experienced higher levels of improvement, although not significant (P>0.05), than the medical groups. Nasal NO correlated inversely with VAS (P<0.001), SCT (P<0.001), endoscopic score (P<0.001), polyp grade (P<0.01) and CT score (P<0.001).

7. Chronic rhinosinusitis should be targeted with maximal medical therapy in the first instance, with surgical treatment being reserved for cases refractory to medical therapy. Neither presence of nasal polyps nor asthma serves as a poor prognostic factor for the efficacy of CRS therapy. The evidence of the link between CRS and asthma is too striking to be denied. Both medical and surgical therapy of CRS improve the clinical course of asthma, with the medical treatment being superior to the surgical, especially in CRS with polyposis. On the other hand, it seems that sinus surgery can trigger or aggravate asthma in a subgroup of CRS patients. Finally, nasal NO is a valuable objective measurement in monitoring medical and surgical therapy for CRS. Contents

Page

Abstract 1

Acknowledgement 4

Abbreviations 5

List of tables 7

List of figures 8

1 Introduction 9

2 Materials and Methods 79

3 Results 100

4 Discussion 128

5 Future work 151

6 Summary 153

7 Appendices 158

8 Bibliography 261 Acknowledgements

I am grateful to my colleagues for their support at all stages of the production of this thesis: Professor Stephen Senn, professor of statistical sciences, department of epidemiology and public health. University College London, for his invaluable and generous statistical advice; the Egyptian government for financial support; the ENT department committee of Tanta University Hospital for supporting my application for the grant; He sham Saleh for the personal support; Yvonne Derby for practical help in the rhino logy laboratory; the ENT team of the Royal National Throat, Nose and Ear Hospital for their help and support in the Rhino logy Clinics; Alex Stagger, the librarian of the Royal National Throat, Nose and Ear Hospital for his help in the bibliography; Andrew Gardner, the photographer of the Royal National Throat, Nose and Ear Hospital for the expert photographic services and Cheryl Overington, the adminstrator of the Institute of Laryngology and Otology, University College London, for administrative help.

Most of all I must express my gratitude for the professional and personal support given to me throughout the planning, conducting and writing of this thesis by Professor Valerie Lund, professor in Rhinology, University College London, Dr. Glenis Sc adding, consultant in Rhinology, allergy and Immunology, Royal National Throat, Nose and Ear Hospital, My wife Ola without whose patience, this work could not have been done and my parents and parents in law without their help allover my life, I could not have reached this stage. Abbreviations

AMP Adenosine monophosphate BHR Bronchial Hyperresponsiveness CBF Ciliary Beat Frequency cNOS Constitutive nitric oxide synthase CNS Coagulase-negative staphylococcus CRS Chronic rhinosinusitis CT Computerised Tomography DRS Dexarhinospray eNOS Endothelial nitric oxide synthase ERS European Respiratory Society. EV Energy/Vitality FEVi Forced Expiratory Volume after 1 second. FEV i% Percentage of FEVI of FVC. FVC Forced Vital Capacity GHP General health perception GMP Guanosine monophosphate GM-CSF Granulocyte-macrophage colony-stimulating factor GNRs Gram-negative rods

Ig Immunoglobulin IL Interleukin iNOS Inducible nitric oxide synthase MCA Minimum cross-sectional area MH Mental Health NO Nitric oxide. nNOS Neuronal nitric oxide synthase NOS Nitric oxide synthase OMC Ostiomeatal complex P Pain PCD Primary ciliary dyskinesia PEF Peak Expiratory Flow. PF Physical Functioning ppb parts per billion PVR Pulmonary vascular resistance RE Role limitation due to emotional problems RET Respiratory Function Tests RNA Ribonucleic acid RP Role limitation due to physical problems SA Staphylococci aureus SCT Saccharine clearance time. SD Standard deviation SF Social functioning SF-36 Short form 36 health status survey SNOT-20 Sinonasal outcome test 20 SPT Skin prick test Staph. Staphylococci Th T-helper TNF Tumour necrosis factor VAS Visual analogue score VC Vital Capacity List of Tables

Table Location Page

Introduction tables la Incidence of major complications of endoscopic Review 42 sinus surgeiy of literature lb Analysis'of the trials investigating the effect of Review 57 sinus surgery upon asthma of literature Ic Isoforms ofNOS Review 65 of literature Materials and Methods tables

2a The interpretation of the SF-36 scores Materials 94 and Methods Results tables

• Baseline data tables Appendix 169 II • CRS study tables Appendix 190 IV • Asthma study tables Appendix 231 VI List of Figures

Figure Location Page

Introduction figures 1.1 Sagittal section of the nose Review 16 of literature 1.2 Coronal section at the level of uncinate process Review 16 of literature 1.3 Sphenoethmoidal cell Review 21 of literature 1.4 Ethmoid roof Review 22 of literature 1.5 Infraorbital cell Review 23 of literature Materials and Methods figures

2.1 Study design Materials 83 and Methods Results figures

• Baseline data figures Appendix 174 III • CRS study figures Appendix 208 V • Asthma study figures Appendix 245 VII • Nitric oxide study figures Appendix 249 v n i 1 - Introduction

Contents Page

1.1 General introduction 10

1.2 Literature review 15

1.2.1 Treatment o f chronic rhinosinusitis 15

Rhinosinusitis and asthma 43

1.2.3 Endogenous nitric oxide and the airways 63

1.3 Aims of the thesis 78 1.1 General introduction

Chronic rhinosinusitis has been reported to affect 5-15% of urban populations in Europe (Melen, 1994). In the United States, approximately 12 % of the Americans below the age of 45 years have been described as suffering symptoms of chronic rhinosinusitis (Hamilos, 2000). However, it is surprising that the definition, pathophysiology, microbiology and consequently treatment of chronic rhinosinusitis have remained a source of debate. The discrepancy of definitions has resulted mainly from the use of different criteria such as symptoms, duration, intensity, investigations and even pathophysiological considerations. The International Conference on Sinus Disease has proposed the criteria of diagnosis of chronic rhinosinusitis in adults to be 8 weeks of persistent symptoms and signs or four episodes per year of recurrent acute sinusitis, each lasting at least 10 days, in association with persistent changes on computed tomography 4 weeks after medical therapy without intervening acute infection (Lund & Kennedy, 1995). The exact pathophysiology of chronic rhinosinusitis is still unknown. However, a popular hypothesis for the development of chronic rhinosinusitis is that aetiological factors trigger a vicious circle of sinus ostial obstruction, local metabolic and gas disturbances, retention of secretions, proliferation of bacteria, accentuation of inflammation and ciliary dysfunction (Stiema, 2001). Recently, nitric oxide has been incriminated in playing a role in the pathogenesis of chronic rhinosinusitis (Lindberg et al, 1997b). Likewise, microbiology of chronic ifiinosinusitis and even the actual role of the organisms are still unclear. Extremely varying results have been provided by microbiologie studies of chronic rhinosinusitis. The variations seem to depend on the sampling technique, the transport system, the specimen processing, the studied population and the presentation of the results. Furthermore, it is still debatable whether most of the isolated organisms represent contaminants fi*om nasal flora and skin or even reflect the commensal flora of the middle meatus and sinuses. Recently, a qualitative and semi-quantitative bacteriological study reported that the clinical value of

10 bacteriological examinations of nasal and paranasal mucosa is doubtful in patients with chronic rhinosinusitis (Kremer et al, 2001). As a consequence of the above confusion, a wide range of medical and surgical therapies has been used to treat chronic rhinosinusitis. Medical therapy of CRS includes antimicrobials, corticosteroids, decongestants, antihistamines, mast cell stabilizers, antileukotrienes, nasal douching, immunotherapy and reduction of irritant environmental factors. The documentation of the medical treatment of CRS is very deficient in the literature, apart from a number of randomised controlled trials investigating the role of corticosteroids in CRS with nasal polyposis (Lund et al, 1998;Tos et al, 1998;Keith et al, 2000;Penttila et al, 2000). On the other hand, sinus surgery is broadly classified into conventional and endoscopic sinus surgery, with endoscopic sinus surgery largely replacing conventional sinus procedures. Endoscopic sinus surgery has yielded excellent subjective (Stammberger, 1991c;Lund & Mackay, 1994;Senior et al, 1998) and objective outcomes (Waguespack, 1995;Lund & Scadding, 1994;Abdel- Hak et al, 1998), with a very low complication rate (Stammberger & Wolf, 1988;Stankiewicz, 1989;Senior et al, 1998). Finally, it has to be mentioned that an emphasis on the importance of the ostiomeatal complex in the development of chronic rhinosinusitis has led to an overemphasis in the importance of the surgical correction of the ostiomeatal abnormalities. This concept, in addition to the high success rate, the low incidence of complications, the increased emphasis on the anatomic variations and the technological advances in optical instmmentation and imaging techniques as well as the deficient documentation of the medical therapy, has developed endoscopic sinus surgery as the primary therapy for chronic rhinosinusitis in the absence of a well-performed, prospective, randomised, controlled trial that fulfils level 1 statement of evidence-based medicine.

The association of rhinosinusitis and bronchial asthma has been noted for a great many years. A number of clinical studies reported a prevalence of rhinosinusitis in asthmatics that varied from 12 % (Bullen, 1932) to 43 %

11 (Chobot, 1930) to 72 % (Weille, 1936) to 90 % (Gottlieb, 1925). Conversely, 34 % of rhinosinusitis patients have been shown to have asthma (Annesi- Maesano, 1999). However, these studies are not conclusive, since they are dependent on the definitions of rhinosinusitis and asthma in the absence of an epidemiological gold standard to make such definitions. Radiological studies have shown 40 (Berman et al, 1974) - 53% (Rachelefsky et al, 1978) abnormal sinus X-rays and 74% (Pfister et al, 1994) mucosal thickening on sinus CT scans of asthmatics. Howver, one can easily argue that sinus X-rays are inaccurate and both sinus X-rays (Odita et al, 1986;Wilson & Grocutt, 1990) and CT scans (Glasier et al, 1986;Diament et al, 1987) have been reported to be abnormal in the absence of any sinus disease. It is worth mentioning that although the first observation of a possible role of rhinosinusitis in triggering or aggravating asthma was made in the second century (AD), the nature of this association is still far from clear. However, the following possible mechanisms have been suggested in favour of upper airway-lower airway interaction: (1) failure of filter, heat and humidification functions of the nose, (2) enhancement of beta adrenergic blockade, (3) presence of a rhinosinobronchial reflex, (4) sino-puLmonary deposition of inflammatory product-rich secretions, (5) enhancement of systemic airway inflammatory responses and (6) a potential role for deficiency or an excess of nasal NO. A number of authors have investigated the link between rhinosinusitis and asthma through studying the effect of the surgical and medical treatment of rhinosinusitis upon asthma. Considerable conflict has been shown in the literature concerning the effect of sinus surgery on asthma. A number of authors has reported improvement (Stammberger, 1991a;Jankowski et al, 1992;Senior & Kennedy, 1996), some have described worsening (Francis, 1929;Samter & Lederer, 1958) and others have shown equivocal effect (Brown et al, 1979;Goldstein et al, 1999) of sinus surgery upon concomitant asthma. On the other hand, adult studies are very defective in investigating the effect of the medical therapy of chronic rhinosinusitis on asthma, with only two studies in the literature. One included 4 medical

12 patients, whereas the other was non-randomised, considered CRS with polyposis only and analysed asthmatics and non-asthmatics as one group. Overall, the epidemiological, radiological and clinical studies suggest a potential role for rhinosinusitis in triggering or aggravating asthma. However, none of them meet the accepted standards for rigorous clinical trials to provide evidence for therapy. The observations concerning the effect of treatment of rhinosinusitis upon concomitant asthma appears to be among the most logical arguments for such an interaction and an increasing attitude to consider asthma as an inflammatory disease emphasises the need for a sensitive method to detect such claimed changes in the inflammatory process. Hence, it is quite clear that we need a randomised prospective study looking at the effect of the medical and surgical treatment of chronic rhinosinusitis upon asthma, applying a reasonable range of subjective and objective parameters, and including an easy and sensitive detector of asthmatic inflammation.

Nitric oxide is a fairly stable gas, being formed in vivo by three iso forms of the enzyme nitric oxide synthase. It is secreted in the respiratory tract with a major contribution from the upper airways especially paranasal sinuses (Lundberg et al, 1994b;Lundberg et al, 1995a). The biological significance of the airway-derived nitric oxide is still far from being settled. Nitric oxide has been suggested to be a bronchodilator (Gaston et al, 1993), a vasodilator (Liu et al, 1991;Martinez et al, 1995) and a major neurotransmitter (Bai & Bramley, 1993;Belvisi et al, 1992a), to have antimicrobial (Wei et al, 1995;Laubach et al, 1995), antitumour (Xie & Tidier, 1998;Lala, 1998) and mucociliary regulating activities (Jain et al, 1993;Runer et al, 1998;Runer & Lindberg, 1998) and to act as an airborne messenger (Gerlach et al, 1993;Puybasset et al, 1994). On the other hand, it has been demonstrated that nitric oxide may have possible pro inflammatory actions (Beckman et al, 1990;Rubbo et al, 1994). Nitric oxide has been reported to decrease in acute rhinosinusitis (Baraldi et al, 1997), primary ciliary dyskinesia (Amal et al, 1999;Lundberg et al, 1994c) and cystic fibrosis (Balfour-Lynn et al.

13 1996;Dotsch et al, 1996) and to increase in allergic rhinitis (Kharitonov et al, 1997b;Martm et al, 1996;Amal et al, 1997) and asthma (Kharitonov et al, 1994b;Persson et al, 1994c;Massaro et al, 1995;Saleh et al, 1998). On the other hand, some conflict has been shown concerning the levels of nasal NO in chronic rhinosinusitis. Lindberg et al. (1997b) showed that patients with chronic rhinosinusitis had lower nasal NO levels than healthy controls. Conversely, Amal et al. (1999) found no significant difference in nasal NO levels between patients with chronic rhinosinusitis and controls. Overall, nitric oxide is a valuable marker in airway inflammatory diseases and its measurement excites considerable interest as it provides a simple non-invasive means of measuring airway inflammation, even in children. However, the situation in chronic rhinosinusitis is not completely clear and the value of nasal NO as a positive indicator of the effect of therapy on chronic rhinosinusitis is still unknown.

14 1.2 Literature review

1.2.1 Treatment of chronic rhinosinusitis

Before reviewing the medical and surgical treatment of chronic rhinosinusitis, a brief discussion of the relevant anatomical, pathophysiological and microbiological factors will be presented below.

1.2.1a Anatomy (Stammberger, 1991d;Stammberger & Kennedy, 1995;Lund, 1997;Bogler,2001) The anatomy of the paranasal sinuses is complex and varies greatly between human subjects. In an attempt to reduce this complexity, a series of lamellae has been suggested on the basis of embryologie precursors. The first lamella is the uncinate process; the second lamella corresponds to the ethmoidal bulla; the third is the basal or ground lamella of the middle turbinate; the fourth is the lamella of the superior turbinate and the fifth lamella is the occasionally present supreme turbinate. The basal lamella of the middle turbinate is especially important, as it separates the anterior and posterior ethmoids. The frontal, maxillary, and anterior ethmoids arise fi*om, and therefore drain into, the middle meatus. The posterior ethmoid cells arise fi*om, and therefore drain into, the superior and supreme meati, while the sphenoid sinus drains into the sphenoethmoid recess.

Figures 1.1 and 1,2 show sagittal and coronal sections of the nose.

15 Figure 1.1 Sagittal section through the nose(Stammberger & Kennedy,

1995).

.cil

— "V .

liitcru'i iiirl'inaiL- l Incmar.- pf

Middle liubinak- M .ixill.ir’. ‘.Kuis o'.iium k 1:1 av. a> i

Figure 1.2 Coronal section at the level of uncinate process(Stammberger

& Kennedy, 1995).

. Siifiralniihir .jnij icl(i)bii,';.ir rccc.ss

16 Middle Turbinate Anteriorly, the turbinate attaches laterally at the crista ethmoidalis of the maxilla. The most posterior aspect of the middle turbinate is its inferior attachment to the lateral wall at the crista ethmoidalis of the perpendicular process of the palatine bone, just anterior to the sphenopalatine foramen. The intervening area of the insertion can be divided into three parts. The anterior third inserts vertically into the lateral edge of the lamina cribrosa. The middle third is fixed to the lamina papyracea in an almost frontal plane. The posterior third inserts into the lamina papyracea and/or the medial wall of the maxillary sinus in an almost horizontal plane forming the roof of the most posterior part of the middle meatus. The middle turbinate can be paradoxically curved or pneumatized.

Anterior Ethmoid Agger Nasi The agger nasi is a prominence at and just anterior to the middle turbinate’s insertion into the lateral nasal wall. In many cases, it is pneumatized by an anterior ethmoid cell, known as the agger nasi cell. The agger nasi cell is bordered anteriorly by the frontal process of the maxilla, superiorly by the frontal recess/sinus, an te ro late rally by the nasal bones, in fero medially by the uncinate process of the ethmoid bone, and in fero laterally by the lacrimal bone. The agger nasi cell has an intimate relationship to the lacrimal bone, frontal sinus and frontal recess.

Uncinate Process The uncinate process is a nearly sagittally oriented bony leaflet, approximately 3 to 4 mm wide and 1.5 to 2 cm in length. Through most of its course, its posterior margin is free and lies parallel to the ethmoid bulla. Anteriorly and superiorly, it attaches to the ethmoidal crest of the maxillae, just inferior to the lateral attachment of the anterior aspect of the middle turbinate and agger nasi. Directly inferior to this, it fuses with the posterior

17 aspect of the lacrimal bone. Its anterior inferior aspect does not have a bony attachment. Posteriorly and inferiorly, the uncinate attaches to the ethmoidal process of the inferior turbinate bone. The uncinate has no bony attachment anterior and posterior to its attachment to the inferior turbinate bone. Here, the lateral nasal wall is made not of bone but rather middle meatal mucosa, a small layer of intervening connective tissue, and sinus mucosa. These areas are referred to as the anterior and posterior fontanelles. An accessory ostium of the maxillary sinus can sometimes be seen in the posterior fontanelle or less commonly the anterior fontanelle. The superior aspect of the uncinate process usually bends laterally to insert on the lamina papyracea of the orbit. Alternatively, it can attach centrally to the skull base or medially to the superior aspect of the vertical lamella of the middle turbinate. It can also divide to attach to the lamina papyracea, skull base, and middle turbinate. The uncinate process itself can show a significant amount of variability. It can be displaced laterally against the orbit producing an atelectatic infundibulum or medially against the middle turbinate. In some cases, the uncinate is bent medially with anterior folding giving a false impression of duplication of the middle turbinate. Additionally, in a small percentage of cases, the uncinate process can be pneumatized.

Ethmoid Bulla The ethmoid bulla is one of the most constant and largest of the anterior ethmoid air cells. It is located within the middle meatus directly posterior to the uncinate process and anterior to the basal lamella of the middle turbinate. The cell is based on the lamina papyracea and projects medially into the middle meatus. Superiorly, the anterior wall of the ethmoid bulla can extend to the skull base and form the posterior limit of the frontal recess. Posteriorly, the bulla can blend with the ground lamella. When unpneumatized, a bony projection fi-om the lamina papyracea results and is referred to as the torus lateralis.

18 Hiatus Semilunaris The hiatus semilunaris is a two-dimensional space between the posterior-free margin of the uncinate process and the anterior wall of the ethmoid bulla, communicating between the middle meatus and the ethmoidal infundibulum. This cleft is further designated as the hiatus semilunaris inferior to distinguish it from the hiatus semilunaris superior. The hiatus semilunaris superior is the cleft formed between the posterior wall of the ethmoid bulla and the basal lamella of the middle turbinate and is the passageway through which the middle meatus communicates with the lateral sinus (retro-and suprabullar recess).

Ethmoidal Infundibulum The ethmoidal infimdibulum is a three-dimensional space, through which the secretions from various anterior ethmoid cells, the maxillary sinus, and, in some cases, the frontal sinus are transported into the middle meatus. It communicates with the middle meatus through the hiatus semilunaris. It is bordered medially by the uncinate process, laterally by the lamina papyracea, and anteriorly and superiorly by the frontal process of the maxilla and lacrimal bone. The anterior wall of the ethmoid bulla forms the posterosuperior border of the ethmoidal infundibulum. The natural ostium of the maxillary sinus is most commonly located between the middle and posterior thirds of the ethmoid infundibulum.

Sinus Lateralis (Suprabullar and Retrobullar Recesses) The sinus lateralis is a variable space that lies behind and above the ethmoid bulla. This space can be highly developed and in such cases, it is bordered by the ethmoid roof superiorly, the lamina papyracea laterally, the ethmoid bulla roof and posterior wall inferiorly and anteriorly, and the basal lamella of the middle turbinate posteriorly. The ethmoid bulla often opens posteriorly into the sinus lateralis.

19 Frontal Recess The frontal recess is the most anterosuperior aspect of the anterior ethmoid sinus that forms the connection with the frontal sinus in an hourglass-like appearance with the frontal ostium being the narrowest portion. The boundaries of the frontal recess are the lamina papyracea laterally, the middle turbinate medially, the posterosuperior wall of the agger nasi cell anteriorly, and the anterior wall of the ethmoid bulla posteriorly. If the anterior wall of the ethmoid bulla does not reach the skull base and form a complete posterior wall, the frontal recess may communicate with the suprabullar recess. The roof is formed by the frontal bone and the frontal ostium opens in its anterior part. There is tremendous variation with respect to the pattern of the nasofrontal connection depending on the attachment of the anterosuperior part of the uncinate process and the anatomic complexity of the surrounding ethmoid cells, such as the agger nasi cell, frontal cells, and supraorbital ethmoid cells. Most commonly, the uncinate bends laterally to attach to the lamina papyracea and the frontal recess will drain medial to the uncinate. Altematively, the uncinate can attach to the ethmoid roof or insert into the middle turbinate. In these cases, the frontal recesses will be contiguous with the ethmoidal infundibulum.

Posterior Ethmoid Sinuses The posterior ethmoid sinuses drain into the superior and supreme meati. They are bounded anteriorly by the basal lamella of the middle turbinate, posteriorly by the anterior wall of the sphenoid sinus, laterally by the lamina papyracea, medially by the vertical portions of the superior and supreme turbinates and their accompanying meati, and superiorly by the ethmoid roof. The posterior ethmoids have a specific surgical significance due to their proximity to the skull base and optic nerve. The most posterior ethmoid cell may extend posteriorly and lateral to the sphenoid sinus resulting in an intimate relationship with the optic nerve and even the internal carotid artery. This is referred to as a sphenoethmoidal (or Onodi) cell (Figure 1.3).

20 Figure 1.3 Sphenoethmoidal cell. (Stammberger & Kennedy, 1995).

a

Roof of the ethmoid

From its orbital plate, the frontal bone extends over the open ethmoidal roof to join with the lateral lamella of the cribriform plate. Thus, the frontal bone

forms the ethmoid roof, which is indented by various ethmoid air cells and

clefts to form foveolae, specifically the foveolae ethmoidales ossis frontalis.

The ethmoid roof may vary in its orientation from being nearly horizontal to

nearly vertical; however, in most patients, the ethmoid roof lies above the

level of the cribriform plate. The medial aspect of the ethmoid roof is formed

by the lateral lamellae of the cribriform plate, also known as the lamina

lateralis of the lamina cribrosa. Keros has described three types of skull-base

conformations that have clinical relevance in sinus surgery. In type one, the

olfactory sulcus is less than 3 mm deep, the corresponding lateral lamella is

short, and there is a significant portion of frontal bone that backs the ethmoid

roof. In type two, the olfactory sulcus is 3 to 7 mm deep, and the

21 corresponding lateral lamella forms a considerable portion of the medial ethmoid roof. In type three, the olfactory sulcus is more than 7 mm deep, and the ethmoid roof lies at a significant level above the cribriform plate (Figure

1.4).

The anterior ethmoid artery is an important structure of the anterior ethmoid roof. As the artery enters the ethmoid from the orbit, it courses across the ethmoid roof, either in a bony canal at or just below the level of the roof. It can lie 1 to 3 mm below the roof in a mesentery. It courses anteriorly as it crosses from lateral to medial, and penetrates the lateral lamellae to enter the olfactory sulcus.

Figure 1.4 Configurations of ethmoid roof. A) Type 1, B) Type 2 and C)

Type 3. (Stammberger & Kennedy, 1995).

Frontal sinus

The frontal sinus is related inferiorly to the orbit, ethmoid labyrinths and nasal cavity, superiorly to anterior cranial fossa, olfactory niche, bulbs and tracts and medially to cribriform plate and olfactory niche. It drains into the frontal recess, usually by an hourglass narrowing rather than by a definite duct.

09 Maxillary Sinus

The maxi liar}' sinus is bounded by the orbital roof superiorly, the hard palate, alveolus and dental portion of the maxilla inferiorly, the zygomatic process laterally, a thin plate of bone separating the cavity from the inffatemporal and pterygopalatine fossa posteriorly, and the uncinate process, fontanelles, and inferior turbinate medially. The maxillary sinus ostium is mostly located between the middle and posterior thirds of the infundibulum. The most common anatomic variation in the maxillary sinus region is the infraorbital ethmoidal cells or Haller's cells (Figure 1.5). The cell is an ethmoid cell that pneumatizes into the floor of the orbit, inferolateral to the ethmoidal bulla.

Figure 1.5 Infraorbital ethmoid cell. (Stammberger & Kennedy, 1995)

Sphenoid Sinus

The sphenoid sinus is related laterally to the carotid artery, the optic nerve, the cavernous sinus, and the third, fourth, fifth, and sixth cranial nerves. If the

23 sphenoid siniis is well pneumatized, the optic nerve and carotid artery can indent the sinus or the overlying bone may even become dehiscent. The left and right sphenoid sinuses are separated by an intersinus septum. The inter- and intrasinus septations have been noted to attach near or on the carotid canal. The ostium of the sphenoid sinus is located in the sphenoethmoidal recess.

1.2.1b Pathophysiology Although the exact pathophysiology of chronic rhinosinusitis is still unknown, three factors appear to be vital for the normal physiology of the sinuses: patency of the ostiomeatal complex, normal mucociliary transport and normal sinonasal secretions. Disruption of these factors can predispose to sinus disease. A general hypothesis for the development of chronic rhinosinusitis is that aetiological factors trigger a vicious circle of sinus ostial obstruction, local metabolic and gas disturbances, retention of secretions, proliferation of bacteria, accentuation of inflammation and ciliary dysfunction (Stiema, 2001). The ostiomeatal complex is a functional rather than an anatomical designation representing the final common pathway for drainage and ventilation of the frontal, maxillary and anterior ethmoid cells (Stammberger & Kennedy, 1995). Maintaining a functional ostial diameter is important for sinus aeration and thus a normal local metabolism. A reduction of ostial patency will lead to local gas disturbances, inflammation, mucosal pathology and retention of secretions. Bacterial infection can occur if inflammation is strong enough to impair local host defence and pathogenic bacteria are present. Pyogenic reactions will considerably reduce oxygen pressure, increase carbon dioxide pressure and enhance lactate accumulation, thus amplifying the inflammatory response (Aust & Drettner, 1974;Carenfelt & Lundberg, 1977;Stiema, 2001). Elevated levels of pro inflammatory cytokines including IL-1 beta (Tokushige et al, 1994), lL-3 (Bachert & Van Cauwenberge, 1997), IL-8 (Takeuchi et al, 1995) have been reported in chronic rhinosinusitis. Interleukin-5 (Bachert et al, 1997), lL-6 (Denburg, 1997), GM-CSF (Hamilos et al, 1998) and

24 transforming growth factors (Elovic et al, 1994) appear to play an additional important role in chronic rhinosinusitis with polyposis. This ongoing inflammation/infection has a negative influence on rhéologie mucous characteristics as well as mucociliary transport. Mucociliary transport function may be affected by inflammatory mediators, bacterial toxins, proteolytic enzymes, low pH, anaerobic mucosal metabolism and epithelial impairment (Waguespack, 1995;A1 Rawi et al, 1998;Hamilos, 2000;Stiema, 2001). The low levels of nitric oxide in chronic rhinosinusitis (Lindberg et al, 1997b) have also been incriminated in the pathophysiology of the disease. Nitric oxide has been reported to be a vasorelaxant (Martinez et al, 1995), a neurotransmitter (Kanazawa et al, 1997), and a regulator for ciliary motility (Jain et al, 1993;Runer et al, 1998;Runer & Lindberg, 1998) and local immune system (Wei et al, 1995). However its exact role is still unknown since nitric oxide has pro inflammatory actions as well (Beckman et al, 1990). Various local and systemic factors may be associated with development of chronic rhinosinusitis (Weir & Golding-Wood, 1997;Drake-Lee, 1997;Hamilos, 2000;Naclerio & Gunger, 2001). These include: 1. Local factors: a. Infection b. Trauma: accidental, surgical and barotrauma. c. Rhinitis: allergic and non-allergic. d. Anatomical variations: septal deviation, concha bullosa, Haller’s cells ... etc. e. Craniofacial anomalies: cleft palate, velopharyngeal insufficiency and choanal atresia. f. Nasal irritants: cigarette smoke, exhaust fumes ... etc. G. Miscellaneous: foreign bodies, tumours.

2, Systemic factors: a. Ciliary dyskinesias b. Cystic fibrosis

25 c. Young’s syndrome d. Asthma e. Aspirin sensitivity. f. Immune deficiencies.

1.2.1c Microbiology Microbiology of chronic rhinosinusitis and the actual role of the organisms in the disease process are very controversial. In many studies, coagulase- negative staphylococcus (CNS) represented the most common isolate, followed by staphylococcus aureus (SA). Biel et al. (1998) isolated CNS (36% of isolates) and SA (25% of isolates) with maxillary sinus swabs, under endoscopic visualisation. Ramadan et al. (1995) demonstrated growth of CNS (79.9% of cultures) and SA (20.7% of cultures) after endoscopic culturing of the surgical sinus cavity. Liu et al. (2000) using a similar technique recovered CNS (68.9% of cultures) and SA (26.7% of cultures). Doyle et al. (1991) reported CNS (71% of isolates) and SA (32% of isolates) in specimens of ethmoid sinus mucosa. However, these organisms may represent nasal contaminants from the skin or nasal vestibule or even an actual commensal flora within the middle meatus. CNS and SA have been retrieved infrequently (0-8%) in cultures obtained with Caldwell-Luc or antral punctures (Sparrevohn & Buch, 1946;Urdal & Berdal, 1949;Palva et al, 1962;Brook, 1989). Rontal et al. (1999) cultured the ethmoid sinus as well as the nasal vestibule in patients undergoing endoscopic sinus surgery and demonstrated a correlation between the organisms of both sites. Nadel et al. (1998) retrieved CNS from 35% of cultures in CRS patients versus 36% in the control group. They also reported 23% SA in patients versus 20% in healthy controls. Klossek et al. (1996) sampled the middle meatus of normal asymptomatic adults under endoscopic guidance. Cultures were positive in 81.3% of the cases with CNS accounting for 46.2% and SA for 12.6% of isolates. Similarly,

26 Chow et al. (1993) cultured the OMC in normal asymptomatic adults and found CNS in 60% of the cultures.

Anaerobes have also been implicated as pathogens in CRS. Decreased oxygen tension that occurs due to reduced blood flow within the sinuses, may provide favourable environmental factors for anaerobic growth. As with CNS and SA, the frequencies of anaerobes have varied widely amongst the studies. Brook (1989) sampled maxillary sinuses via a Caldwell-Luc approach and found anaerobes in 71% of the isolates. The predominant anaerobes were anaerobic cocci (30% of the anaerobic isolates). Nadel et al. (1998) reported 35% positive anaerobic results in 102 endoscopically guided cultures. Propionibacterium acnes was the predominant anaerobe, accounting for 57% of the isolates. Klossek et al. (1998) isolated anaerobes in 25% of cultures. In contrast, other studies have demonstrated a low yield of anaerobes ranging from 0 % of the cultures (Liu et al, 2000;Doyle & Woodham, 1991) to 6.4 % of the isolates (Biel et al, 1998) to 7.6 % of the cultures (Ramadan, 1995). On the other hand, endoscopically guided cultures from the middle meatus of normal asymptomatic adults have shown anaerobes in 15.8% (Klossek et al, 1996) and 20% (Nadel et al, 1999) of the cultures. The most common anaerobe was Propionibacterium acnes accounting for 62% (Klossek et al, 1996) and 70% (Nadel etal, 1999) of the anaerobic isolates.

The role of gram-negative rods (GNRs) including Pseudomonas aeruginosa is another area of dispute. The prevalence of GNRs has ranged from 0-15% of cultures during Caldwell-Luc or antral puncture (Sparrevohn & Buch, 1946;Urdal & Berdal, 1949f alva et al, 1962;Karma et al, 1979;Su et al, 1983;Brook, 1989)with the exception of one study showing Pseudomonas aeruginosa in 36.5% of all isolates (Umenai et al, 1980). Using endoscopic techniques, authors have reported GNRs in 22.2-32% of isolates (Bogler, 1994;Hsu et al, 1998;Liu et al, 2000). Nadel et al. (1998) demonstrated GNRS in 27% of cultures, with 59% of these being Pseudomonas aeruginosa. They

27 also reported a significantly higher prevalence of GNRs and Pseudomonas aeruginosa in patients treated with systemic steroids, nasal imgation and/or previous sinus surgery. Brook et al. (2001) confirmed that Pseudomonas aeruginosa were significantly isolated more often in patients who had previous surgery.

A few studies have described a different profile for the most common organisms. Jiang et al. (1997) sampled the ethmoid cavity and maxillary sinus after disinfecting the anterior nose and oral mucosa with Povidone-Iodine solution. They reported the first and second commonest bacteria to be Streptococcus viridans (21% of the isolates) and Streptococcus pneumoniae (17.5% the isolates) in the maxillary sinus and Streptococcus viridans (15.5% the isolates) and Haemophilus parainfluenzae, Klebsiella pneumoniae and Proteus mirabilis (10% of the isolates, each) in the ethmoid sinus. Interestingly, 72.5% of the specimens showed different isolates in the ipsilateral ethmoid and maxillary sinuses. Su et al. (1983) investigated nasal swabs, sinus secretions and sinus mucosa in patients with chronic maxillary sinusitis. The most common organism in nasal swabs was CNS (28% of the cultures), whereas it was Streptococcus alph-haemolyticus in sinus secretions (40% the cultures) and sinus mucosa (57% the cultures). Dunnette et al. (1986) cultured 20 nasal polyps for aerobic and anaerobic bacteria, viruses, fungi, mycoplasmas and mycobacteria. Eight were sterile, 9 grew aerobic bacteria, two grew fungi and one had anaerobic bacteria.

Other organisms have been inconsistently reported in studies of adult chronic rhinosinusitis, including Haemophilus influenzae, Corynbacterium diphtheriae, Streptococcus beta-haemolyticus, Moraxilla catarrhal is and Neisseria.

Finally, fungi have not generally been considered to play a major role in chronic rhinosinusitis. However, a study fi-om Mayo clinic reported that

28 fungal cultures were positive in 202 (96%) of 210 consecutive CRS patients. It claimed that this alarming figure was due to better collection and culturing methods (Ponikau et al, 1999). Should this finding be confirmed by other studies, it would change the whole concept of management of chronic rhinosinusitis.

1..2.1d Medical treatment of chronic rhinosinusitis The main goals of the medical therapy of chronic rhinosinusitis are to control the microbiological load in the involved tissues, reduce tissue inflammation, facilitate drainage, maintain patency of sinus ostia, restore mucociliary clearance and break the vicious cycle of chronic rhinosinusitis. Generally speaking, this can be attained mainly with a combination of antimicrobial therapy and/or corticosteroids. Adjuvant therapy includes decongestants, antihistamines, mast cell stabilizers, antileukotrienes, nasal douching and occasionally immunotherapy. Reduction or elimination of irritant environmental factors should also be targeted whenever possible.

Antimicrobial therapy Despite the prevalence and morbidity of chronic rhinosinusitis, very few trials of antimicrobial treatment in chronic rhinosinusitis have been performed. As discussed above, the microbiology of CRS and the role of the organisms in the disease process are not universally accepted. Consequently, the role of antimicrobial therapy in control of CRS, although supported by many clinicians, is not generally accepted. Huck et al. (1993) performed a double blind randomised trial comparing 10-day courses of cefaclor, 500 mg twice daily, and amoxicillin, 500 mg three times daily, in the treatment of acute, recurrent, and chronic maxillary rhinosinusitis. They reported that patients with chronic rhinosinusitis were too few (15 patients) to allow statistical analysis of the differences in outcome between them and patients with recurrent or acute rhinosinusitis. They also demonstrated that the rate of clinical improvement was poor in chronic maxillary rhinosinusitis regardless

29 of the study drug used, with the outcome being unrelated to the susceptibility of organisms to the study drugs. McNally et al. (1997) conducted a study on medical treatment of chronic rhinosinusitis. The medical treatment consisted of 4 weeks of oral antibiotics, nasal corticosteroids, nasal lavage and topical decongestants. Using no quantitative scores, the symptoms and signs were graded as improved or worse. The medical treatment improved all symptoms in 23-75% and signs in 50-84% of the patients. During follow up of the patients for 1-27 months, 6% required surgery. Scadding et al. (1995b) demonstrated that 12 weeks of continuous antibiotics improved ciliary beat frequency in 10 patients with chronic purulent or mucopurulent nasal discharge. Some authors have investigated the effect of long-term low-dose macrolide antibiotics after the notable observation of Kudoh in 1984 that symptoms of chronic rhinosinusitis in patients with diffuse panbronchiolitis have been relieved during long-term, low-dose erythromycin (Kudoh, 1998). They reported that 8-12 weeks of macrolides alleviated patients’ symptoms, improved rhinoscopic findings and decreased the size of nasal polyps (Hashiba & Baba, 1996;Ichimura et al, 1996;Kimura et al, 1997;Yamada et al, 2000). The first macrolide, erythromycin, was discovered in 1952 as a metabolite of Streptomyces erythreus. It consists of a 14-membered macrocyclic lactone ring with 2 appended sugar moieties. Clarithromycin, roxithromycin, flurithromycin and azithromycin are semi-synthetic derivatives of erythromycin. Erythromycin exhibits good activity against Gram-positive aerobes, some Gram-negative aerobes, some anerobes and atypical pathogens (Mycoplasma pneumoniae, Legionella pneumoniae and chlamydia pneumoniae), whereas it is poorly active against Haemophilus influenzae. It is mainly a bacteriostatic agent that exerts its action through binding to ribosomal RNA and blocking protein synthesis. However, the precise mechanism of action has not yet been elucidated, since bactericidal activity has also been achieved. Erythromycin generally has a low adverse effect profile and is considered to be one of the safest antibacterials. The main adverse effects are abdominal discomfort, nausea, vomiting and diarrhoea.

30 These gastrointestinal disorders are known to be dose-related. Other adverse effects including allergic reactions, cardiotoxicity, hepatotoxicity, ototoxicity, psychiatric complications, haemolytic anaemia, asthma, pancreatitis and pseudomembranous colitis have been reported. Risk factors include hepatic impairment, renal dysfunction, prolonged Q-T interval on electrocardiograph and dosages of 4 gram/day or greater. Clinically significant drug interactions include warfarin, carbamazebine, cisapride, cyclosporin, digoxin, ergot alkaloids, theophylline, methylprednisone, astemizole, loratadine and terfinadine (Nilsen, 1987;Bahal & Nahata, 1992;Williams & Seflon, 1993;Periti et al, 1993;Shah, 1998;Zhanel et al, 2001).

The use of topical antibacterial preparations has also been described in the literature with conflicting results. Rebhun (1993) and Kamijyo et al. (2001) reported that the use of topical antibacterial preparations were highly effective in chronic rhinosinusitis, whereas Sykes et al. (1986) described topical antibiotics as unnecessary. Recently, Gosepath et al. (2002) reported that topical antibiotic solutions decreased nasal ciliary activity.

Corticosteroids The mechanism of action of corticosteroids in chronic rhinosinusitis includes downregulation of proinflammatory cytokines and mediators (Kamada & Szefler, 1995), reduction of leucocytes and mast cells in the affected tissues (Barnes et al, 1998), decreased vascular permeability (Boschetto et al, 1991) and reduction of mucous secretions (Shimura et al, 1990). Downregulation of proinflammatory mediators is mediated through decreased gene transcription of several cytokines, iNOS, inducible cyclo-oxygenase, inducible phospholipase M, endothelin-1 and intercellular adhesion molecules. Reduction of leucocytes mainly affects eosinophils, basophils and monocytes. T-Lymphocytes are affected more than B-lymphocytes (Kamada & Szefler, 1995;Bames et al, 1998).

31 Few clinical trials have specifically considered the use of topical corticosteroid sprays in chronic rhinosinusitis. Sykes et al. (1986) randomly allocated 50 patients with chronic mucopurulent rhinosinusitis to three types of nasal sprays; an antibiotic-corticosteroid-decongestant, a corticosteroid- decongestant and a placebo nasal spray. Both active preparations were more effective (14 of 20 patients in antibiotic spray, 12 of 20 patients in non­ antibiotic spray) than the placebo (2 of 10 patients), whereas no difference was found between the active preparations. Cuenant et al. (1986) randomised 60 patients with chronic maxillary rhinosinusitis to an 11-day course of once daily antibiotic-corticosteroid or antibiotic intrasinus irrigation. The antibiotic- corticosteroid preparation showed significantly better subjective results than the antibiotic preparations. Qvamberg et al. (1992) investigated the effect of the addition of budesonide aerosol, 400 micro grams daily for 3 months, to sinus washout and 7 days of erythromycin in 40 patients with chronic or recurrent maxillary sinusitis. No significant difference in clinical outcome was found between budesonide and placebo, whereas there was a trend for significant improvement in radiology of the sinuses. Recently, Parikh et al. (2001) were also unable to show a significant difference between fluticasone propionate aqueous nasal spray, 200 micro grams twice daily, and placebo groups in VAS, endoscopic score, acoustic rhino me try measurements or haematological parameters, but there was a trend for significant improvement in diary card score.

On the contrary, several double-blind, placebo-controlled, randomised trials have investigated the role of intranasal corticosteroids in nasal polyposis. Vendelo et al. (1993) showed that budesonide, 200 microgram twice daily, was effective in treatment of small and medium size polyps. Lildholdt et al. (1997) reported that about 85% of the patients experienced total or substantial control over the symptoms and signs, with equal results being obtained with budesonide powder 400 or 800 micrograms per day. Lund et al. (1998) demonstrated that 200 micrograms twice daily of fluticasone propionate or

32 beclomethasone dipropionate aqueous nasal spray significantly decreased polyp score, increased nasal cavity volume and reduced nasal blockage, with no significant difference between the two medications. Tos et al. (1998) found that both an aqueous and a powder formulation of budesonide were effective in reducing polyp size and patient symptoms including sense of smell. The proportion of patients rating substantial or total control over symptoms after 6 weeks was 60.9% in the aqueous and 48.2% in the powder preparations. Using corticosteroid nasal drops in the head down and forwards position has been claimed to be more effective method of nasal corticosteroid application. Chalton et al. (1985) reported that nine of 15 patients taking betamethasone nasal drops showed disappearance of visible nasal polyps compared with 2 of 15 in the placebo group. Fluticasone propionate nasal drops have been demonstrated recently to be effective in controlling mild and moderate nasal polyposis with the advantage of overcoming the potential systemic side effects as well as the lack of metered doses of the betamethasone drops (Keith et al, 2000;Penttila et al, 2000). Other studies have confirmed the efficacy of topical corticosteroid preparations in reducing polyp size, improving nasal airway, and control of symptoms (Mygind et al, 1975;Holopainen et al, 1982;Ruhno et al, 1990;Holmberg et al, 1997). Recurrence of nasal polyps after surgical removal has also been diminished with use of topical corticosteroids. Virolainen and Puhakka (1980) reported that in 12-month follow-up period, beclomethasone dipropionate markedly reduced subjective nasal symptoms in 86% of the patients versus 60% in the placebo group. In clinical examination polyps were absent in 54% in the beclomethasone group and in 13% in the placebo group. Rhinomanometrically, there was normal nasal patency in 68% in the beclomethasone and in 33% in the placebo group. Similar results have been shown by other authors (Drettner et al, 1982 ;Dingsor et al, 1985;Hartwig et al, 1988).

To study the effect of surgery over topical corticosteroids, Blomqvist et al. (2001) conducted a randomised controlled study evaluating the additive effect

33 of endoscopic sinus surgery over topical budesonide therapy in 32 patients with nasal polyposis after p re-treatment with oral prednisolone for 10 days and local budesonide for 1 month. The surgery was done unilaterally and postoperatively patients received local budesonide in both sides. Surgery had an additional effect on nasal obstmction but not on sense of smell. Twenty five percent of the patients were willing to undergo an operation on the unoperated side at the end of the study.

The effect of systemic corticosteroids on nasal polyposis has been discussed in three studies. Lildholdt et al. (1988) performed a randomised study comparing the effect of snare polypectomy versus a depot-injection of 14 mg of betamethasone. All patients continued with 400 micro gram per day of beclomethasone nasal spray. Both regimens were alike with a temporary statistically significant difference in sense of smell in favour of the systemic corticosteroids. Nine years later, the same author (1997) randomised 33 patients, who failed to respond to 400 or 800 micro grams per day of budesonide powder, to either snare polypectomy or a depot-injection of 14 mg of betamethasone and reported no difference between the treatment groups. Van Camp and Clement (1994), in non-randomised, uncontrolled study, found that oral prednisolone, 60 mg per day for 4 days then progressive reduction of the dose by 5 mg per day, induced subjective improvement in 72% and clear improvement in CT scans in 52% of the cases. However, nasal polyps recurred within 5 months after the successful oral corticosteroid therapy.

Short-term courses of corticosteroids appear to be safe in comparison to the well-known side effects of long-term courses. However, not enough information is available on the efficacy and safety of repeated administration of short courses. The adverse effects of long-term use of systemic corticosteroids include: endocrine and metabolic (suppression of the hypophyseal pituitary adrenal axis, reduction of sex hormones, growth suppression, cushinoid habitus, weight gain, reduced carbohydrate tolerance

34 and increased blood glucose, elevated serum lipids, negative nitrogen and calcium balance, sodium and water retention, potassium loss and alkalosis); haemato logical (decreased lymphocytes, monocytes, basophils and eosinophils and promotion of blood coagulation); musculoskeletal (osteoporosis, myopathy and osteonecrosis, previously called avascular necrosis); dermatological (thin fragile skin, hirsutism, impaired wound healing and acne); behavioural changes (psychosis and sleep disturbances); altered immune response (inhibition of immune response and increased susceptibility to infection); ophthalmological (cataract and glaucoma); gatroentestinal (peptic ulcer and pancreatitis) and if taken during pregnancy and lactation they may cause intrauterine growth retardation and adrenal suppression (Stanbury & Graham, 1998;Bialas & Routledge, 1998). On the other hand, nasal corticosteroids appear to have very low risk of systemic side effects (Cave et al, 1999). The systemic availability o f the new intranasal corticosteroids is low especially fluticasone propionate and mometasone flu orate (Szefler, 2001). The mean absolute bioavailabilities for doses of 800 microgram per day of fluticasone drops and spray were estimated to be 0.06% (drops) and 0.51% (spray) (Daley-Yates & Baker, 2001). However, care has to be taken in children especially when long-term treatment is considered since an effect on the growth of children has been reported in few trials (Wolthers & Pedersen, 1993;Skoner et al, 2000). It has also been described that nasal corticosteroids occasionally cause local side effects. Crusting, itching, irritation, dryness and minor epistaxis have been reported (Andersson et al, 1995;Graft et al, 1996;Passalacqua et al, 2000). Septal perforation, due to prolonged use, has also been mentioned(Soderberg-Wamer, 1984). There is also one report in the literature indicating that the use of fluticasone propionate nasal spray following endoscopic sinus surgery increased the incidence of acute pansinusitis whilst beclomethasone dipropionate did not (Mostafa, 1996).

35 Adjuvant therapy Adjuvant therapy in chronic rhinosinusitis includes decongestants, antihistamines, mast cell stabilizers, antileukotrienes, nasal douching, immunotherapy and reduction or elimination of irritant environmental factors.

Decongestants are alpha-adrenergic agonists that restrict blood supply, decrease mucosal oedema and reduce resistance to nasal airflow. They have been reported to increase sinus ostial patency and to have a ciliostimulatory effect when used at low concentrations and for short periods of time. However, caution must be exercised because of side effects, including rhinitis medicamentosa associated with long-term use of topical decongestants (Melen etal, 1986;Phillips etal, 1990).

Antihistamines play an important role in the management of allergic rhinitis. However, their importance in the treatment of chronic rhinosinusitis appears to be limited to those patients with allergic manifestations. Later-generation antihistamines have fewer side effects than first generation (Simons & Simons, 1991 ).

Mast cell stabilizers prevent the release of inflammatory mediators, thereby reducing nasal manifestations of allergy. They are virtually lacking significant side effects, but must be used frequently and with limited effectiveness (Bruijnzeel et al, 1990;Kaulbach et al, 1992).

Antileukotrienes inhibit the formation and action of leukotrienes, which are inflammatory mediators generated from arachidonic acid. Antileukotrienes have been found to be helpful in treatment of nasal polyposis and asthma (Ragab et al, 2001).

Nasal douching has always been perceived as a valuable adjunct in the management of chronic rhinosinusitis. It has been suggested that it exerts its

36 action through removing excess nasal discharge, providing an optimal environment for mucociliary function and changing the mucus rheology (Homer et al, 1999;Taccariello et al, 1999;Homer et al, 2000;Bachmann et al,

2000).

Finally, immunotherapy is sometimes needed in patients with refractory sinusitis who do not respond to conventional therapies. Patients with low serum IgG and hyperimmunoglobulinemia E were found to be more prone to recurrent infections (Shapiro et al, 1991;Lund & Scadding, 1991 ;al Mohanna et al, 1993;Nishioka et al, 1994b;Scadding et al, 1994). Similarly, desensitisation therapy has proven he Ip hi 1 in some allergic cases e.g. aspirin desensitisation in aspirin intolerant nasal polyposis (Sweet et al,

1990;Scadding e /<7 /, 1995a).

1.2.le Surgical treatment of chronic rhinosinusitis

Surgical treatment of chronic rhinosinusitis was a subject of significant controversy in the last century. However, based on continued improvement of the understanding of the pathogenesis of chronic rhinosinusitis, the more conservative endoscopic sinus surgery has now largely replaced the more radical conventional sinus procedures which were based on the concept that irreversibly diseased mucosa had to be surgically removed. The concept of functional endoscopic sinus surgery is to restore ventilation and mucociliary clearance through the natural sinus ostia.

Messerklinger is considered the first to have developed a systematic endoscopic diagnostic approach to the lateral nasal wall. His studies beginning in the 1950s demonstrated that in most cases, the frontal and maxillary sinuses were indirectly involved by a primary disease in the narrow spaces of the

37 lateral nasal wall and the anterior ethmoid. This in turn resulted in an endoscopic surgical technique that was directed specifically at the primary disease in the ethmoid region. Messerklinger observed that limited endoscopic sinus surgery at the anterior ethmoidal area resulted in the recovery of even massive mucosal pathology in the adjacent paranasal sinuses(Stammberger, 1991b). The improved ability to visualize the anatomy and extent of the disease using rigid endoscopes and CT scanning has made a significant contribution to the further development and popularisation of the technique(Kennedy et al, 1985).

Initially, endoscopic sinus surgery was divided into two schools. The first school, usually following the Messerklinger technique, was theoretically more conservative. It followed an anterior to posterior approach, aiming at removal of pathology in the ostiomeatal complex, sufficient to achieve ventilation and drainage of the sinuses (Kennedy, 1985;Stammberger, 199le). The second school, usually referred to as the Wigand technique, was potentially more radical. It followed a posterior to anterior approach, benefiting from the anatomic fact that the floor of the anterior cranial fossa slopes downwards from anterior to posterior, thus minimising complications of surgery in cases of profuse pathology with loss of surgical landmarks e.g. extensive polyposis (Wigand, 1981). The distinction between the two schools, however, is considerably less than might be inferred from the literature witli an overlap of techniques dependent on the individual pathology.

Nowadays, endoscopic sinus surgery is a well-established surgical procedure, which has yielded excellent outcomes at least in the hands of well-trained surgeons. Kennedy et al. (1987) reported that 69 patients (92%) were either asymptomatic (25 patients) or had a significant symptomatic improvement (44 patients) during a follow-up period of 4-32 months after endoscopic sinus surgery. Schaefer (1989) performed endoscopic total sphenoethmoidectomy on 60 patients and showed 85% significant improvement in their symptoms

38 within a 3 to 36-month follow-up period. Levine (1990) demonstrated an overall symptomatic success rate of 84.1% (80.1% chronic rhinosinusitis and 88.3% nasal polyps) in 250 patients during a follow-up period of 12-42 months. Stammberger (1991c) examined 500 postoperative patients with a follow-up time of 8 months to 10 years and showed a satisfactory improvement of symptoms in 91% (85% very good/good and 6% fair) of patients. Schaitkin (1993) described that the overall success rate in relieving sinus symptoms in 100 patients dropped from 98% at 9-month follow-up to 91% at 4-year follow-up. Lund and Mackay (1994), in a 6-month follow-up period, demonstrated a subjective improvement in 87% (78% improved and 9% cured) of 650 patients. Others have reported similar successful results (Kamel, 1989;Toffel et al, 1989d^ice, 1989;Marks & Shamsa, 1997;Senior et al, 1998;Jiang & Hsu, 2000;Kennedy et al, 2000).

The physiological basis of this symptomatic relief has attracted a number of investigators. Endoscopic sinus surgery has been shown to have a positive impact on the mucociliary function. Nasal mucociliary transport (Waguespack, 1995;Elwany et al, 1998;Asai et al, 2000) and ciliary beat frequency (Lund et al, 1991 ;Lund & Scadding, 1994;Abdel-Hak et al, 1998) have been reported to improve in chronic rhinosinusitis patients following endoscopic sinus surgery. Other studies have suggested that nitric oxide is mainly secreted in the paranasal sinuses (Lundberg et al, 1994b;Lundberg et al, 1995a) and plays a role in mucociliary regulation (Jain et al, 1993;Runer et al, 1998;Runer & Lindberg, 1998;Lindberg et al, 1997a). However, the use of nitric oxide as an indirect marker of improvement in chronic rhinosinusitis is still to be confirmed. The objective olfactory tests in chronic rhinosinusitis patients have also improved after endoscopic sinus surgery (Lund & Scadding, 1994;Delank & Stoll, 1998;Abdel-Hak et al, 1998;Rowe-Jones & Mackay, 1997). However, the long-term validity of the olfactory results is still questionable. Conversely, the objective assessment of the nasal airway, e.g. by nasal inspiratory peak flow, anterior rhinomanometry and acoustic

39 rhinometry, failed to show any significant improvement, although the sensation of nasal obstruction/congestion significantly improved following endoscopic sinus surgery (Lund et al, 1991;Lund & Scadding, 1994).

Endoscopic sinus surgery has also been shown to significantly improve quality of life of chronic rhinosinusitis patients. Quality of life instruments include general health status questionnaires as the short form 36-item health status survey (SF-36) (Ware, Jr. & Sherboume, 1992)and disease specific ones such as the RJiinoconjunctivitis quality-of-life Questionnaire (RQLQ) (Juniper & Guyatt, 1991), RJiinosinusitis Outcome Measurement 31 (RSOM- 31) (Piccirillo et al, 1995), Sinonasal Outcome Test 20 (SNOT-20) (Leopold et al, 1997), Chronic Sinusitis Survey (CSS) (Gliklich & Metson, 1995) and Rhinosinusitis Disability Index (RSDI) (Benninger & Senior, 1997). Gliklich‘s team reported a significant improvement in several SF-36 subscales and all CSS subscales after endoscopic sinus surgery, with the disease specific CSS being more sensitive to change than SF-36 (Gliklich & Hilinski, 1995;Gliklich & Metson, 1997;Metson & Gliklich, 1998). Winstead and Barnett (1998) confirmed the significant improvement in all SF-36 scores except physical functioning. SNOT-20 scores were significantly improved after endoscopic sinus surgery as well (Jones et al, 1998;Gosepath et al,

2000).

With the increasing popularity of endoscopic sinus surgery, attention has been paid to its possible serious complications. Fortunately the reported complications, though sometimes catastrophic, are few at least in the hands of the experienced. Major complications includes cerebrospinal fluid leak, intracranial infection, orbital complications (visual loss, haemato ma and diplopia), haemorrhage requiring transfusion or surgical control and even death. Minor complications include synechiae, nasolacrimal duct injury, subcutaneous emphysema, ostial stenosis or closure and minor bleeding. Stankiewicz (1989) suggested that the complication rate decreased with

40 increasing experience reporting a drop from 29% in the first 90 cases (Stankiewicz, 1987)to 2.2% (Stankiewicz, 1989) in the subsequent 90, with incidence of major complications decreasing from 7.7% (Stankiewicz, 1987) to 1.1% (Stankiewicz, 1989). Stammberger and Wolf (1988) reported two cases of CSF leak with no other major complications in a series of over 4000cases. Levine (1990) showed a complication rate of 8.3% minor and 0.7% major in 250 cases. Schaefer et al. (1989) described an incidence of 14% minor and 0% major complications in 60 patients. Other reports have confirmed such a low incidence of complications with CSF leak being the commonest major and synechiae and minor bleeding the most frequent minor complications (Vleming et al, 1992;May et al, 1994;Danielsen & Olofsson, 1996;Jakobsen & Svendstrup, 2000). Table la shows incidence of major complications of endoscopic sinus surgery in the literature.

41 Table la : Incidence of major complications of endoscopic sinus surgery

Authors No of M ajor CSF O rbital Intracranial Haemorrhage death patients complications leak complications infection

7.7% 1 1 5 Stankiewicz 90 - - (1987) 4000 0.05 % 2 Stammberger - -- - and W olf (1988) 90 1.1 % 1 Stankiewicz -- -- (1989) 60 0 % Schaefer et - -- - - al. (1989) 170 0 .6% 1 Toffel et ai. --- - (1989) 100 0 % Rice - - - - (1989)

250 1.2 % 3 Levine -- (1990) 1000 1.4 % 10 2 1 1 W igand and - Hosem an (1991) Kennedy 125 0 % - --- - (1992) 0.67 % 2 2 V elm ing et 593 -- - al. (1992) M ay et al. 2108 0.71 % 10 1 4 . - - (1994) 1 1 Lund and 650 0.3 % -- - M ackay (1994) 230 0 % Danielsen - --- - and Olofsson (1996) 1 % 1 2 1 Sobol et al. 393 - - (1998) Jakobsen and 237 0 % - - - Svendstrup (2000)

42 1.2.2 Rhinosinusitis and asthma

In the second century, Galen (130 - 200 AD) was the first to note the association between nasal symptoms and asthma, believing that secretions dripped into the airways producing disease (McFadden, 1986). Thus, he advocated purging the nostrils to relieve the breathing passages. After this historical observation, the interest in the relationship between nasal disease and asthma remained dormant for several hundred years, till it re-emerged again in the late 19th and early 20th. In 1870, Kratchmer reported that irritants such as cigarette smoke and sulphur dioxide, when applied to nasal mucosa of cats and rabbits, produce bronchoconstriction (Kiyoshi & Ogura, 1966). In 1903, Dixon and Brodie showed that electrical stimulation of the nose can also result in increased lower airway responsiveness in cats. Later on, Sluder (1919) first hypothesized a rhinosinobronchial reflex, ie, a reflex bronchoconstriction by activation of a trigeminal afferent - vagal efferent neural arc. His statement, indeed, was a milestone that excited many researchers to investigate the relationship between the upper and lower airways, including rhinosinusitis and asthma. In this chapter, the literature will be reviewed in an attempt to evaluate the nature of the relationship between rhinosinusitis and asthma, discuss the evidence for this and explore the possible mechanisms of interactions.

1.2.2a Epidemiological evidence The frequent association of rhinosinusitis and bronchial asthma has been noted for a great many years. At the beginning of the previous century, a number of clinical studies reported a prevalence of rhinosinusitis in asthmatics that varied from 12 % (Bullen, 1932)to 43 % (Chobot, 1930) to 72 % (Weille, 1936) to 90 % (Gottlieb, 1925). Conversely, 34 % of sinusitis patients have been shown to have asthma (Annesi-Maesano, 1999). The prevalence of nasal polyps in adult asthma has been found to be about 7 %, with a greater percentage in non-lgE-mediated asthma (13%) than in IgE-mediated (5%) and

43 in asthmatics over 40 years of age (12.4 %) than under 40 years (3.1 %) (Chobot, 1930). The frequency of nasal polyps in aspirin sensitive asthmatics ranged from 11.4 % to 30 % (Settipane & Chafee, 1977;Schiavino et al, 2000). Conversely, the frequency of asthma in nasal polyposis ranged from 46.3 % to 72 %(Annesi-Maesano, 1999).

On the other hand, Lombardi et al. (1996) reported that physician-diagnosed rhinosinusitis was not significantly associated with physician-diagnosed asthma. The authors acknowledged that parental reporting of physician- diagnosed rhinosinusitis might be imprecise. Their results matched another study by Sherman et al. (1990), who reported that physician-diagnosed rhinosinusitis was not a significant predictor for having physician-diagnosed asthma.

Indeed, the interpretation of all the above observations is dependent on the definitions of rhinosinusitis, asthma and aspirin intolerance and since there is no epidemiological gold standard to make such definitions, the credibility of the results must be viewed with some circumspection.

1.2.2b Radiological evidence Abnormal sinus X-rays in asthmatics have been reported by a number of authors over the years. Berman et al. (1974) described 40 % abnormal sinus radiographs in cases of bronchial asthma. Rachelefsky et al. (1978) studied the prevalence of sinus disease in children with respiratory allergy and reported 53 % abnormal sinus radiographs. Fuller et al. (1994) showed abnormal plain sinus radiographs in 75 % of status asthmaticus cases. Rossi et al. (1994) found that 87% of patients with acute asthma had abnormal sinus X-rays. However, one can easily argue that sinus X-rays lack the sensitivity in diagnosing rhinosinusitis with false positive and negative radiographs. Normal sinus radiographs have been shown in 45 % of 70 children who had both

44 clinical evidence of recurrent rhinosinusitis and mucosal disease on computerized tomography (CT) scans (McAlister et al, 1989). Moreover, it is also well known that developmentally poorly aerated sinuses appear opaque in X-rays and different percentages of opaque sinus radiographs, ranging from 7% to 57 %, have been reported in asymptomatic children and adults as well (Shopfrier & Rossi, 1973;Kovatch et al, 1984;Odita et al, 1986;Wilson & Grocutt, 1990).

Despite the fact that sinus CT scans are far better than sinus plain radiographs, few authors have shown interest in studying sinus CT scan abnormalities in asthmatic patients from the epidemiological point of view. Pfister et al. (1994) screened 19 asthmatic adults and although, only 16 % had symptoms of sinus disease, 74 % of them showed mucosal thickening on the sinus CT scans. Newman et al. (1994) reported that the association between chronic sinusitis with asthma and allergy appeared to be restricted to the group of extensive sinus disease as documented by CT scans. On the other hand, sinus CT scans have also been reported to be abnormal in about 18 % of asymptomatic children, and this percentage increased to 31 % in children with a recent history of upper respiratory tract infection (Glasier et al, 1986;Diament et al, 1987).

1.2.2c Possible mechanisms for interactions between rhinosinusitis and asthma

It is not clear whether the association between rhinosinusitis and asthma represents a mere co-existence of two common disorders, or that they both arise due to common factors in their pathogenesis or whether it is an actual cause-effect phenomenon. Evidence in various studies over the years has suggested the following possible mechanisms of interactions between tlie upper and lower airways:

45 1. Failure of nasal functions Failure of filter, heat and humidification fiinctions of the nose have been incriminated in the pathogenesis of rhinosinusitis-induced asthma. The nose serves as an important filter of inspired air. Relatively large particles are captured by the hairs within the nostrils, while other noxious substances are caught up in the mucus during nasal breathing (Ricketti, 1985). Failure of this filter function or mouth breathing can occur due to sinus disease, resulting in increased allergen as well as irritant burden to the lower airway, thus potentiating lower airway hyperresponsiveness (Agarwal et al, 1984;Eccles, 1989).

On the other hand, the highly vascularized mucosa of the turbinates and septum plays an important role in heating and humidification of the inspired air. During mouth breathing, a cooler, drier air is delivered to the lungs, resulting in an increase in the lower airway resistance. This is thought to be one of the mechanisms responsible for the development of exercise induced asthma and patients have been found to reduce the severity of exercise induced asthma by breathing through their nose rather than their mouth during exercise (Shturman-Ellstein er a/, 1978;Eccles, 1989).

2. Enhancement o f beta adrenergic blockade Partial beta adrenergic blockade has been postulated to be present in patients with bronchial asthma. Infections of the respiratory tract can enhance this blockade, resulting in increased hyperirritability of the bronchial tree. As long as the sinuses are part of the respiratory tract it can be assumed that sinusitis would also enhance this blockade (Slavin, 1982).

3. Rhinosinobronchial reflex It has been suggested that neuroanatomic pathways reflexly connect the paranasal sinuses to the lower airways and stimulation of nasal and sinus receptors could result in bronchospasm (Sluder, 1919). Sinus pathology could

46 be postulated to influence the lower airways through a rhinosinobronchial reflex. Various studies have provided evidence for and against the existence of such a reflex. A substantial increase in the lower airway resistance has been demonstrated after stimulation of the nose of cats with ether or sulphur dioxide or an electrical stimulus (Kiyoshi & Ogura, 1966). Sectioning of the vagus nerve blocked the changes in the lower airway resistance caused by the electrical stimulation (Dixon & Brodie, 1903). In asthmatic patients, a single cold stimulus into the nose resulted in a sudden increase in airway resistance and intrabronchial application of an anticholinergic drug was found to block this response (Nolte & Berger, 1983). In healthy volunteers, an increase in lower airways resistance has been reported in response to intranasal sulphur dioxide (Speizer & Frank, 1966) and nasopharyngeal silica particles (Kaufinan & Wright, 1969). Repeating the latter experiment after injection of atropine, the authors demonstrated that the lower airway response was totally abolished (Kaufinan & Wright, 1969).

Studies on the effect of nasal challenge on the lower airways have provided considerable confusion, since some authors were able and others were unable to provoke an increase in the lower airway resistance in response to nasal challenge. Corren et al. (1991) studied the relationship between nasal challenge with allergen and bronchial responsiveness to methacholine in patients with seasonal allergic rhinitis outside the pollen season. He reported that baseline pulmonary functions, including forced expiratory volume in 1 second, did not change, whereas bronchial responsiveness was significantly greater 1 hour and 5 hours after antigen challenge than after placebo challenge. Yan and Salome (1983) performed intranasal histamine challenge on patients with perennial allergic rhinitis and reported a significant fall in their forced expiratory volume in 1 second. In contrast, Hoehne and Reed (1971) demonstrated no effect on lower airway performance, when patients with grass or ragweed-induced allergic rhinitis were subjected to intranasal challenge with specific allergen. Schumacher et al. (1986) using intranasal

47 histamine challenge in patients with allergic rhinitis, were similarly unable to show any effect on lower airway responsiveness. This would suggest that a certain critical threshold of nasal disease severity might be necessary to provoke reflex changes in lower airway as a response to nasal challenge.

In an animal model of anaesthetised, tracheostomised, ovalbumin-sensitised rats, Bellofiore et al. (1987) investigated the effect of intranasal and endotracheal ovalbumin challenge on the upper and lower airway resistance. They reported that intranasal ovalbumin challenge induced a significant increase in the upper and lower airway resistance and that pre-treatment of the lower airways with inhaled atropine attenuated the response of the lower airways. On the other hand, endotracheal ovalbumin challenge increased the lower airway resistance, with virtually no influence on the upper airways. These findings support the existence of an upper-lower airway interaction, which is partly mediated by cholinergic mechanisms, and argue against the possibility of a lower-upper airway interaction.

4. The drip hypothesis Sino-pulmonary deposition of inflammatory product-rich secretions has been suggested as another possible mechanism for rhinosinusitis as an aggravator for asthma. Huxley and colleagues (1978) investigated the occurrence of pharyngeal aspiration and found that forty five percent of the normal subjects aspirated during deep sleep. In contrast, Bardin et al. (1990) injected a radionucleotide into the maxillary sinuses of patients with rhinosinusitis and asthma, but failed to detect any aspiration in the lower airways. In fact, the most elegant series related to this concept has been derived from a rabbit model of inflammatory sterile sinusitis, induced by a chemotactic complement fragment (Brugman et al, 1993). The authors described a number of interesting observations. First, animals, kept in a head-up position following induction of experimental sinusitis, demonstrated a significant increase in the lower airway responsiveness, whereas, the control group did not show such

48 increase. Second, this increase in lower airway responsiveness was prevented by positioning the animals with head down or intubating them. Third, injecting the complement fragments into the knee joint did not alter the airway responsiveness, despite inducing a local inflammation. Fourth, decreasing complement activity, before placing the animal into a head-up position, did not change the degree of airway responsiveness. Fifth, neither the histology nor the bronchoalveolar lavage data demonstrated significant lower airway inflammation in any group. The authors concluded that sterile sinusitis can increase lower airway responsiveness and the most likely mechanism for this effect seems to be postnasal dripping of cells and their inflammatory products into the lower airways (Brugman et al, 1993).

5. Enhancement of systemic airway inflammatory responses It has been postulated that localised inflammatory airway reactions can induce a generalized enhancement of airway inflammation especially in allergic airways. Braunstahl and colleagues have recently presented us with the possibility of a bi-directional cross-interaction between the upper and lower airways. Their work on nonasthmatic allergic rhinitis patients has demonstrated that not only nasal allergen provocation, but also segmental bronchial bronchoprovocation can induce a generalised airway inflammation affecting both the upper and lower airways (Braunstahl et al, 2000;Braunstahl et al, 2001a;Braunstahl et al, 2001b). Denburg and colleagues have shown that the bone marrow plays an active role in this process by supplying the eosinophil/basophil progenitor cells that can home to allergic tissues in response to allergen provocation (Denburg, 1999;Inman et al, 1999;Denburg et al, 2000;Denburg, 2000;Cyr & Denburg, 2001;Saito et al, 2001). Locally produced cytokines have been suggested to be released into the circulation, leading to bone marrow activation and an increased number of circulating and local tissue inflammatory cells and their progenitors which in turn can lead to up-regulation of the airway inflammatory responses. Inereased expression of lL-5 has been detected in the serum of allergic rhinitis patients after nasal

49 allergen provocation as well as after segmental bronchoprovocation (Braunstahl et al, 2000;Braunstahl et al, 2001b). IL-5 is known to play a central role on haemopoietic progenitors and in the development of eosinophilic inflammations. It stimulates the release of mature eosinophils from the bone marrow, enhances eosinophil survival, chemotaxis, endothelial adhesion and activation and promotes terminal differentiation and maturation of eosinophil/basophil progenitors (Denburg, 1999;Denburg et al, 2000;Cyr & Denburg, 2001). Other cytokines have been suggested to play a role in this systemic airway inflammatory process such as IL-3 and GM-CSF (Denburg, 1999;Denburg et al, 2000;Cyr & Denburg, 2001). In contrast, Saito et al. (2001) using a murine experimental model of isolated allergic rhinitis showed that nasal allergen provocation failed to induce any inflammatory changes or hyperresponsiveness in the lower airways, whereas it upregulated the nasal inflammatory reaction as well as the bone marrow haemopoietic progenitors. Newman et al. (1994) noted a significant correlation between extensive sinus disease and eosinophilia even in negative radioallergosorbent test (RAST). Thus, he suggested that sinus inflammation rather than coexistent asthma or allergy was the cause of peripheral eosinophilia. Another possible mechanism is that rhinosinusitis induces endothelial activation and increases expression of adhesion molecules which results in increased transe ndo the liai migration of leucocytes and exacerbation of the airway inflammatory process (Togias, 1999). Braunstahl et al. (2001b) reported that nasal allergen provocation in nonasthmatic allergic rhinitis patients resulted in generalised airway inflammation through upregulation of adhesion molecules in the upper and lower airways. A third potential pathway could involve the absorption of spasmogens from the sinus mucosa to the systemic circulation, inducing bronchoconstriction and aggravation of asthma. Antihistaminics have been shown to prevent the reduction in lung functions, observed 6 hours after nasal allergen challenge, in patients with asthma. However, this hypothesis has been overshadowed by some doubts as the reduction in lung functions has not been observed acutely after nasal challenge when the spasmogenic mediators

50 should be at the highest levels (Togias, 1999). Besides the above possible mechanisms, a total increase in Immunoglobulin E (IgE) has been suggested in individuals who are genetically prone to allergy and increased production of IgE, especially as a response to infections of a viral aetiology. Saryan et al. (1983) suggested an imbalance between the T-helper cell subsets in subjects with atopy, possibly exacerbated by viral infection, resulting in increased production of IgE through Interleukin-4 mediated mechanism. Frick et al. (1979; 1986) described significant rises in total IgE after infections with parainfluenza 3 virus and respiratory syncetial virus as well as after viral vaccinations in dogs.

6. Role of nitric oxide NO has been observed to have bronchodilator (Dupuy et al, 1992;Ward et al, 1995b) and vasodilator actions (Martinez et al, 1995 ;Higenbottam, 1995), with a possible role in ventilation/perfusion matching. Nasal breathing has been reported to reduce pulmonary vascular resistance (PVR) and improve arterial oxygenation compared with oral breathing in subjects without lung disease (Lundberg, I996;Lundberg et al, I996c;Settergren et al, 1998) and the addition of 100 ppb of NO during oral breathing mimicked the effect of nasal breathing (Lundberg et al, 1996c).Conversely, NO was reported to have pro- inflammatory actions mainly depending on the relative concentrations of NO species and supreoxide anion produced at the sites of inflammation (Rubbo et al, 1994). Studies on murine cells suggested that NO can alter the balance between T-helper (Th) 1 and Th2 cell types, leading to the proliferation of Th2 cells which putatively produce a cytokine profile that has been associated with exacerbation of asthma (Taylor-Robinson et al, 1993;Bames & Liew, 1995). NO has also been shown to promote chemotaxis (Ferreira et al, 1996) and increase survival of eosinophils (Beauvais et al, 1995). On the other hand, NO has been found to be mainly secreted in the nose and paranasal sinuses (Lundberg et al, 1994b;Lundberg et al, 1995a), with diseases involving them modulating nasal NO levels (Kharitonov et al, 1997b;Lindberg et al, 1997b).

51 Therefore, nasal NO can be postulated to follow the airstream to the lower respiratory tract in a continuous low dose flushing manner (Gaston et al, 1994;Bames & Kharitonov, 1996), with a suggestion that a deficiency or an excess of nasal NO levels can play a role in the development of lower respiratory tract diseases including asthma.

1.2.2d The effect of medical treatment of rhinosinusitis on asthma A number of authors have reported the impact of the medical management of rhinosinusitis upon concomitant asthma. Businco et al. (1981) investigated 80 asthmatic children aged 4-14 years, of whom 55 showed clinical and radiological findings of sinusitis. 13 patients had a purulent postnasal discharge and were treated with antibiotics, antihistaminics and oral decongestants, whereas the other 42 were treated with topical steroids, antihistaminics and oral decongestants. 62 % of the children showed an improvement in their sinus X-rays and 36 % had a marked drop in asthma severity. Rachelefsky et al. (1984) looked at a cohort of 48 children and reported a resolution of clinical signs and symptoms, a reduction in bronchodilator use and a normalization of FEVl in 71 %, 79 % and 67 % respectively, after antibiotic therapy. Friedman et al. (1984) showed a clinical improvement and FEVl rise from 93 toi 01 % after 5-7 days of antibiotics in 6 out of 8 children. Oliveira et al. (1997) detected an improved bronchial hyperresponsiveness and symptoms in children with allergic rhinitis and sinusitis with asthma after treatment with antibiotics, nasal saline, antihistaminic/decongestant and five days of prednisone.

Unfortunately, there are few studies in adults concerning the effect of topical medical treatment for rhinosinusitis upon the lower airways. Slavin et al. (1980) published a series of 15 patients, of whom only 4 had medical and 11 surgical treatment and mentioned that it was not possible to improve their asthma except after control of their sinus disease. In 1997 Lamblin et al. published a study with 1 year follow-up, considering a topical nasal

52 corticosteroid and microscopic intranasal sphenoethmoidectomy in 44 patients with nasal polyps, of whom 17 were asthmatic and 8 aspirin sensitive. Her parameters were pulmonary symptoms, spirometric measurements and bronchial hyperresponsiveness (BHR), assessed by a carbachol challenge test to determine the provocating dose (PD20) necessary to decrease FEVl by 20 % from baseline values. 21 patients responded to the topical steroid treatment, in whom no changes in any parameter has been found, whereas, significant enhancement in BHR and reduction in respiratory function tests have been reported in the other group who did not respond to the topical medical therapy and underwent surgery. Neither of the two groups described changes in pulmonary symptoms and/or asthma severity. 4 years later, the author extended her follow-up period claiming consistent changes and describing a non-reversible airflow obstruction in topical steroid non-responders undergoing nasal surgery for nasal polyposis (Lamblin et al, 2000).

Many authors have evaluated the effect of control of the nasal inflammatory process in allergic rhinitis by intranasal corticosteroids on asthma symptoms, pulmonary functions and bronchial hyperreponsiveness, reporting the improvement of one or more of these (Henriksen & Wenzel, 1984;Welsh et al, 1987;Corren et al, 1992;Foresi et al, 1996). One can argue that the intranasal corticosteroids might be inhaled and induce a direct effect on the lower airways. However, Watson et al. (1993), using a radiolabelled corticosteroid aerosol, showed that only 2 % of the drug has been deposited in the lower airways. Other possibility is that intranasal corticosteroids might be partly absorbed into the systemic circulation, with subsequent effects on the bone marrow progenitors and the lower airways. However, this would seem improbable since comparable oral corticosteroid doses have no clinical effects compared to intranasal corticosteroids (Durham, 1999).

Finally, systemic treatments, such as oral corticosteroids, antileukotrienes and systemic aspirin desensitisation, usually improves both the upper and lower

53 respiratory tract manifestations through a direct effect. However, one can still argue that the effect on asthma may be both direct and indirect after control of the associated upper airway inflammatory disease.

1.2.2e The effect of surgical treatment of rhinosinusitis upon asthma There is considerable conflict in the literature as to whether the effect of sinonasal surgery on asthma is on the positive or negative side of the equation. Several studies claimed that asthma improved after sinonasal surgery. In 1933, Weille demonstrated that 22 % out of 40 asthmatics improved, whereas 18 % worsened after polypectomy. In 1936, he published another study reporting that 65 % out of 100 sinus operations resulted in improvement in asthma. In 1951, Weille looked at a larger series of 197 patients, where he found 52 % of improvement and 18 % of worsening after surgery. In 1982, Friedman et al. considered 30 asthmatics undergoing intranasal sphenoethmoidectomy and reported that out of the 28 patients using corticosteroids 93 % were able to reduce or even eliminate their requirements. In the same year, Slavin showed a subjective improvement in 85 % of his patients as well as a reduction in steroid requirements Ifom an average of 20 mg / day to 3 mg / day in 83 % of the cases. In 1984, Juntunen et al. followed up a group of 15 children, 3-12 years after Caldwell-Luc operation for resistant chronic riiinosinusitis, reporting a significant improvement in both subjective and respiratory function tests. In 1986, English looked at 205 patients undergoing intranasal polypectomy and described 85 % subjective improvement in asthma after polypectomy. In 1988, Mings et al demonstrated 65 % and 62 % subjective improvement after bilateral intranasal sphenoethmoidectomy in 2 and 5 years follow-up period respectively, showing that the improvement in astlima at 2 years had for the most part persisted at 5 years. In 1990, McFadden et al. looked retrospectively at 25 patients undergoing intranasal etlimoidectomy, of whom 9 patients had also had Caldwell-Luc operation, and he found a 68 % subjective improvement, a rise in respiratory function tests and a reduction in

54 medication over a follow-up period of 1 to 11 years. In 1991, Lawson reported only 33 % subjective improvement in 2 to 14 years follow-up period. The 1990s were an era of increasing interest in both endoscopic sinus surgery and its effect upon the lower respiratory tract. Most authors claimed a subjective improvement in asthma greater than that obtained by other types of sinonasal surgery (78 - 91%) (Stammberger, 1991a;Jankowski et al, 1992;Nishioka et al, 1994a;Manning et al, 1994;Senior & Kennedy, 1996;Nakamura et al, 1999;Dhong ei al, 2001), whereas only one study showed 40 % improvement and 6 % worsening (Dunlop et al, 1999). Most of these studies also showed improvement in some objective measurements such as reduction in the use of medication, frequency of hospitalisation, number of outpatient visits and occasionally improvement in respiratory function tests. Jankowski et al. (1992) also included a carbomyl choline challenge and reported that bronchial hyperreactivity became negative in 30 % of those in whom it preoperative ly had been positive.

In contrast, some authors reported that asthma was adversely affected by sinonasal surgery. Van de Veer (1920) was the first to state this, although he did not offer any specific clinical details (Lund, 1999). In 1929, Francis described worsening of asthma in 46 % out of 24 patients who underwent sinonasal surgery. In 1958, Sam ter and Lederer looked at 17 patients undergoing intranasal polypecomy reporting an increase in their bronchial reactivity. Other authors also had similar findings (Samter & Beers, Jr., 1967;synder & Seigel, 1967;Saberman & Ross, 1973;Moloney, 1977). Recently, Lamblin et al. (2000) demonstrated an irreversible increase in bronchial hyperresponsiveness and a slight, but significant, drop in spirometric measurements in topical steroid non-responders undergoing sinonasal surgery. It is also worth mentioning that some of the authors who encouraged sinonasal surgery in asthmatics, reported different ranges (1-18 %) of worsening in asthma after surgery (Weille, 1933;Weille, 1936;Weille & Richards, 1951 ;Lawson, 1991;Stammberger, 1991a;Dunlop et al, 1999).

55 On the other hand, a number of authors reported an equivocal effect of sinonasal surgery upon concomitant asthma, reporting that nasal polypectomy was safe and did not alter the course of asthma (Schenck, 1974;Speer, 1975;Brown et al, 1979). In 1999, Goldstein et al. using endoscopic sinus surgery, found no significant changes in asthma symptom score, score of medication use and respiratory function tests after surgery. Uri et al. (2002) also reported that endoscopic sinus surgery did not improve asthma in patients with massive nasal polyposis. Table lb shows analysis of the trials investigating the effect of sinus surgery upon asthma, reflecting the inherent problems in their study design.

56 Table lb Analysis of the trials investigating the effect of sinus surgery upon asthma

A uthor No N o No o f Subjective assessment Objective assessment Study design Follow - O peration o f o f CRS up in patients ASA with years patients polyposis % o f % o f % o f General RFT/ improvement w orsening no BHR change Francis 24 13 24 42 46 12 Retrospective 0.5-4 Polypectomy (1929) Weille (1933) 40 N ot 40 22 18 60 Retrospective 0.5 - 7 Polypectomy stated Weille (1936) 100 N ot 45 65 8 27 Retrospective Not All classic stated stated operations W eille and 197 Not 109 52 18 30 Retrospective Average All classic R ichards stated 8.5 operations (1951) Schenck 18 18 18 28 33 39 Retrospective 0.5-4 Polypectomy (1974) M oloney 95 9 95 Not stated 27 Not Retrospective N ot Polypectomy (1977) stated stated Brown et al. 101 101 101 30 14 56 ^Hospitalisation Retrospective 1-4 Polypectomy (1979) Friedman et 30 ■ 15 26 Not stated Not stated Not 1 Medications Retrospective 0.5-4 Intranasal al. (1982) stated (93%) sphenoethmoidectomy Slavin (1982) 31 17 30 85 Not stated Not 1 Medications Retrospective N ot Intranasal stated (83%) stated sphenoethmoidectomy (26), Caldwell-Luc (3), Antrostomy (2)

57 A uthor No No N o o f Subjective assessment Objective assessment Study design Follow- O peration o f o f CRS up in patients ASA with years patients polyposis % o f % o f % o f General RFT/ improvement w orsening no BHR change Juntunen et 15 0 0 66 Not stated Not Retrospective 3 - 12 Caldwell-Luc al. (1984) children stated f F E V l English 205 205 205 85 0 15 1 Medications Retrospective 0.5 - 13 Polypectomy +/- (1986) (84%) ethmoidectomy (168)+/- Caldwell- Luc (95) +/- frontal sinus obliteration (13) Mings et al 31 18 28 65 (2 years) Not stated Not ^ Medications Retrospective 2 - 5 Intranasal (19881) 62 (5 years, stated (60%) f F E V l sphenoethmoidectomy only 16 patients were available) McFadden et 25 25 25 68 N ot stated N ot ^ Medications Retrospective 1 - 11 Intranasal al. (1990) stated f RFT ethmoidectomy +/- Caldwell-Luc (9 cases) Law son 36 18 36 33 1 66 Retrospective 2-14 Intranasal (1991) ethmoidectomy Stammberger 54 Not 54 . 83 13 4 Prospective, 1 Endoscopic surgery (1991a) stated fR F T N on­ randomised, N on­ controlled

58 A uthor No N o No o f Subjective assessment Objective assessment Study design Follow - O peration o f o f CRS up in patients ASA with years patients polyposis % o f % of % o f G eneral RFT/ improvement w orsening no BHR change W igand and 51 13 51 Beneficial for many patients suffering Retrospective Average Endoscopic surgery H osem ann from bronchial asthma 4.3 (1991) Jankowski et 30 12 30 91 0 9 Prospective, 1-3.3 Endoscopic surgery al. (1992) Medications | r f t N on­ No of attacks randomised, f | b h r controlled by 20 patients of CRS with polyposis Nishioka et 20 3 12 80 0 20 Retrospective 1 Endoscopic surgery al. (1994a) Medications (53.8% ) Hospitalisations , (75%)

M anning et 14 N ot 0 79 0 21 Medications N o Prospective, 1 Endoscopic surgery al. (1994) children stated (86%) significant N on­ Hospitalisations change in randomised, (70%) RFT Non- Missed school control led ^ days (35%)

59 A uthor No No No o f Subjective assessment Objective assessment Study design Follow - O peration o f o f CRS up in patients ASA with years pa tients polyposis % of % o f % o f G eneral RFT/ improvement w orsening no BHR change Rosen et al. 39 39 39 82 0 18 ^ Medication Retrospective 2 -1 5 Endoscopic surgery (1996) (17), open surgery (12) and intranasal ethmoidectomy (10) Senior and 42 Not N ot 86 7 7 1 Oral steroids Retrospective 1 Endoscopic surgery K ennedy stated stated (79%) (1996) Dinis and 43 2 14 81.4 18.6 0 N o Prospective, 1 Endoscopic surgery Gomes (1997) Hospitalisations significant N on­ r change in randomised, RFT N on­ controlled Park et a I. 79 37 58 80 N ot stated Not Hospitalisations Retrospective 4 - 10 Endoscopic surgery (1998) stated T Oral steroids Senior et al. 30 Not Not 89.9 0 11.1 bronchodilator Retrospective 0.6- Endoscopic surgery (1999) stated stated inhalers (46%) 10.6 Oral steroids (65%) Dunlop et al. 50 10 34 40 6 54 Medications Better Retrospective 1 Endoscopic surgery (1999) (40%) PEF in 14 Hospitalisations out o f the , (38%) 23 who recorded PEF

60 A uthor No No No o f Subjective assessment Objective assessment Study design Follow- O peration o f o f CRS up in patients ASA w ith years patients polyposis % o f % of % o f General RFT/ improvement w orsening no BHR change Nakamura et 22 22 22 90.9 0 9.1 Oral steroids Retrospective 1 Endoscopic surgery al. (1999) (60%) fRFT +/- Caldwell-Luc (12 Steroid inhalers cases) (47.1) f Hospitalisations (38%)

Goldstein et 13 1 9 No significant change No significant N o Retrospective 0.5- Endoscopic surgery al. (1999) change significant 2.5 change in RFT Ikeda et al. 15 Not N ot N ot stated ^ oral steroids prospective, 0.5 Endoscopic surgery (1999) stated stated (55%) f PEF non­ randomised conroiled (6 patients of CRS with asthma) Dhong et al. 19 G 6 Significant improvement in all ^ Medications N o Prospective, 1.5-3 Endoscopic surgery (2001) asthma symptoms significant N on­ change in randomised, RFT N on­ controlled Palmer et al. 15 N ot N ot N ot stated ^ Medications Retrospective 1 Endoscopic surgery (2001) stated stated

61 A uthor No No N o o f Subjective assessment Objective assessment Study design Follow - O peration o f o f CRS up in patients ASA with yea rs patients polyposis % o f % of % o f G eneral RFT/ improvement w orsening no BHR change Uri et al. 34 (only Not 34 41% satisfied 59% not satisfied ^Medications No Retrospective Average Endoscopic surgery (2002) 13 stated significant 2.1 patients change in had RFT complete data)

62 1.2.3 Endogenous nitric oxide and the airways

In 1980, Furchgott & Zawadzki first reported that the relaxation of rabbit aortic strips in response to acetylcholine required the presence of an intact endothelium and suggested the existence of the endothelium-derived relaxing factor. In 1987, nitric oxide (NO) was identified as the endothelium-derived relaxing factor (Ignarro et al, 1987;Palmer et al, 1987) . The discovery of L- arginine-dependent NO was made shortly after (Palmer et al, 1988). Since then, a considerable body of research has been devoted to investigating the role of NO in various body systems, including the respiratory system, with increasing evidence that endogenous NO plays a key role in the normal physiology as well as the abnormal pathophysiology of airway diseases (Barnes, 1993;Gaston et al, 1994;Bames, 1995).

1.2.3a Nitric oxide synthesis NO is a fairly stable gas, formed in vivo by several iso forms of the enzyme, NO synthase (NOS), which catalyses conversion of the amino acid L-arginine to citrulline via N-hydroxy-L-arginine (Goretski & Hollocher, 1988;Stuehr et al, 1991 ;Nathan, 1992). NOS is a heme-containing enzyme with a structure and spectral properties resembling cytochrome P-450 reductase (Bredt et al, 1991). The enzyme utilizes molecular oxygen and nicotinamide adenine dinucleotide phosphate (NADPH) as cosubstrates and thiol, tetrahydrobiopterin and calmodulin as cofactors (Pou et al, 1990;Bredt & Snyder, I990;Bredte/n/, 1991 ;Nathan, 1992).

NOS isoforms are generally classified as either constitutive (cNOS) and calcium dependent or inducible (iNOS or type II NOS) and calcium

63 independent (Forstermann et al, 1991;Nathan, 1992). The constitutive iso forms comprise the neuronal NOS (nNOS or type I NOS) and the endothelial NOS (eNOS or type III NOS) after their being firstly described in the brain and vascular endothelium respectively (Knowles & Moncada, 1994;Morris & Billiar, 1994;Nathan & Xie, 1994b). This classification depends on calmodulin binding to the constitutive iso forms, which is activated by calcium, whereas the inducible isoform is both induced by immunological and inflammatory stimuli and independent of calcium/calmodulin because of its tightly bound calmodulin (Bredt & Snyder, 1990;Nathan, 1992). The constitutive iso forms release low amounts of NO for short periods and their calcium mediated calmodulin binding is stimulated by mediators such as bradykinin, acetylcholine, calcium ionophore, histamine, leukotrienes, and platelet activating factor (Bredt & Snyder, 1990;Nathan, 1992;Lamas et al, 1992). On the other hand, the inducible isoform generates a relatively large amount of NO for a more sustained period and its regulation is at the level of transcription where the messenger RNA expression of the iNOS isoform can be induced by interpheron y, endotoxin, tumour necrosis factor (TNT) a, and

TNT (3 as well as a variety of other cytokines (Knowles et al, 1990a;Knowles et al, 1990b;Wong & Garbers, 1992;Geller et al, 1993a;Geller al, 1993c;Gaston et al, 1994;Knowles & Moncada, 1994). Further studies, including cloning of the complementary deoxyribonucleic acid, have revealed further differences and provided useful information concerning the role of each iso form and the effect of its deletion(Charles et al, 1993b;Charles et al, 1993a;Geller & Billiar, 1993;Geller et al, 1993b;Marsden et a/, 1992;Nakane et al, 1993;Huang & Fishman, 1996). A comparison between the three iso forms is shown in Table Ic.

64 Table le

Isoforms of NOS

nNOS eNOS iNOS (Type 1 NOS) (Type 111 NOS) (Type 11 NOS) Type Constitutive Constitutive Inducible Gene location Chromosome 12 Chromosome 7 Chromosome 17 Primary regulation Ca^^/Calmodulin Ca^^/Calmodulin Gene expression NO output Low Low High General function Cell signalling Cell signalling Cytotoxic Cytostatic Cytoprotective

Indeed, the apparent association of the three NOS isoenzymes with endothelium, neurones and inducibility is an oversimplification. For example, eNOS has been located in platelets (Radomski et al, 1990), and in certain neuronal populations in the brain (Dinerman et al, 1994), whereas the nNOS has been found in skeletal muscles (Kobzik et al, 1994). In addition, the constitutive eNOS can be induced in certain situations such as chronic exercise (Sessa et al, 1994) and pregnancy (Weiner et al, 1994), whereas the iNOS appears to be present constitutively in some tissues, including rat kidney (Mohaupt et al, 1994) and human paranasal sinuses (Lundberg et al, 1995a). Furthermore, some differences have been identified between iNOS obtained from different tissues within the same species (Mohaupt et al, 1994).

1.2.3b Origin of NO in the airways NO is mainly produced within the upper airways, with only a minor contribution fi'om the lower respiratory tract (Alving et al, 1993;Gerlach et al, 1994;Lundberg et al, 1994c). This difference becomes more apparent when the actual amounts of NO released in different parts of the airways per unit of time are compared. Total NO release in the entire normal lower airways has

65 been found to be less than 5 nmol/minute at rest, whereas that from a single maxillary sinus has been found to be about 20 nmol/minute (Trolin et al, 1994;Lundberg et al, 1995a), However, it is difficult to exclude the possibility that a substantial amount of NO is produced in the lower respiratory tract, but this NO may be trapped there following reactions with haemoglobin or other compounds that react rapidly with NO (Gaston et al, 1994).

In the upper airways, human paranasal sinuses have been demonstrated to be a major source of NO production, which floods through the sinus ostia and makes a large contribution to the levels of NO found in the nasal cavity (Lundberg et al, 1994b;Lundberg et al, 1995a). On the other hand, the contribution from the nasal cavity mucosa seems to be of less importance (Lundberg et al, 1995a).

Immunohistochemical studies have identified all three iso forms of NOS in human airways (Kobzik et al, 1993;Ward et al, 1995a;Saleh et al, 1998). Endothelial NOS has been identified not only in the endothelium of the bronchial circulation but also in the bronchial epithelium (Shaul et al, 1994). Neuronal NOS has been localised in the airway nerves as well as the bronchial epithelium (Asano et al, 1994)). Inducible NOS has been found to be expressed in human bronchial epithelium in asthma (Hamid et al, 1993g;Saleh et al, 1998) as well as in inflammatory cells including macrophages (Yui et al, 1991a), eosinophils (Zanardo et al, 1997), neutrophils (Yui et al, 1991b) and fibroblasts (Jorens et al, 1992). On the other hand, there has been considerable conflict in the literature as to whether iNOS is also present in healthy bronchial epithelium. Some authors found no evidence of iNOS expression in healthy bronchial epithelium (Hamid et al, 1993g;Asano et al, 1994), whereas others reported its expression in bronchial mucosa of healthy subjects (Guo et al, 1995;Saleh et al, 1998). Meanwhile, it has been found that a Ca independent NOS isoform, very closely related to the iNOS that has been cloned in activated human hepatocytes (Geller et al, 1993b) is constantly

66 expressed in healthy paranasal sinus epithelium (Lundberg et al, 1995a;Lundberg et al, 1996e). However, the regulation of expression and the activity of the sinus iNOS seems to differ from what has been described for this isoform, since it is constitutively expressed and seems resistant to steroids, properties that are normally associated with cNOS (Lundberg et al, 1995a;Lundberg et al, 1996e). This may be explained by the presence of multiple iNOS-like sequences in the human genome that encode iNOS-like products (Xu et al, 1995).

1.2.3c Factors influencing levels of NO in nasal and exhaled air Although there is increasing knowledge about NO, much further study is still required to explore the frill range of the physiological and pathological factors that influence its level in nasal and exhaled air.

1. Height, weight, age and sex Lewandowski et al. (1996) found no relationship between exhaled NO and size of Asian elephants. In human studies, some authors reported no significant correlation between body weight or surface area and exhaled NO in either sex (Jilma et al, 1996), whereas others observed a significant correlation between exhaled NO, expressed as NO release per square meter of body surface area, and body surface area (Phillips et al, 1996).

Nasal NO levels have been reported to be age-dependent in the first 10 years of life, since they were lower in newborns and increased with age, reaching levels similar to those of adults at approximately the age of 10 years (Lundberg et al, 1995a). It seems that nasal NO levels follow the development and pneumatization of the paranasal sinuses which occur primarily during the first 10-12 years (Shechtman et al, 1993).

In adult males and children, intraindividual changes in nasal and exhaled NO over time have been reported to be of no significant value (Lundberg et al.

67 1994c). Menstruating females, on the other hand, showed great variations of exhaled NO levels in synchrony with the menstrual cycle. Exhaled NO peaked at midcycle during ovulation, whereas its lowest values have been observed just before and during menstruation (Kharitonov et al, 1994a). However, it is not clear whether the cyclic alterations in exhaled NO levels reflects the cyclic hormonal changes in women, since no significant changes in exhaled NO levels have been observed either in the follicular phase of the cycle (Morris et al, 1996) or during pregnancy (Morris et al, 1995), while at the same time the plasma nitrite/nitrate concentration has been observed to increase during the follicular phase and decrease during the luteal phase of the cycle (Rosselli et al, 1994).

2. Physical exercise Exercise has been shown to increase the total amount of NO excreted in the lower airways, as measured in the orally-exhaled air, which may be due to increased blood flow and availability of substrates for enzymatic NO synthesis (Persson et al, 1993;Iwamoto et al, 1994) as well as increased endothelial NO production, since increased NO in the circulation has been detected in the exhaled air with the use of nitroglycerine (Persson et al, 1994a). In contrast, nasal NO has been reported to decrease acutely with heavy physical exercise (Lundberg et al, 1997), possibly due to a reduction in mucosal blood flow, which is known to occur both in sinus mucosa (Falck et al, 1989), and nasal cavity during exercise (Ohki et al, 1987). This, in turn, might result in local deficiency of L-arginine and molecular oxygen, the substrates for NOS. This explanation has been supported by the increase of nasal (Lundberg et al, 1996e), and exhaled NO (Kharitonov et al, 1995a;Sapienza et al, 1998), in a dose dependent manner, upon administration of L-arginine.

3. Cigarette smoking and alcohol Chronic cigarette smoking has been found to significantly reduce exhaled NO levels (Persson et al, 1994c;Schilling et al, 1994;Kharitonov et al, 1995b).

68 This reduction correlated with the daily consumption of cigarettes (Kharitonov et al, 1995b). Furthermore, acute exposure to cigarette smoke caused a small and transient reduction in the exhaled NO levels (Kharitonov et al, 1995b). The reason for this is not clear, but it could be due to a downregulation of endogenous NO synthesis because of the high NO content in cigarette smoke or a damage of NO producing cells by toxic agents in cigarette smoke (Kharitonov et al, 1995b).

Alcohol ingestion has been proved to reduce levels of NO in exhaled air in asthmatic patients but not in normal individuals (Yates et al, 1996). This may reflect a preferential effect on iNOS, since ethanol has been observed to have an inhibitory effect on iNOS (Persson et al, 1994b).

4. Drugs Various drugs have been reported to influence NO synthesis and release in nasal and exhaled air. Glucocorticoids have been reported to inhibit the expression of iNOS (Nathan & Xie, 1994a), with both systemic and inhaled steroids reducing the already elevated NO levels in the exhaled air of asthmatic patients (Massaro et al, 1995;Lundberg et al, 1996b;Kharitonov et al, 1996b). Interestingly, basal nasal NO concentrations and sinus NOS activity, in subjects with normal upper airways, have also been found to be resistant to intranasal and systemic steroids (Lundberg et al, 1994c;Lundberg et al, 1995a;Lundberg et al, 1996e). On the other hand, Kharitonov et al. (1997b) demonstrated that topical nasal glucocorticoids significantly lowered the already elevated nasal NO levels in patients with seasonal allergic rhinitis. Baraldi et al. (1998) also described a significant reduction in nasal NO in children with perennial allergic rhinitis after treatment with topical glucocorticoids.

Several inhibitors of NOS have been developed. Among the most commonly employed are analogues of L-arginine such as N“ -monomethyl-L-arginine,

69 (L-NMMA) and N“ -nitro-L-arginine methyl ester (L-NAME), which act as competitive (and in some cases, irreversible) inhibitors of both the constitutive and inducible NOS (Moncada & Higgs, 1993;Moncada et al, 1989). Newly identified inhibitors show promise for even greater selectivity (Moncada et al, 1997). NOS inhibitors have been reported to decrease nasal and exhaled NO levels in both controls and patients (Lundberg et al, 1995a;Yates et al, 1995;Lundberg, 1996). Interestingly, asymmetric dimethyl-L-arginine, an inhibitor of NOS, and L-NMMA have been found in human plasma and urine and their accumulation in plasma may contribute to the pathophysiology of some conditions (Moncada et al, 1997).

In contrast, the term, NO donors, has been adopted for those drugs whose clinical actions are now known to result from their ability to liberate NO. Such compounds include organic nitrates (e.g. glyceryl trinitrate), organic nitrites (e.g. amyl nitrite), inorganic nitroso compounds (e.g. sodium nitroprusside) and S-nitrosothiols (e.g. S-nitrosoglutathione) (Moncada et al, 1997). Nitrovasodilators, such as nitroglycerine, have been found to increase NO levels in the exhaled air (Persson et al, 1994a).

L-arginine has been shown to increase nasal (Lundberg et al, 1996e) and exhaled NO (Kharitonov et al, 1995a;Sapienza et al, 1998) in a dose dependent manner. Conversely, leukotriene antagonists decreased the elevated NO levels in asthmatic patients (Kobayashi et al, 1999;Bisgaard et al, 1999;Bratton et al, 1999). Locally administered a-adrenergic agonists reduced nasal NO levels in healthy individuals (Holden et al, 1999) and in patients with allergic rhinitis without symptoms on the day of the test (Amal et al, 1997), whereas increased nasal NO levels were observed in patients with allergic rhinitis with symptoms on the day of the test (Amal et al, 1997). Antibiotics, on the other hand, did not alter the excretion of NO in the healthy upper airways in (Lundberg et al, 1994c), whereas it increased the low nasal NO levels in children with acute maxillary sinusitis (Baraldi et al, 1997).

70 5. Respiratory tract diseases Nasal NO levels have been found to be modulated by upper respiratory tract diseases. Kharitonov et al. (1995d) described increased NO levels during the symptomatic period in subjects with acute upper respiratory tract infections. However, no significant difference in nasal NO levels has been shown between patients with common cold and control groups (Ferguson & Eccles, 1997a;Lindberg et al, 1997b). Furthermore, Kaul et al. (1999) found no differences in nasal nitrite levels between patients with rhinovirus infection and non-infected volunteers. Patients with untreated seasonal allergic rhinitis have been found to have significantly higher NO levels during the pollen season (Kharitonov et al, 1997b). Other studies also described increased NO levels in allergic rhinitis both in adults (Martin et al, 1996) (Amal et al, 1997) and children (Baraldi et al, 1998). Kawamoto et al. (1998), using immunohistochemical techniques, showed marked increase in the cellular expression of iNOS in patients with allergic rhinitis. In contrast, Henriksen et al. (1999) reported that nasal NO levels in patients with allergic rhinitis neither significantly differed from controls in the non-pollen season nor significantly increased in the pollen season. Diseases affecting paranasal sinuses and ostiomeatal complexes have also been reported to influence nasal NO levels. Baraldi et al. (1997) reported decreased nasal NO levels in children with acute maxillary sinusitis. Lindberg et al. (1997b) also showed that nasal NO levels were significantly lower in patients with chronic rhinosinusitis. Amal et al. (1999), on the other hand, found no significant difference in nasal NO levels between patients with chronic sinusitis and controls. The latter study also reported that nasal NO concentrations in nasal nonallergic polyposis were significantly lower than both controls and allergic nasal polyposis. Conversely, in polyposis with allergy, nasal NO levels tended to increase compared with controls (Amal et al, 1999). Furthermore, patients with primary ciliary dyskinesia (PCD) and Kartagener’s syndrome have been

71 described to have very low or absent levels of nasal NO, despite the presence of open paranasal sinuses apparent on the CT scan (Lundberg et al, 1994c;Loukides et al, 1998;Amal et al, 1999). Cystic fibrosis has also been reported to have significantly low nasal NO levels (Balfour-Lynn et al, 1996;Dotsch et al, 1996;Lundberg et al, 1996b).

On the other hand, exhaled NO levels have been reported to be affected by lower respiratory tract diseases. Alving et al. (1993) reported increased NO levels in the exhaled air of asthmatics. In the same year, Hamid et al., described increased expression of iNOS in asthmatic airways. These findings have been confirmed by several research groups (Kharitonov et al, 1994b;Persson et al, l994c;Massaro et al, 1995;Saleh et al, 1998). Furthermore, these elevated NO levels have been proved to derive from the lower airways (Kharitonov et al, 1996a;Massaro et al, 1996), to increase during exacerbation (Massaro et al, 1995) and to decrease with glucocorticoids (Massaro et al, 1995;Lundberg et al, 1996b;Kharitonov et al, 1996b) and leukotriene antagonists (Kobayashi et al, 1999;Bisgaard et al, 1999;Bratton et al, 1999). Elevated levels of exhaled NO have also been demonstrated in unstable chronic obstructive pulmonary disease (COPD) (Maziak et al, 1998) and bronchiectasis (Kharitonov et al, 1995c). On the other hand, controversial results have been shown in cystic fibrosis (Lundberg et al, 1996b;Dotsch et al, 1996;Grasemann et al, 1997;Ho et al, 1998) and clinically stable COPD (Robbins et al, 1996;Kanazawa et al, 1996;Roger et al, 1997;Corradi et al, 1999). Moreover, patients with primary lung cancer showed a significant rise in exhaled NO and nitrite levels, but this was not specific to the side of the tumour (Liu et al, 1998).

1.2.3d Biological significance of airway-derived NO Despite the fact that a considerable number of research groups have devoted themselves to discover the biological significance of the airway-derived NO,

72 it is still far from being settled and many aspects are still a matter of speculation.

I. Role of NO in airway smooth muscle NO and NO donors have been found to relax human airway smooth muscle in vitro via activation of guanylyl cyclase which stimulates the production of cyclic guanosine monophosphate (cGMP) (Gaston et al, 1993;Ward et al, 1995b). High concentrations of inhaled NO produced bronchodilatation and protected against cholinergic bronchoconstriction in guinea pigs in vivo (Dupuy et al, 1992). In humans, inhalation of high concentrations of NO had no effect on lung functions in healthy subjects and produced only weak and variable bronchodilatation in asthmatic patients (Hogman et al, 1993;Sanna et al, 1994;Kacmarek et al, 1996).

II. Role of NO in airway vessels NO has been reported to be a potent vasodilator in the bronchial circulation and may play an important role in regulating airway blood flow, as in the pulmonary circulation (Crawley et al, 1990;Liu et al, 1991;Martinez et al, 1995;Higenbottam, 1995). Likewise, some authors have suggested a role for NO in regulating nasal vascular tone and/or blood flow (Runer & Lindberg, 1998;Holden et al, 1999). However, others have found no relationship between nasal nitric oxide and total nasal airway resistance (Ferguson & Eccles, 1997b), minimum cross-sectional area (Silkoff et al, 1999)and nasal cavity volume (Chatkin etal, 1999).

III. Role of NO in airway nerves It has been suggested that NO may be the major neurotransmitter for the bronchodilating nerves, since NOS inhibitors virtually abolished the inhibitory nonadrenergic noncholinergic (i-NANC) bronchodilating neural mechanism (Belvisi et al, 1992a;Belvisi et al, 1992b;Bai & B ram ley, 1993). Furthermore, stimulation of i-NANC in human airways has been

73 reported to increase cyclic GMP without any increase in cyclic AMP levels (Ward et al, 1995b). The density of nNOS immunoreactive nerves has been reported to increase in proximal airways and to diminish in peripheral ones, which is consistent with a reduction of i-NANC responses in the more peripheral airways (Ward et al, 1995a). It has also been mentioned that NO may be released with acetylcholine from cholinergic nerves and may modulate cholinergic neural responses (Belvisi et al, 1991;Ward et al, 1993). However, this appears to be the result of a functional antagonism at the level of the airway smooth muscle rather than an effect on acetylcholine release (Brave et al, 1991;Ward et al, 1993).

In addition, it has been suggested that NO plays a prominent role in the neural regulation of nasal mucosal vasculature and fluid production (Hanazawa et al, 1997;Lane et al, 1997;Okita & Ichimura, 1998). Hanazwa et al. (1997), using immunohistochemical studies, reported that NOS-containing nerve fibres were distributed around blood vessels and seromucous glands and suggested its origin to be the pterygopalatine ganglion.

IV. Role of NO in host defence High concentrations of NO generated in the paranasal sinuses may have a sterilising effect in the sinuses and upper respiratory tract, since NO has been found to be toxic to bacteria, parasites and viruses (Liew & Cox, 1991;Mancinelli & McKay, 1983;Nathan & Xie, 1994a;Sanders et al, 1998;Reiss & Komatsu, 1998;Rimmelzwaan et al, 1999). Targeted disruption of the iNOS gene in mice resulted in a marked increase in susceptibility to infection (Wei et al, 1995 ;Laubach et al, 1995). Hence, speculation can be made that very low NO levels in children with Kartagners syndrome (Lundberg et al, 1994c) and cystic fibrosis (Lundberg et al, 1996b) contribute to the increased susceptibility to airway infections in these patients.

74 Besides its toxic role on micro-organisms, NO may also contribute to local host defence by stimulating ciliary motility. NO has been shown to increase ciliary beat frequency in airway epithelium both in vitro (Jain et al, 1993) and in vivo(Runer et al, 1998;Runer & Lindberg, 1998). Furthermore, Lindberg et al. (1997a) reported that low levels of nasal NO correlated with impaired mucociliary function in the upper airways.

In addition, NO has also been reported to have cytotoxic effects against tumours (Xie & F idler, 1998;Lala, 1998) and the antitumour activities of macrophages have been attributed to NO production (Chang et al, 2001). Liu et al. (1998) described a significant rise in exhaled NO and nitrite levels in patients with primary lung cancer, but this was not specific to the side of the tumour and he attributed it to the tumour associated non­ specific immunological and inflammatory processes of the host. However, other studies have reported that NO may differently modulate tumour progression (Brennan et al, 1999;Lewko et al, 2001 ;de Wilt et al, 2000;Brennan, 2000;Brennan et al, 2000;Jadeski et al, 2000;Shi et al, 2000).

V. Role of NO in Inflammation NO produced by iNOS has been implicated in the pathogenesis of inflammation (Nussler & Billiar, 1993). Indeed, enhanced NO synthesis has been described in various inflammatory diseases, for example, asthma (Alving et al, 1993), ulcerative colitis (Lundberg et al, 1994a) and cystitis (Lundberg et al, 1996a). However, it is not quite clear whether NO has a harmful role or a protective one. Possible pro-inflammatory actions ofNO may be through activation of enzymes, such as cyclo-oxygenase (Salvemini et al, 1993), or metalloproteases (Murrell et al, 1995). NO also reacts rapidly with superoxide anions to form the potent cytotoxic peroxynitrite anion which may directly induce tissue damage or further

75 decompose to even more oxidizing compounds (Beckman et al, 1990). At sites of inflammation where cogeneration of NO and superoxide anions occurs, the outcome of the reaction depends on the relative concentrations of the reactive species (Rubbo et al, 1994). This suggests that the high concentrations of NO, produced by iNOS during inflammation, may have a key role in the inflammatory process. Furthermore, some studies in murine cells have suggested that NO may amplify inflammation by altering the balance between T-helper (Th) 1 and Th2 cell types, leading to the proliferation of Th2 cells which putatively produce a cytokine profile that has been associated with exacerbation of asthma (Barnes & Liew, 1995). NO has also been shown to promote chemotaxis (Ferreira et al, 1996) and increase survival of eosinophils (Beauvais et al, 1995). These observations, however, have not yet been extended to humans.

On the other hand, NO may serve important protective functions in the airways as discussed above. Moreover, it has been suggested that up regulation of NO synthesis in asthma serves to counterbalance bronchoconstrictor stimuli (Gaston et al, 1994).

VI. Role of NO as an airborne messenger Several studies observed clear effects on arterial oxygenation and pulmonary arterial blood pressure using concentrations of inhaled NO as low as 10-1 GO parts per billion (ppb) (Gerlach et al, 1993;Puybasset et al, 1994;Davidson et al, 1998). Nasal breathing has also been reported to reduce pulmonary vascular resistance (PVR) and improve arterial oxygenation compared with oral breathing in subjects without lung disease (Lundberg, 1996;Lundberg et al, 1996c;Settergren et al, 1998), and the addition of 100 ppb of NO during oral breathing mimicked the effect of nasal breathing (Lundberg et al, 1996c). Moreover, supplementation of nasal air to intubated patients resulted in a significant fall in PVR and an increase in arterial oxygenation (Lundberg et al, 1995b). The above

76 findings lead to a suggestion that NO produced in the nose follows the airstream to the lower respiratory tract with every inhalation in a continuous low dose flushing manner (Lundberg et al, 1996d). Taking into consideration its vasodilator and bronchodilator actions as well as this enrichment of ventilated alveoli with NO flushing, a possible role of NO in ventilation/perfusion (V/Q) matching has been suggested (Gaston et al, 1994;Bames & Kharitonov, 1996). In addition, some authors have gone beyond the limits of the airways, suggesting a major role for NO in the control of oxygen delivery to the tissues (Jia et al, 1996;Stamler et al, 1997).

77 1.3 Aims of the thesis

1. To conduct the first prospective randomised controlled trial, evaluating and comparing the medical and surgical treatment of chronic rhinosinusitis and its subgroups through a reasonable range of subjective and objective measurements.

2. To study whether the presence of nasal polyps serves as a poor prognostic factor for the efficacy of CRS therapy.

3. To study whether asthma serves as a poor prognostic factor for the efficacy of CRS therapy.

4. To elucidate the relationship between upper and lower airway diseases, considering specifically the relationship between chronic rhinosinusitis and asthma.

5. To conduct the first prospective randomised study evaluating and comparing the effect of the medical and surgical treatment of chronic rhinosinusitis and its subgroups upon asthma, applying a range of subjective and objective parameters, and including an easy and sensitive detector of asthmatic inflammation.

6. To study whether the presence of nasal polyps serves as a poor prognostic factor for asthma control in CRS patients.

7. To study the effect of medical and surgical therapy of chronic rhinosinusitis upon nasal NO levels.

8. To investigate the value of nasal NO as an objective indicator of the effect of therapy on chronic rhinosinusitis.

78 2 - Materials and Methods

2.1 Subjects Patients were recruited from the Rhinology Clinics of the Royal National Throat, Nose and Ear Hospital, London. The process of recruitment took place over two years. After application of the exclusion criteria, the study was discussed with three hundreds and twenty seven consecutive patients with a primary diagnosis of chronic rhinosinusitis. Of these, one hundred and thirty one patients (40.1%) agreed to take part in the study. Out of this group, twenty six patients (19.9%) responded to the initial medical treatment, eight patients (6.1%) had minimal or no changes on the CT scans and seven patients (5.3%) were lost during this early phase of the study, leaving ninety patients (68.7%) with a diagnosis of chronic rhinosinusitis with (43 patients) or without (47 patients) asthma to be enrolled in the trial. The study comprised 45 males and 45 females, with a mean age ± (SD) of 43 ± (13) and a range from 24 to 71 years. The patients were randomised into two equal medical and surgical groups with 45 patients in each group.

2.2 Inclusion criteria Ninety patients who agreed to the process of randomisation and suffered chronic rhinosinusitis with or without asthma were included in the study. The diagnosis of chronic rhinosinusitis was primarily based on the criteria described by the Staging and Therapy Group (Lund & Kennedy, 1995). 1. Eight weeks of persistent symptoms and signs, with at least two major or one major and two minor symptoms; • Major: * Nasal congestion or obstruction. * Nasal discharge. * Facial pain or pressure. * Headache. * Olfactory disturbance.

79 • Minor: * Fever * Halitosis. OR 2. Four episodes per year of recurrent acute rhinosinusitis, each lasting at least 10 days. In association with Persistent changes on computed tomography 4 weeks after medical therapy without intervening acute infection.

The criteria for diagnosis of asthma were (Moxham & Costello, 1997;Crompton & Haslett, 1995;Bames & Godfrey, 2000): 1. Reversible airway obstruction that varied markedly, both spontaneously and with treatment. 2. Intermittent experience of wheeze (usually worse on expiration and characteristically relieved by inhaled B] agonists), cough (usually unproductive), shortness of breath (not always associated with wheeze) and chest tightness. 3. The possibility of being triggered by a number of factors including allergens, irritants, physical factors, emotions, occupational agents, food additives, changes in the weather, endocrinal factors and upper respiratory tract viral infections. 4. Reduction of FEVl, FEV1% and PEF during the attacks.

2.3 Exclusion criteria The exclusion criteria included: 1. Pregnancy and lactation. 2. Patients with significant psychological problems. 3. Patients with learning difficulties or inability to comply with study protocol. 4. Children under 18 years of age.

80 5. Systemic diseases affecting the nose, including Wegener’s disease, sarcoidosis, cystic fibrosis and primary abnormalities of mucociliary clearance. 6. Acute upper or lower respiratory tract infections within two weeks prior to the inclusion visit. 7. Use of systemic corticosteroids within four weeks prior to the inclusion visit. 8. Systemic diseases preventing participation in the study. 9. Medical and/or surgical treatments influencing the study.

2.4 Ethics Patients were given both verbal and written explanations of the aim of the study, the object of randomisation, the design of the study, the techniques involved, and the treatment offered. They also had an opportunity to discuss any points of concern and to receive satisfactory answers to all their questions. They were then given a written consent to sign which allowed them to unconditionally withdraw from the study should they choose to do so. The protocol of the study and the methods of consent had been approved by the Royal Free Hospital and Medical School Ethics Committee.

2.5 Setting Patients were examined in a dedicated rhinology laboratory in the Royal National Throat, Nose and Ear Hospital, with all tests taking place between 10 AM and 6 PM. The rooms used were at a comfortable room temperature around 20° C and an acceptable level of background noise throughout the test periods. All patients remained seated for 20 minutes to acclimatize before any measurements being performed. Patients were requested to blow their nose prior to testing. Calibration of the machines was performed before every series of measurements. All tests were carried out in the sitting position, with the exception of spirometry, which was performed while standing. In all cases.

81 endoscopie examination of the nose was performed after the other tests with the setting proceeding in the following order: 1. History, introduction to the instruments and filling in the questionnaires during the acclimatization period. 2. Nasal examination including anterior rhinoscopy 3. Nasal and exhaled nitric oxide measurements. 4. Acoustic rhinometry. 5. Saccharine clearance test 6. Spirometry. 7. Nasal endoscopy.

2.6 Documentation A detailed sheet was completed for each setting for ease of data collection and analysis. The main data proforma constitutes Appendix I.

2.7 Study reporting considerations The revised recommendations of the Consolidated Standards of Reporting Trials (CONSORT) group on reporting randomised controlled trials were considered in reporting this study (Moher et al, 2001 ).

2.8 Study design This study was designed with the help of a professional statistician, aiming at a prospective randomised controlled study in patients suffering from chronic rhinosinusitis with or without asthma. All patients who agreed to take part in the study were given an initial 6-week regimen of intranasal steroids and alkaline nasal douche. Those who did well on that treatment were excluded from the study, whereas a CT scan was ordered for the patients whose sinus problems were not controlled. If the CT scan showed persistent changes, the patient was enrolled in the study and according to the randomisation code he/she was assigned either to the medical or the surgical group. Each patient

82 had three assessments: before starting the treatment, after six months and finally after one year. The study design is shown in Figure 2.1.

Fig.2.1 Study design

Patients of chronic rhinosinusitis with or without asthma

Initial medical treatment for chronic rhinosinusitis for six weeks

Failed Improved

No persistent changes-

E xcluded from the studyCT scan Excluded from the studyCT

Persistent changes

Randomisation

-First set of investigations

Medical treatment Surgery followed by medical treatment

Second set of investigations after 6 months

Third set of investigations after 1 year

83 2.9 Specific methods 2.9.1 H istory Patients were asked about their nasal symptoms. Nasal blockage or congestion, nasal discharge, olfactory disturbance, facial pain or pressure, headache and overall discomfort were used for the scoring criteria. Using a visual analogue scale (Lund & Kennedy, 1995), the patients were asked to indicate the above symptoms. Each symptom was represented by a 10 cm unmarked line labelled between 0 at the beginning and 10 at the terminus, with 0 indicating no symptoms and 10 indicating greatest severity. The patients were asked to mark their current level of symptoms on the line. These marks were measured to provide a score of 0-10 for each symptom and a total score was also calculated for each visit. Other symptoms including running nose, colour and consistency of the discharge, itchy nose, sneezing, nasal bleeding, nasal tone of voice, mouth breathing, snoring, halitosis and fever were listed as diagnostic criteria but not for staging purposes.

Patients were also requested to report any chest symptoms, such as wheezing, difficulty in breathing, cough, haemoptysis and chest pain, as well as any history of chest infections. The onset of their symptoms, the correlation between the nasal and chest symptoms and any particular time, place or condition that could worsen their symptoms, were described as well. Asthma symptoms were graded as 0 (no symptoms), 1 (symptoms present but causing little or no discomfort), 2 (symptoms present and troublesome but not causing interference with either daily activities or with sleep), 3 (symptoms present, troublesome and interfering with either daily activities or with sleep) or 4 (symptoms intolerable). On the other hand, overall asthma control was scored as 0 (not controlled), 1 (slightly controlled), 2 (adequately controlled), 3 (well controlled) or 4 (very well controlled).

Other relevant history was noted such as allergy, smoking, alcohol, aspirin intolerance, drug sensitivity, family history of allergy or similar conditions.

84 systemic diseases, hospitalisation, nasal trauma, nasal surgery and topical or systemic medications.

2.9.2 Examination of the nose Complete nasal examination including external and intranasal assessment was performed. The nasal cavities were examined with a bulls eye mirror and a Thudicum’s nasal speculum.

Nasal endoscopy was performed using a 4 mm diameter rigid Hopkins rod lens telescope (Karl Storz, West Germany) with an angle of 30 degrees. Occasionally, 2.7 mm diameter and 0 degree angle telescopes were used. A rubber coated fiberoptic cable and a portable light source (CLS 100-1 compact light source; Rimmer Brothers, London, United Kingdom) was used for illumination. A local anaesthetic (Legnocaine 5% solution) and a suction tip were used when necessary. The patient was placed sitting with his head turned to the right towards the side of the examiner. Endoscopy of the nose was accomplished in an organized manner with three passes of the telescope. Initially the telescope was passed along the floor of the nose to evaluate the overall anatomy, the condition of the nasal mucosa, the presence of pathologic secretions and the nasopharynx. Then, the telescope was reinserted between the middle and inferior turbinates to examine the anterior and inferior aspects of the middle meatus, the fontanelles and any accessory maxillary sinus ostia. The sphenoethmoidal recess was visualized, if possible, by passing the telescope medial to the middle turbinate and by rotating it superiorly and slightly laterally, the superior turbinate and meatus were inspected. The third pass was performed as the endoscope was withdrawn by rotating it laterally under the middle turbinate into the posterior aspect of the middle meatus to examine the bulla ethmoidalis, the hiatus semilunaris, the infundibular entrance, the uncinate process, the frontal recess area and occasionally the maxillary ostium.

85 Two endoscopic scoring systems were applied in the study. The first one (Lund & Mackay, 1993) was used in all cases of the study applying a 0-2 score, with the endoscopic appearance being quantified for the presence of polyps (O=none, l=confined to the middle meatus, 2=beyond the middle meatus), discharge (O=none, l=clear and thin, 2=thick and purulent), oedema (O=none, l=mild, 2=severe), scarring or adhesions (O=none, l=mild, 2=severe) and crusting (O=none, l=mild, 2=severe). Total points were calculated for both sides. The second scoring system was only used in cases of chronic rhinosinusitis with polyposis (Mackay & Lund, 1997). Polyps were scored as 0 (no polyps), 1 (within the middle meatus), 2 (beyond the middle meatus) or 3 (filling the nasal cavity), with the total points being calculated for both nasal cavities.

2.9.3 Skin prick test A skin prick test was done for each patient using the Dome-Hollister-Stier prick test allergens distributed by Bio-Diagnostics Limited, Worcestershire, United Kingdom. History of anaphylaxis, significant eczema and dermographism were enquired about before testing the patient. The patient was also requested not to use oral antihistamines or topical skin corticosteroids 48 hours before the test date. Each patient was tested against house dust, dust mite, moulds, grasses, feathers, trees, cats, dogs and sheep wool allergens. A negative and a positive control were used to test the patient’ s reaction to the diluent and histamine respectively. The skin was cleaned and a single drop of each extract was applied to the properly identified test site on the front of the forearm. Using disposable prick lancets, the skin was pierced through the drops and lifted slightly. After about 1 minute the extracts were wiped away. The weal from each substance was recorded and reactions at least 3 mm in diameter greater than the negative control were considered positive.

86 2.9.4 Radiological assessment A CT scan was ordered if the initial medical treatment failed to control the patient s symptoms. Non-enhanced direct coronal sequence with 4 mm cuts on wide window settings was performed in all cases. An axial sequence was performed in extensive CRS affecting posterior ethmoid and sphenoid. CT scans were assessed and scored in order to define the surgical anatomy and the extent of the disease (Lund & Mackay, 1993). Each sinus group was graded as 0 for clear sinuses, 1 for partial opacification or 2 for total opacification, whereas, the ostiomeatal complex was scored only as 0 if it was not included or 2 if it was included. Total points were calculated for both sides. Anatomic variants such as concha bullosa and agger nasi cells were noted but not included in the score.

2.9.5 Nitric oxide measurements 2.9.5a. The equipment A nitric oxide gas analyser (Model LR 2000; Logan Research Limited, United Kingdom) was used in the study. The device simply consisted of sampling tubes, a sampling flow rate selector, a mode selector, a vacuum pump, an ozone generator, a reaction chamber, a photometric detector, a mouth pressure instrumentation, a mouth flow instrumentation, a patient feedback visual display module and a carbon dioxide (CO 2) analyser. The entire system was under the control of a 486 PC computer. The computer utilised the LR2000 analyser system software running within a Microsoft Windows 3.11 operating system environment. The nitric oxide analyser had a range from 1 to 5000 parts per billion (ppb), a sensitivity of 1 ppb, an accuracy of 0.3 ppb and a response time’ (90%) less than 0.5 seconds. The carbon dioxide analyser had a range from 0 to 10%, an accuracy of 0.1% and a response time (90%) of 200

’ The response time is defined as the delay fi'om the introduction of a square-wave signal and achievement of 90% of the maximum signal, inclusive of electronic delays and physical delays because of sample introduction, but not including tubing length.

87 ms. The sampling flow rate was adjusted to 250 ml / minute. The lag time^ at this flow rate was 1.8 and 1,4 seconds for the nitric oxide and carbon dioxide analysers respectively.

2.9.5b. The principle The nitric oxide analyser utilises photometric detection of the chemiluminescence resulting from the reaction of nitric oxide (NO) with ozone. In this reaction, NO] is produced in an electronically excited state. The excited NO] immediately decays to the ground state while emitting light in the spectral region of 600 nm to 2400 nm, with a peak at about 1200 nm. The intensity of the light generated is proportional to the reactant concentration of nitric oxide. The carbon dioxide analyser utilises the infrared absorption principle. It uses a single beam, single wavelength technique.

2.9.5c. General precautions • The recommendations of the European Respiratory Task Force were considered (Kharitonov etal, 1997a). • Patients were requested to avoid alcohol, smoking, medications, eating and strenuous physical exercise for 4 hours before testing. • Periodic flushing of the analyser with dry air and changing of the filters were maintained. • Females were asked about their menstrual cycle and measurements 5 days before and after the cycle were avoided.

• NO measurements were discarded if the patient sneezed, coughed or belched during the test.

^ The lag time is the time between the gas sample leaving the patient and arriving in the first instance at the analyser, inclusive o f the transit time through sample tubing. 2.9.5d. Exhaled nitric oxide measurements • The equipment was checked and the settings were secured. • Ambient NO was recorded to be sure that there was no NO contamination, • The idea and procedures of the test were discussed with the patient. He/She was instructed not to start until the indicator lit up on the patient interface. Nasal clips were not used.

• The test was started up in the ozone phase followed by the zeroing phase and finally the running phase. • The patient was asked to take a deep inspiration and then exhale slowly and steadily through the mouth piece, keeping 80% of the Bio feedback indicator lightening on to allow a constant exhalation flow rate of 200 ml / second and to maintain a mouth pressure of about 5 cm water. This mouth pressure level should close the velopharyngeal aperture preventing contamination of the exhaled air by the high levels

of nasal NO. • The value of the last plateau part of the exhaled NO trace was recorded representing the lower respiratory tract sample. This was confirmed by

measuring the corresponding CO 2 level. • The mean of three recordings was used as the estimate of the exhaled NO level. Two minutes were allowed between consecutive recordings.

2.9.5e. Nasal nitric oxide measurements • The equipment was checked and the settings were adjusted.

• Ambient NO was recorded to be sure that there was no NO contamination. • The idea and procedures of the test were discussed with the patient. He/She was instructed not to start until the indicator lit up on the patient interface. The test was performed without a nose clip or a mouthpiece.

89 • The test was started up in the ozone phase followed by the zeroing phase and finally the running phase. • The patient was asked to take a deep inspiration and to hold his breath to keep the soft palate closed while sampling from the nostril. This

was confirmed by the absence of CO 2 increase during sampling. • The value of the last plateau part of the nasal NO trace was recorded. • The mean of three recordings was used as the estimate of the nasal NO level. Two minutes were allowed between consecutive recordings. • The process was repeated through the other nostril.

2.9.6 Acoustic rhinometrv 2.9.6a. The equipment Acoustic rhino meter Al 12 (G.M.Instruments Ltd, Kilwinning, UK) with a software release 3.02 was used in the study. The device consisted of a spark source, a sound tube, a nosepiece, a customised stand, a microphone, an amplifier and a programmed IBM compatible computer. The nosepieces were modified test tubes with a length of 7 cm and an internal diameter of 8, 10 or 12 mm. They were housed in a 1 cm recess in the end of the sound tube. The default software settings were used for the parameters of most interest, which were minimum cross-sectional area and nasal cavity volume from 0 to 7 cm from the end of the nosepiece.

2.9.6b. The principle The sound impulse is generated by the spark source, propagating in the sound tube and entering the nasal cavity through the nosepiece. Then, it is reflected by local variations in the nasal cross-sectional areas, recorded by the sensitive microphone and amplified by the amplifier. The programmed IBM compatible computer is used for data acquisition and analysis. From these measurements, the cross-sectional area is calculated and plotted as a function of the distance into the nasal cavity and, by integration of the curve, the volume of the nasal cavity is assessed.

90 2.9.6c. The test sequence • The equipment was checked and the settings were adjusted.

• The idea and procedures of the test were discussed with the patient. He/she was instructed to sit erect in the chair, to keep their head perpendicular to the horizontal plane and to hold their breath during the measurement. He/She was also asked not to move or swallow or speak during the test. • The appropriate nosepiece size was chosen for each nostril and fitted in the sound tube. • The angle and height of the sound tube were adjusted to give the minimum deformity of the nostrils and the maximum comfort for the patient. The nosepiece was positioned parallel to the sagittal plane of the head. • Five measurements were taken for each side and were accepted if the coefficient of variation for the intra-test determination of nasal volume was less than 5 %. • The test was repeated three times and estimates of minimum cross- sectional area and volume of the nasal cavity were calculated fi'om the mean of the three sets. • The process was repeated on the other side. • The same nosepiece size and angle were used in the follow-up measurements.

2.9.7 Saccharine clearance test The mucociliary transport time was investigated by using saccharine particles of 0.5 mm diameter. A saccharine particle was placed on the lateral nasal wall, 1 cm behind the anterior end of the inferior turbinate using the endoscope. The patient was instmcted to avoid sniffing, sneezing, eating, drinking or blowing his nose. He/she was also asked to sit quietly and to swallow once a minute. The transport time was measured from the placement of the saccharine

91 particle to the first perception of the saccharine taste. If no taste was noticed within one hour, the test was aborted and a piece of the saccharine was placed on the tip of the tongue to test the subject’s ability to taste the saccharine. The nature of the test substance was unknown to the patient.

2.9.8 Spirometry 2.9.8a. The equipment A spirometer (Model Vitalograph 2160; Vitalograph Limited, Buckingham, England) was used in the study. Briefly, the device consisted of a mouthpiece, a bacteria/viral filter, a breathing tube, a chart carrier, a stylus, dry wedge bellows and a keypad/display unit. The spirometer had a volumetric accuracy of 3% or 50 ml whichever was greater and a maximum recording volume of 8 litres. The spirometric standards complied with the European Respiratory Society recommendations (European Respiratory Society, 1993).

2.9.8b. The principle The vitalograph 2160 spirometer measures the expired lung volumes by means of a wedge-shaped bellows that inflates as air enters into them. When the subject exhales into the breathing tube, the bellows inflates and the stylus needle moves across the chart. The stylus needle traces either a straight line representing the amount of air exhaled (VC test) or a curved line showing the amount of air exhaled with respect to time (FVC test). The deflection of the stylus results in voltage changes which are sent to the electronics assembly in the top cover where the results are automatically calculated and displayed.

2.9.8c. The test sequence • The equipment was checked and the settings were adjusted. • The patient was asked to hold the breathing tube in one hand away from his mouth and breath in and out normally. • Then, he/she was instructed to inhale as deeply as possible, to insert the mouth piece into their mouth making sure that no air could leak

92 around and to breathe out into the mouth piece as hard and as fast as he/she could.

• Three tests were performed. The spirometer was adjusted to accept the test if the session achieved the European Respiratory Society criteria where the best FVC and the best FEVi must be within 5% or 0.1 Litre, whichever was greater, of the second best.

2.9.9 The quality of life instruments 2.9.9a. The Sinonasal Outcome Test-20 (SNOT-20) (Leopold et al, 1997) SNOT-20, a validated rhinosinusitis specific health-related quality of life instrument, was used in the study. The patients were asked to score a list of 20 symptoms, social and emotional consequences, grading them as 0 (No problem), 1 (Very mild problem), 2 (Mild or slight problem), 3 (Moderate problem), 4 (Severe problem), or 5 (Problem as bad as it could be). Then they were requested to mark the most important 5 items, but these are not directly included in the scoring of SNOT-20. The list included the need to blow the nose, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, facial pain/pressure, difficulty falling asleep, waking up at night, lack of a good night’s sleep, waking up tired, fatigue, reduced productivity, reduced concentration, frustrated/restless/irritable, sad and embarrassed.

2.9.9b. The Short Form 36 Health Survey (SF-36) (Ware, Jr. & Sherboume, 1992) The SF-36, a general health-status quality of life instrument, was used in the study permitting scoring of a set of eight domains. The eight domains were physical functioning (PF), role limitation due to physical problems (RP), role limitation due to emotional problems (RE), social functioning (SF), mental health (MH), Energy/vitality (EV), pain (P) and general health perception (GHP). The number of items involved in the eight domains was ten, four, three, two, five, four, two and five respectively. Change in health was another

93 subscale in the questionnaire but it was not presented in terms of means and standard deviations. Data were collected and scored according to the SF-36 analysis and interpretation manual. Permission to use this measure was obtained from the Medical Outcome Trust, Boston, United States of America. The interpretation of the SF-36 scores is described in Table 2a.

Table 2a The interpretation of the SF-36 scores. Modified from Ware et al.(1992)

Domain Score interpretation Lowest possible score Highest possible score Physical functioning All physical activities All types of physical including bathing or activities including the dressing were limited a most vigorous were not lot due to the patient’s limited at all. health Role limitation due to During the previous 4 During the previous 4 physical problems weeks, the patient had weeks, the patient had problems with work or no problems with work other daily activities as or other daily activities a result of physical as a result of physical health. health

Role limitation due to During the previous 4 During the previous 4 emotional problems weeks, the patient had weeks, the patient had problems with work or no problems with work other daily activities or other daily activities due to emotional due to emotional problems. problems.

94 Social functioning During the previous 4 During the previous 4 weeks, the patient’s weeks, the patient’ s physical health or physical health or emotional problems emotional problems did severely interfered with not interfere with his his normal social normal social activities. activities. Mental health During the previous 4 During the previous 4 weeks, the patient felt weeks, the patient felt nervous and depressed happy, calm and all the time. peaceful all the time. Energy/vitality During the previous 4 During the previous 4 weeks, the patient felt weeks, the patient felt tired and worn out all full of pep and energy the time. all the time. Pain During the previous 4 The patient did not have weeks, pain was very any pain or interference severe and seriously with his work due to interfered with the pain in the previous 4 patient’ s normal work. weeks.

General health The patient believed The patient believed perception that his personal health that his health was was poor and likely to excellent. get worse.

2.9.10 The medical treatment 2.9.10a. The initial medical treatment The initial medical treatment included a six-week regimen of Dexarhinospray (DRS) and an alkaline nasal douche. DRS is an intranasal corticosteroid- decongestant spray containing dexamethasone-21 -isonicotinate and

95 tramazoline hydrochloride as active ingredients. It was delivered as two puffs into each nostril twice daily, with each metered dose containing 20 micrograms of dexamethasone-21-isonicotinate and 120 micro grams of tramazoline hydrochloride. The alkaline nasal douche powder was prepared by the hospital pharmacy in a 1:1 mixture of sodium chloride and sodium bicarbonate. The patients were instructed to add half a level spoonful of the powder to 60 ml of warm water and to sniff it from the cupped hand. A fresh preparation was to be used every time. The douche was also used twice daily. Patients with positive SPT were given allergen avoidance measures.

2,9.10b. The medical treatment for the medically randomised group All patients received a 12-week course of erythromycin, alkaline nasal douche and intranasal corticosteroid preparations. Erythromycin was prescribed orally as 500 mg twice daily for two weeks, followed by 250 mg twice daily for 10 weeks. Alkaline nasal douche was prepared and used as instmcted above. Intranasal corticosteroid preparations, in patients of CRS without polyposis, were given as DRS, two puffs into each nostril, twice daily, for two weeks, followed by a twice daily dose of 100 micrograms (2 sprays) of fluticasone propionate spray into each nostril for 10 weeks. On the other hand, patients suffering CRS with polyposis received a 12-week course of twice daily use of 200 micro grams (6 drops) of fluticasone propionate drops into each nostril. In addition, 3 patients of CRS with polyposis were prescribed a 9-day course of oral prednisolone tablets, 30 mg for 3 days, 20 mg for 3 days and 10 mg for 3 days after failure of the above regimen to control their manifestations. After that, the medical treatment was tailored to the patient’s manifestations.

2.9.10c. The medical treatment after surgery Following endoscopic sinus surgery, all patients were prescribed a two-week course of twice-daily use of 500 mg erythromycin, DRS and alkaline nasal douche. This was followed by a three-month course of twice-daily use of 100 micrograms (2 sprays) of fluticasone propionate intranasal spray, into each

96 nostril and alkaline nasal douche. After that, the medical treatment was tailored to the patient’s manifestations.

2.9.11 The surgical treatment Endoscopic sinus surgery was performed in all patients following the Messerklinger technique (Stammberger, 199le). Surgery was performed using 4 mm diameter, rigid Hopkins rod lens telescopes (Karl Storz, West Germany) with angles of 0 and 30 degrees. All cases were done under general anaesthesia. Nasal cavities were treated with Moffet’s^ solution in the anaesthetic room. The extent of the procedure, including partial middle turbinate reduction, uncinectomy, middle meatal antrostomy, anterior ethmoidectomy, posterior ethmoidectomy, sphenoidectomy and frontal recess surgery, was tailored to the extent of sinus disease as documented by nasal endoscopy and CT scan findings. A microdebrider was used in some cases of CRS with grade 2 and 3 polyposis. At the end of the procedure, a piece of Telfa was inserted into the ethmoidal cavity and taken out on the following day. Operative findings and complications were recorded in every case. Surgical steps were scored according to Lund and Mackay scoring system (Lund & Mackay, 1993). Uncinectomy, middle meatal antrostomy, anterior ethmoidectomy, posterior ethmoidectomy, sphenoidectomy, frontal recess surgery and reduction of the middle turbinate were scored as 0 or 1 points, with 0 awarded if no procedure was done and 1 if surgery was done. Total points were calculated for both sides.

2.10 Statistical methods Professional statistical advice was a fundamental part of designing the study, calculating the sample size, randomising the patients and choosing the appropriate statistical tests for data analysis.

^ The constituents ofM offet’s solution are 2 mis 10% cocaine, 1ml 1/1000 adrenaline and 2 mis 1% sodium bicarbonate.

97 2.10.1 Randomisation In order to maintain exactly equal treatment numbers in both groups, randomisation was done using random blocks. The randomisation list was prepared and transferred to a sequence of sealed envelopes. Each envelope contained the assigned treatment and was marked externally with the trial number. The envelope was opened when the patient formally entered the trial. At the time of randomisation, both the patient and the investigator were not aware of the group assignment.

2.10.2 Sample size The sample size was calculated using Wilcoxon two-sample test, two-sided, at the 5% level of significance to have a statistical power of 80% in detecting a 20 VAS score difference between the two groups. The sample size was determined to be 66 patients using as the primary end point the visual analogue scale for chronic rhinosinusitis. However, the number of the patients intended to be recruited was 90 in order to raise the power of the study as well as to compensate for any loss, which might occur during the follow up period.

2.10 J Statistical analysis Data were entered into a Microsoft ® excel 2000 spreadsheet and the analysis was done using SPSS for windows version 9 statistics software package. Data were expressed as mean ± standard deviation (SD). Spirometric measurements were expressed as % of the predicted values. P-values <0.05 were considered significant. Parametric tests such as paired t test, two-sample t test, analysis of variance and Pearson’s correlations were applied for data that followed or were transformed to a normal distribution. Either logarithmic or square transformation was tried to normalise the distribution so as to allow the use of parametric tests. Non-parametric tests such as Mann-Whitney U test, Wilcoxon signed ranks test. Sign test, Chi-squared test, Kruskal-Wallis test and Kendall’s rank correlation coefficient were applied for data that did not follow a normal distribution. Correlations between parametric data were tested

98 using Pearson’s correlation coefficient, whereas Kendall’s rank correlation coefficient was applied whenever non-parametric data were tested. The correlation between NO and SCT was tested using simple linear regression. The individual tests are described in the appropriate chapters and tables together with the results.

99 3 — Results

Contents Page

3.1 Treatment of chronic rhinosinusitis 101

3.2 Effect of treatment of chronic rhinosinusitis upon 117 concomitant asthma 3.3 Nasal nitric oxide 124

List of tables

Table Location Page

• Baseline data tables Appendix 169 II • CRS study tables Appendix 190 IV • Asthma study tables Appendix 231 VI

List of Figures

Figure Location Page

• Baseline data figures Appendix 174 III • CRS study figures Appendix 208 V • Asthma study figures Appendix 245 VII • Nitric oxide study figures Appendix 249 v n i

100 3.1 Treatment of chronic rhinosinusitis

3.1.1 Participant flow Of 327 eligible patients with a primary diagnosis of chronic rhinosinusitis with or without asthma, 196 refused to participate in a randomised trial, 7 were lost before randomisation and 34 did not meet the inclusion criteria, whereas 90 patients were enrolled in the study. The 90 patients were randomised equally between the medical and surgical arms of the trial. All the 45 medical patients received their treatment, of whom 4 and 7 were unavailable for the 6 and 12-month follow-up periods respectively. In contrast, one patient of the surgical group did not undergo the surgery because she was unavailable, 1 patient missed the 6-month follow-up and 4 patients did not attend the 12-month visit. The number of patients analysed for the primary outcome in the 6 and 12-month follow-up settings was 41 and 38 in the medical group and 43 and 40 in the surgical group respectively. Figure V.l shows the flow chart of the study.

3.1.2 Baseline data 3.1.2a Demographic characteristics The surgical group included 45 patients with the following characteristics: 20 males and 25 females, a mean age of 42 (±13) with a range from 24 to 71 years, 23 asthmatics and 22 non-asthmatics, and 26 CRS without polyposis and 19 CRS with polyposis. The surgical group also included 25 patients with positive SPT, 14 with grass pollen sensitivity, 24 with positive family history of allergy, 2 with a history of aspirin sensitivity and 6 smokers. On the other hand, the characteristics of the 45 medical patients were: 25 males and 20 females, a mean age of 45 (±13) with a range from 26 to 70 years, 20 asthmatics and 25 non-asthmatics, and 29 CRS without polyposis and 16 CRS with polyposis. The medical group also included 24 patients with positive SPT, 13 with grass pollen sensitivity, 24 with positive family history of allergy, 1 with a history of aspirin sensitivity and 7 smokers. The differences

101 in the baseline demographic characteristics between the surgical and medical groups were statistically insignificant (P > 0,05).

Of the 55 patients suffering CRS without polyposis, 26 were randomised to the surgical and 29 to the medical group. The characteristics of the surgical patients were: 8 males and 18 females, a mean age of 41 (±13) with a range from 24 to 71 years and 11 asthmatics and 15 non-asthmatics. The surgical group included 14 patients with positive SPT, 8 with grass pollen sensitivity, 13 with positive family history of allergy, 1 with a history of aspirin sensitivity and 6 smokers. The medical group characteristics were: 15 males and 14 females, a mean age of 43 (±13) with a range from 26 to 67 years and 10 asthmatics and 19 non-asthmatics. The medical group included 15 patients with positive SPT, 7 with grass pollen sensitivity, 17 with positive family history of allergy and 5 smokers. There were no statistically significant differences between the characteristics of both groups (P > 0.05).

On the other hand, of the 35 patients suffering CRS with polyposis, 19 were randomised to the surgical and 16 to the medical group. The characteristics of the surgical patients were: 12 males and 7 females, a mean age of ±43 (12) with a range from 27 to 71 years and 12 asthmatic and 7 non-asthmatic. The surgical group included 11 patients with positive SPT, 6 with grass pollen sensitivity, 11 with positive family history of allergy and 1 with a history of aspirin sensitivity. The medical group characteristics were: 10 males and 6 females, a mean age of 48 (±14) with a range from 28 to 70 years and 10 asthmatics and 6 non-asthmatics. The medical group included 9 patients with positive SPT, 6 with grass pollen sensitivity, 7 with positive family history of allergy, 1 with a history of aspirin sensitivity and 2 smokers. The differences between the characteristics of the groups were statistically insignificant (P > 0.05).

102 Tables Ila-c demonstrate the demographic characteristics of the groups. Bar charts comparing the percentages of these findings within the surgical and medical groups are shown in Figures III. 1-3.

3.1.2b VAS The surgical patients had a mean VAS of 40 ±11, whereas the medical group showed a mean of 38 ± 9. The means of the individual symptoms were 8 ± 2, 7±2, 7±3,5±4, 5±4 and 8 ± 2 for nasal blockage, nasal discharge, olfactory disturbance, pain, headache and overall discomfort of the surgical patients of CRS. The medical group individual symptom means were 7 ± 2, 8 ± 2 , 6±3,4±3,5±3 and 7 ± 2 respectively. The VAS means observed in the surgical and medical groups of CRS without polyposis were 40 ±11 and 40 ± 10 respectively. On the other hand, patients with CRS with polyposis showed VAS means of 38± 9 and 38 ± 8 for the surgical and medical groups respectively. There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Table lid and Figures 111.4-9 illustrate the means of the baseline VAS and individual symptom scores of the surgical and medical groups.

3.1.2c SNOT The surgical patients had a mean baseline total SNOT score of 2.2 ± 1 and most important 5 item score of 3.8 ± 0.8, whereas the medical group showed a means of 2 ± 0.9 and 3.7 ± 0.8 respectively. The observed means in patients of CRS without polyposis were 2.3 ±0.9 and 3.9 ± 0.9 for the surgical group and 2.1 ± 1 and 3.8 ± 0.9 for the medical group. On the other hand, means of 2 ± 1 and 3.6 ± 0.8 were detected in the surgical and 1.6 ± 0.6 and 3.5 ± 0.7 in the medical divisions of CRS with polyposis. There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups.

103 Figures 111.10-12 show the mean scores of the baseline SNOT of surgical and medical groups.

3.1.2d SF-36 The mean scores of the baseline 8 domains of SF-36 of the surgical group were 76 ± 27 for PF, 53 ± 38 for RP, 60 ± 42 for RE, 66 ± 27 for SF, 64 ± 22 for MH, 52 ± 20 for EV, 62 ± 29 for P and 58 ± 20 for GHP, whereas the medical group showed mean scores of 81 ±21 for PF, 61 ±39 for RP, 66 ± 39 for RE, 68 ± 27 for SF, 67 ± 21 for MH, 57 ±19 for EV, 62 ± 22 for P and 61 ±21 for GHP. The mean scores of the 8 domains of the surgical patients of CRS without polyposis were 73 ±30 for PF, 42 ± 37 for RP, 45 ± 41 for RE, 60 ± 26 for SF, 59 ± 24 for MH, 50 ± 18 for EV, 56 ± 27 for P and 60 ± 18 for GHP, whereas the medical group showed mean scores of 81 ±21 for PF, 57 ± 42 for RP, 56 ± 42 for RE, 67 ± 28 for SF, 67 ± 22 for MH, 56 ± 18 for EV, 56 ± 21 for P and 60 ± 23 for GHP. The mean scores of the 8 domains of the surgical patients of CRS with polyposis were 81 ±21 for PF, 68 ± 35 for RP, 79 ± 36 for RE, 74 ± 28 for SF, 70 ±16 for MH, 55 ± 22 for EV, 70 ± 30 for P and 55 ± 23 for GHP, whereas the medical group showed mean scores of 81 ± 22 for PF, 67 ± 33 for RP, 83 ± 26 for RE, 69 ± 25 for SF, 68 ± 18 for MH, 60 ± 20 for EV, 74 ± 19 for P and 63 ±16 for GHP. The differences between the medical and surgical groups were statistically insignificant (P > 0,05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Figures 111.13-15 show the mean scores of the baseline SF-36 eight domains of surgical and medical groups.

3.1.2e Saccharine clearance time The mean baseline SCT of the surgical patients of CRS was 23.9 ± 12minutes, whereas that of the medical group was 20.8 ± 9 minutes. The means detected in patients of CRS without polyposis were 19.7 ± 7.9 and 19 ±7 minutes for the surgical and medical groups respectively, whereas the surgical and

104 medical groups of CRS with polyposis showed means of 30.4 ± 14.5 and 24.8 ±11.5 minutes respectively. The differences in the baseline SCT amongst the groups were statistically insignificant (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Table H e shows means, standard deviations and ranges of SCT. Figures IU.16-18 illustrate medians and interquartile ranges of the same data.

3,1.2f Total nasal nitric oxide levels The surgical patients had a mean baseline total nasal nitric oxide level of 723 ± 486 ppb, whereas the medical group showed a mean of 773 ± 426 ppb. On the other hand, higher means were detected in patients with CRS without polyposis. The means were 918 ± 477 and 976 ± 350 ppb for the surgical and medical groups respectively. In contrast, patients with CRS with polyposis showed lower means, which were 468 ± 373 and 405 ± 283 ppb for the surgical and medical groups respectively. There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Table I l f shows means, standard deviations and ranges of the baseline total nasal nitric oxide levels. Figures 111.19-21 illustrate medians and interquartile ranges of the baseline NO data.

3.1.2g Total nasal volume The mean baseline total nasal volumes of the surgical and medical groups were 15.78 ±6.13 and 15.99 ± 6.39 cm3 respectively. The surgical and medical groups of CRS without polyposis had means of 17.66 ±1.13 and 18.6 ± 6.08 cm^ respectively. 13.31 ±5.94 and 11.24 ±3.6 cm^ were the mean total nasal volumes of the surgical and medical groups of CRS with polyposis. The differences between the medical and surgical groups were statistically insignificant (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Means, standard

105 deviations and ranges of the baseline total nasal volumes are expressed in Table Ilg. Box plots of the data are shown in Figures 111.22-24.

3.1.2h Total minimum cross-sectional area The surgical patients had a mean baseline total MCA of 0.93 ± 0.43 cm^, whereas the medical group showed a mean of 0.87 ± 0.35 cm^. The observed means in patients of CRS without polyposis were 1.04 ±0.43 and 1.01 ± 0.34 cm^ for the surgical and medical groups respectively. Means of 0.80 ±0.41 and 0.62 ± 0.22 cm^ were detected in the surgical and medical divisions of CRS with polyposis respectively. There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Table Ilh and Figures 111.25-27 illustrate the baseline total nasal MCA information.

3.1.21 Endoscopic Score The mean baseline total endoscopic scores of the surgical group and medical groups were 5.6 ± 1.8 and 6 ± 1.7. The surgical and medical groups of CRS without polyposis had means of 5 ± 1.5 and 5.5 ± 1.4 respectively. On the other hand, 6.3 ± 2 and 7.2 ± 1.6 were the mean endoscopic scores of the surgical and medical groups of CRS with polyposis. The differences between the medical and surgical groups were statistically insignificant (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Means, standard deviations and ranges of the baseline endoscopic scores are expressed in Table Hi.

3.1.2J CT score The surgical patients had a mean CT score of 14 ± 0.8, whereas the medical group showed a mean of 12 ± 0.7. The observed means in patients of CRS without polyposis were 10 ± 3 and 9 ± 2 for the surgical and medical groups respectively. Means of 18 ± 5 and 16 ±5 were detected in the surgical and

106 medical divisions of CRS with polyposis respectively. There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). Likewise, no significant difference was found between the asthmatic medical and surgical groups. Table I lj and Figures IIL28-30 illustrate CT score information.

3.1.3 Evaluation and comparison of the surgical and medical treatment of CRS

3.1.3a VAS In the 6 and 12-month follow up settings, all groups experienced a significant improvement in the total VAS as well as the individual symptom scores (P < 0.01). Changes in the olfactory disturbance parameter in the medical group of CRS with polyposis were only significant at 95% confidence level (P < 0.05). There was no statistical evidence for differences between the medical and surgical groups (P > 0.05). All groups consistently tended to show a slightly better improvement when compared to the 6 month VAS except for the medical group of CRS with polyposis, which showed a higher improvement percentage (8.5% difference). However, the differences between the 6 and 12- month VAS and individual symptom scores were statistically insignificant in all groups (P>0.05). Table IVa, b, m, n and o illustrate changes and significance tests of VAS in the medical and surgical groups.

In the 6-month follow up setting, the surgical patients had a mean VAS improvement percentage of 49.7 ± 27.9, whereas the medical group showed a mean improvement percentage of 45.3 ± 26.9. The VAS improvement percentage means observed in the surgical and medical groups of CRS without polyposis were 46.6 ± 30.5 and 40.9 ± 30.2 respectively. On the other hand, patients with CRS with polyposis showed VAS improvement

107 percentage means of 54 ± 24.4 and 52.7 ± 18.3 for the surgical and medical groups respectively.

In the 12-month follow up setting, the surgical patients had a mean VAS improvement percentage of 51.6 ± 30, whereas the medical group showed a mean improvement percentage of 50.4 ± 29. The VAS improvement percentage means observed in the surgical and medical groups of CRS without polyposis were 48.7 ± 32.7 and 44.8 ±31.9 respectively. On the other hand, patients with CRS with polyposis showed VAS improvement percentage means of 54.7 ± 27.3 and 61.2 ± 19.1 for the surgical and medical groups respectively.

Similarly, the asthmatic surgical and medical groups showed significant improvement in VAS in the 6 (P < 0.01, paired t-test) and 12-month (P < 0.01, paired t-test) settings. No significant difference was found either between the asthmatic surgical and medical groups (P>0.05, two sample t-test) or between the 6 and 12-month settings (P>0.05, paired t-test).

Figures V.2-15 illustrate the changes of the VAS and the individual symptom score means of the surgical and medical groups.

3.1.3b SNOT In the 6 and 12-month follow up settings, The total SNOT and the most important 5 item scores showed a significant improvement in all groups (P<0.01, Wilcoxon test), whereas there was no statistical evidence for differences between the medical and surgical groups (P>0.05, Mann-Whitney test). The differences between the 6 and 12- month scores were statistically insignificant in all groups (P >0.05, Wilcoxon test) except for the total SNOT of the medical group of CRS with polyposis (P < 0.05, Wilcoxon test).

108 In the 6-month follow up setting, The surgical patients had a mean improvement percentage in the total SNOT score of 49.3 ± 33.7 and in the most important 5 item score of 49.5 ± 30, whereas the medical group showed mean improvement percentages of 40.2 ± 27.67 and 43.4 ± 31.3 respectively. The observed improvement percentage means in patients of CRS without polyposis were 44.6 ± 32.4 and 44.4 ± 30.2 for the surgical group and 36.7 ± 31.3 and 40.7 ± 35.6 for the medical group. On the other hand, mean improvement percentages of 55.4 ± 35.3 and 55.9 ± 30.2 were detected in the surgical and 46.4 ± 19.3 and 48.3 ± 22.5 in the medical divisions of CRS with polyposis.

In the 12 month follow-up setting, the surgical patients had a mean improvement percentage in the total SNOT score of 52.5 ± 32.8 and in the most important 5 item score of 53.6 ± 31.3, whereas the medical group showed mean improvement percentages of 46 ± 32.9 and 49 ± 33.6 respectively. The observed improvement percentage means in patients of CRS without polyposis were 45.3 ± 34.7 and 48.5 ± 33.3 for the surgical group and 39.9 ± 37.7 and 43.9 ± 38.3 for the medical group. On the other hand, mean improvement percentages of 60.5 ± 29.6 and 59.3 ± 28.7 were detected in the surgical and 57.8 ± 16.1 and 58.9 ± 19.6 in the medical divisions of CRS with polyposis.

Likewise, the asthmatic surgical and medical groups showed significant improvements (P<0.01 in total groups and <0.05 in subgroups, Wilcoxon test) in the total SNOT and the most important 5 item scores, whereas there was no statistical evidence for differences between the medical and surgical groups (P>0.05, Mann-Whitney test). The differences between the 6 and 12- month scores were statistically insignificant in all groups (P > 0.05, Wilcoxon test) except for the total SNOT of the medical group of CRS with polyposis (P < 0.05, Wilcoxon test).

109 Figures V.16-19 show changes in the mean SNOT scores of surgical and medical groups.

3.1.3c SF-36 In the 6 and 12 month follow-up setting, PF did not change significantly from the baseline in all groups (?>0.05, Wilcoxon test), whereas the other 7 domains showed a significant improvement (?<0.01, Wilcoxon test). The differences between the medical and surgical groups were statistically insignificant (?>0.05, Mann-Whitney test). The differences between the 6 and 12-month EV scores were statistically significant (?<0.05, Wilcoxon test), whereas the other 7 domains were not (P > 0.05, Wilcoxon test).

Likewise, the asthmatic surgical and medical groups behaved the same. Physical Functioning domain did not change significantly from the baseline in all groups (P>0.05, Wilcoxon test), whereas the other 7 domains showed a significant improvement (P<0.01, Wilcoxon test). The differences between the medical and surgical groups were statistically insignificant (P>0.05, Mann- Whitney test).

Figures V.20-35 show changes in the mean the SF-36 scores of surgical and medical groups.

3.1.3d Saccharine clearance time In the 6 and 12-month follow-up setting, SCT improved significantly (P < 0.01), whereas there was no statistical evidence for differences between the medical and surgical groups (P > 0.05). The differences between the 6 and 12 month SCT were statistically insignificant (P > 0.05) except for the medical group of CRS with polyposis (P < 0.05). Table IVc, d, p, q, r and s illustrate changes and significance tests of SCT in the medical and surgical groups.

110 In the 6-month follow-up setting, the mean SCT improvement percentage of the surgical patients was 30.1 ± 20.3, whereas that of the medical group was 26.8 ± 21.5. The mean improvement percentages detected in patients of CRS without polyposis were 24.2 ± 15.8 and 20.1 ± 20.8 for the surgical and medical groups respectively, whereas the surgical and medical groups of CRS with polyposis showed mean improvement percentages of 38 ± 23.4 and 41.3 ±15.3 respectively.

In the 12-month follow-up setting, the mean SCT improvement percentage of the surgical patients was 32.2 ± 20.3, whereas that of the medical group was 30.6 ±21.8. The mean improvement percentages detected in patients of CRS without polyposis were 28.6 ± 17.6 and 24.2 ± 20.5 for the surgical and medical groups respectively, whereas the surgical and medical groups of CRS with polyposis showed mean improvement percentages of 37.2 ± 22 and 45 ± 18 respectively.

Likewise, the asthmatic surgical and medical groups showed a significant improvement in SCT (P<0.01 in total groups and <0.05 in subgroups, Wilcoxon test). There was no statistical evidence for differences either between the medical and surgical groups (P>0.05, Mann-Whitney test) or between the 6 and 12- month settings (P > 0.05, Wilcoxon test).

Figures V.36 and V.37 illustrate the changes in the mean SCT of the surgical and medical groups.

3.1.3e Total nasal nitric oxide levels In the 6 and 12-month settings, NO increased significantly when compared to the baseline levels (P < 0.01). The mean improvement percentages from the baseline were consistently higher in the surgical groups. However, the differences between the surgical and medical groups did not reach statistical significance (P > 0.05). The differences between the 6 and 12-month levels

111 were statistically insignificant in all groups (P > 0.05) except for the medical group of CRS with polyposis (P < 0.01). Table I V e , f p, q, r and s illustrate changes and significance tests of total nasal NO in the medical and surgical groups.

In the 6-month follow-up setting, the surgical patients had a mean improvement percentage of 117 ± 172.7, whereas the medical group showed a mean improvement percentage of 80.1 ± 110.7. The mean improvement percentages detected in patients with CRS without polyposis were 56 ± 60.6 and 40.4 ± 53.3 for the surgical and medical groups respectively. Patients with CRS with polyposis showed mean improvement percentages of 190.9 ± 230 and 149.1 ± 147.9 for the surgical and medical groups respectively.

In the 12-month follow-up setting, the surgical patients had a mean improvement percentage of 129.4 ± 180, whereas the medical group showed a mean improvement percentage of 92.7 ± 127.6. The mean improvement percentages detected in patients of CRS without polyposis were 67.3 ± 63.1 and 46.5 ± 52.4 for the surgical and medical groups respectively. Patients with CRS with polyposis showed mean improvement percentages of 198 ± 237.3 and 181.5 ± 178.2 for the surgical and medical groups respectively.

Similarly, the asthmatic surgical and medical groups showed significant improvements (P<0.001 in total groups and <0.01 in subgroups, Paired t-test) in the total nasal NO measurements, whereas there was no statistical evidence for differences between the medical and surgical groups (P>0.05, Two sample t-test). The differences between the 6 and 12- month levels were statistically insignificant in all groups (P > 0.05, Paired t-test) except for the medical group of CRS with polyposis (P < 0.05, Paired t-test).

Figures V.38 and V.39 illustrate the changes in the mean total nasal NO levels of the surgical and medical groups.

112 3.1.3f Total nasal volume The 6 and 12-month nasal volumes of the medical group of CRS without polyposis did not show any significant changes from the baseline measurements, whereas the other groups did increase significantly (P < 0.01). The differences between the surgical and medical groups were significant in CRS without polyposis (P < 0.01) but not in CRS with polyposis (P > 0.05). Differences between the 6 and 12-month nasal volumes were insignificant in all groups (P > 0.05). However the medical group of CRS with polyposis showed a higher tendency for improvement (8.4% difference). Table IVg, h, p, q, r and s illustrate changes and significance tests of total nasal volume in the medical and surgical groups.

In the 6-month follow-up setting, the mean volume improvement percentages of the surgical and medical groups were 37.9 ± 35 and 17.3 ± 33 respectively. The surgical and medical groups of CRS without polyposis had mean improvement percentages of 21.8 ± 23 and 3.2 ± 11.9 respectively. On the other hand, 57.3 ± 37.6 and 41.9 ± 42.8 were the mean improvement percentages of the surgical and medical groups of CRS with polyposis respectively.

In the 12-month follow-up setting, the mean volume improvement percentages of the surgical and medical groups were 37.5 ± 35.9 and 20 ± 38.1 respectively. The surgical and medical groups of CRS without polyposis had mean improvement percentages of 18.1 ± 15.8 and 4.3 ± 14.1 respectively. On the other hand, 58.8 ± 40 and 50.3 ± 50.7 were the mean improvement percentages of the surgical and medical groups of CRS with polyposis respectively.

The 6 and 12-month nasal volumes of the asthmatic groups of CRS without polyposis did not show any significant changes from the baseline

113 measurements (P>0.05, Wilcoxon test), whereas the other groups did increase significantly (P<0.01, Wilcoxon test). The differences between the surgical and medical groups were significant in CRS without polyposis (P<0.05, Mann-Whitney test) but not in CRS with polyposis (P>0.05, Mann-Whitney test). Differences between the 6 and 12-month nasal volumes were insignificant in all groups (P>0.05, Wilcoxon test).

Figures V.40 and V.41 illustrate the changes in the mean total nasal volume of the surgical and medical groups.

3.1.3g Total minimum cross-sectional area The 6 and 12-month MCA in CRS with polyposis showed a significant increase from the baseline values (P < 0.01). In contrast, the MCA changes in CRS without polyposis did not reach statistical significance (P > 0.05). The differences between the surgical and medical groups as well as between the 6 and 12-month MCA were statistically insignificant (P > 0.05). Table IV i,j, p, q, r and s illustrate changes and significance tests of total MCA in the medical and surgical groups.

In the 6-month follow-up setting, the surgical patients had a mean MCA improvement percentage of 43.7 ± 78.2, whereas the medical group showed a mean of 25.4 ± 51. The observed mean improvement percentages in patients of CRS without polyposis were 8.5 ± 30.4 and 5.8 ± 16.4 for the surgical and medical groups respectively. On the other hand, mean improvement percentages of 86.1 ± 96.5 and 59.2 ± 70.9 were detected in the surgical and medical divisions of CRS with polyposis respectively.

In the 12-month follow-up setting, the surgical patients had a mean MCA improvement percentage of 42.4 ± 79, whereas the medical group showed a mean improvement percentage of 29.8 ± 61.1. The observed mean

114 improvement percentages in patients of CRS without polyposis were 10.3 ± 24.2 and 5.7 ± 16.6 for the surgical and medical groups respectively. On the other hand, mean improvement percentages of 77.9 ± 101.6 and 76.1 ± 86.2 were detected in the surgical and medical divisions of CRS with polyposis respectively.

The 6 and 12-month MCA of the asthmatic groups of CRS without polyposis did not show any significant changes from the baseline measurements (P>0.05, Wilcoxon test), whereas the other groups did increase significantly (P<0.01, Wilcoxon test). The differences between the surgical and medical groups were significant in CRS without polyposis (P<0.05, Mann-Whitney test) but not in CRS with polyposis (P>0.05, Mann-Whitney test). Differences between the 6 and 12-month nasal volumes were insignificant in all groups (P>0.05, Wilcoxon test).

Figures V.42 and V.43 illustrate the changes in the mean total MCA of the surgical and medical groups.

3.1.3h Endoscopic Score In the 6 and 12-month settings, endoscopic scores increased significantly when compared to the baseline levels (P<0,01). No statistical evidence for significant difference was detected amongst the surgical and medical groups (P>0.05). The differences between the 6 and 12-month scores were statistically insignificant as well (P>0.05). Table IVk, /, p, q, r and s illustrate changes and significance tests of total endoscopic score in the medical and surgical groups.

In the 6-month setting, the mean improvement percentage of the surgical group and medical groups were 58.7 ± 32.1 and 56.2 ±26.4. The surgical and medical groups of CRS without polyposis had mean improvement percentage of 54.8 ± 38 and 52.8 ± 30.2 respectively. On the other hand, 63.7 ± 22.7 and

115 62 ± 17.8 were the mean improvement percentages of the surgical and medical groups of CRS with polyposis.

In the 12-month setting, the mean improvement percentage of the surgical group and medical groups were 62.6 ± 33.3 and 60.7 ±26.3. The surgical and medical groups of CRS without polyposis had mean improvement percentage of 62.3 ± 39.1 and 58.3 ± 30.1 respectively. On the other hand, 62.9 ± 26.6 and 65.2 ± 16.8 were the mean improvement percentages of the surgical and medical groups of CRS with polyposis.

The 6 and 12-month endoscopic scores in the asthmatic surgical and medical groups increased significantly when compared to the baseline levels (P<0.01in total groups and <0.05 in subgroups, Wilcoxon test). No statistical evidence for significant difference was detected between the surgical and medical groups (P>0.05, Mann-Whitney test). The differences between the 6 and 12- month scores were statistically insignificant as well (P>0.05, Wilcoxon test).

Figures V.44 and V.45 illustrate the changes in the mean endoscopic score of the surgical and medical groups.

3.1.3i Adverse events In the surgical group, a patient suffered epistaxis on the 6^^ post-operative day. She was admitted for nasal packing and intravenous antibiotics. Two patients got sinonasal infection and received courses of antibiotics. Another patient developed a mild synechia between the septum and middle turbinate. On the other hand, one patient in the medical group reported feeling of mild nausea upon using erythromycin but it was tolerable and he continued using the medication. Two further patients developed mild epistaxis. They were asked to stop the nasal spray for a couple of weeks until the condition settled.

116 3.2 Effect of treatment of chronic rhinosinusitis upon concomitant asthma

3.2.1 Participant flow Of 102 eligible patients with a primary diagnosis of chronic rhinosinusitis with asthma, 51 refused to participate in a randomised trial and 8 did not meet the inclusion criteria, thereafter 43 patients were enrolled in the study. Twenty patients were randomised to medical and twenty three to surgical treatment of CRS. All medical patients received their treatment, of whom 1 and 3 were unavailable for the 6 and 12-month follow-up periods respectively. One patient in the surgical group did not undergo the surgery because she was unavailable and 1 patient missed the objective 6-month follow-up. The same patient missed the subjective and objective 12-month setting. The number of patients analysed for the primary outcome in the 6 and 12-month follow-up settings was 19 and 17 in the medical group and 22 and 21 in the surgical group respectively. Figure VII.1 shows the flow chart of the study.

3.2.2 Baseline data 3.2.2a Demographic characteristics The surgical group included 23 patients with the following characteristics: 9 males and 14 females, a mean age of 43 (±14) with a range from 27 to 70 years. Eleven had CRS without polyposis and 12 CRS with polyposis. The surgical group also included 16 patients with positive SPT, 9 with grass pollen sensitivity, 14 with positive family history of allergy, 2 with a history of aspirin sensitivity and 2 smokers. The characteristics of the medical patients were: 11 males and 9 females, a mean age of 45 (±13) with a range from 26 to 68 years. Ten had CRS without polyposis and 10 CRS with polyposis. The medical group included 14 patients with positive SPT, 7 with grass pollen sensitivity, 12 with positive family history of allergy, 1 with a history of

117 aspirin sensitivity and 2 smokers. Differences in the baseline demographic characteristics between the surgical and medical groups were statistically insignificant (P > 0.05).

Of the 21 patients who suffered CRS without polyposis, 11 were randomised to the surgical and 10 to the medical group. The characteristics of the surgical patients were: 3 males and 8 females and a mean age of 45 (±15) with a range from 28 to 67 years. The surgical group included 8 patients with positive SPT, 4 with grass pollen sensitivity, 6 with positive family history of allergy, 1 with a history of aspirin sensitivity and 2 smokers. The medical group characteristics were: 5 males and 5 females and a mean age of 41 (±13) with a range from 24 to 65 years. The medical group included 7 patients with positive SPT, 3 with grass pollen sensitivity, 7 with positive family history of allergy and 1 smoker. There were no statistically significant differences between the characteristics of both groups (P > 0.05).

Of the 22 patients who suffered CRS with polyposis, 12 were randomised to the surgical and 10 to the medical group. The characteristics of the surgical patients were: 6 males and 6 females and a mean age of 41 (±12) with a range from 27 to 70 years. The surgical group included 8 patients with positive SPT, 5 with grass pollen sensitivity, 8 with positive family history of allergy and 1 with a history o f aspirin sensitivity. The medical group characteristics were: 6 males and 4 females, a mean age of 49 (±12) with a range from 34 to 68 years. Differences between the characteristics of the surgical and medical groups were statistically insignificant (P > 0.05). The medical group included 7 patients with positive SPT, 4 with grass pollen sensitivity, 5 with positive family history of allergy, 1 with a history of aspirin sensitivity and 1 smoker.

No significant differences in the baseline demographic characteristics were detected between CRS without and with polyposis within each intervention (P>0.05).

118 3.2.2b Subjective assessment Differences in chest scores, medication use, number of hospitalisation for asthma and overall asthma control score between the medical and surgical groups as well as between CRS without and with polyposis within each allocated treatment were statistically insignificant (P>0.05).

3.2.2c Objective assessment Differences in exhaled NO, FEV1% and PEF between the medical and surgical groups as well as between CRS without and with polyposis within each intervention were statistically insignificant (P>0.05).

3.2.3 Effects of the surgical and medical treatment upon concomitant asthma

3.2.3a Chest score Although there was a general trend for improvement in the chest score of all groups, this only reached statistical significance in the medical group of CRS (Table Via). Interestingly, the surgical group contained variable responses. One patient of CRS without polyposis developed asthma for the first time 3 months after surgery, while another patient of CRS with polyposis reported that his asthma after surgery was worse than any time before. On the other hand, the only patient reporting that asthma highly improved belonged to the surgical group of CRS without polyposis. In contrast, the medical group showed only two variants either improved or no change. No significant difference was observed between the 6 and 12-month chest scores (P>0.05, Sign test). Differences in the chest scores between the medical and surgical groups as well as between CRS without and with polyposis within each intervention were statistically insignificant (P>0.05, Mann-Whitney test).

119 3.2.3b Medication use

• Bronchodilator inhalers There was a consistent decrease in the use of bronchodilator inhalers among all groups. The only patient reporting an increase in bronchodilator use was in the surgical group of the CRS with polyposis. Although changes within the medical groups tended to have a higher significance, differences amongst the surgical and medical groups were statistically insignificant (P>0.05, Mann- Whitney test). Differences between the 6 and 12-month use of bronchodilators (P >0.05, Sign test) as well as between CRS without and with polyposis (P >0.05, Mann-Whitney test) were statistically insignificant as well. Table VIb shows the 6 and 12-month % change (compared to baseline) in use of bronchodilator inhalers.

• Corticosteroid inhalers Changes in the use of corticosteroid inhalers attained no statistical significance (P > 0.05, Sign test) in all groups (Table Vic). Differences in chest scores between the medical and surgical groups as well as between CRS without and with polyposis within each intervention were statistically insignificant (P >0.05, Mann-Whitney test).

• Systemic corticosteroids for asthma In the surgical group, 10 short courses of systemic corticosteroid therapy were required in the 12 months before surgery, whereas only 4 courses were needed postoperatively (P < 0.05, Wilcoxon signed ranks test). The medical treatment of chronic rhinosinusitis also reduced the need of systemic corticosteroid therapy Jfrom 7 courses to only one (P < 0.05, Wilcoxon signed ranks test). No significant difference was found amongst the surgical and medical groups (P > 0.05, Mann-Whitney test). Differences between CRS without and with polyposis within each treatment were statistically insignificant as well (P > 0.05, Mann-Whitney test).

120 3.2.3c Number of hospitalisations for asthma Surgery managed to reduce the number of hospitalisations for asthma from 7 admissions in the preoperative 12 months to only two postoperatively (P < 0.05, Wilcoxon signed ranks test). On the other hand, the medical treatment of CRS reduced it from 5 admissions to only one (P < 0.05, Wilcoxon signed ranks test). Difference between the surgical and medical groups was statistically insignificant (P > 0.05, Mann-Whitney test). No significant difference was detected between CRS without and with polyposis within each intervention as well (P >0.05, Mann-Whitney test).

3.2.3d Overall asthma control score Improvement in the overall asthma control score of the surgical groups was significant only in the total group of CRS with a decreasing significance from the 6 (P < 0.01) to the 12-month (P < 0.05) scores. The medical groups, on the other hand, showed a constant significant improvement in the total group (P < 0.01) as well as in CRS with polyposis (P<0.05). No significant difference was detected between the 6 and 12-month overall asthma control scores (P >0.05, Sign test). Differences in overall asthma control scores between the medical and surgical groups as well as between CRS without and with polyposis within each intervention were statistically insignificant (P>0.05, Mann-Whitney test). Table VId shows the changes in the overall asthma control score.

3.2.3e Exhaled NO During follow-up periods, exhaled NO levels decreased significantly in all groups except the surgical groups of CRS without and with polyposis (P > 0.05). The medical groups tended to have a higher significance than the corresponding surgical groups (Tables Vie and VIJ). Although there was a tendency for lower levels of exhaled NO in the 12-month setting than in the 6-

121 month setting, this tendency did not reach statistical significance except in the medical groups of CRS (P < 0.01) and CRS with polyposis (P < 0.05) (Tables Vim and VIn). The exhaled NO % improvement in the medical groups was consistently higher than the corresponding surgical groups. However, the difference was statistically significant only in CRS with polyposis (P < 0.05) (Tables VJk and VII). Differences between CRS without and with polyposis within each treatment were statistically insignificant as well (P > 0.05). Figure VII.2 and VIL3 illustrate changes in the mean exhaled NO over the 12-month follow-up period.

3.2.3f FEV1% The 6 and 12-month FEV1% of the surgical groups followed the same course with the total group experiencing a significant increase (P<0.05), whereas the subgroups of CRS without and with polyposis failed to attain a significant level of improvement (P>0.05). In the medical groups, the 6-month FEV1% improved significantly only in CRS (P<0.01) and CRS without polyposis (P<0.01). Interestingly, the 12-month FEV1% was significantly better in all medical groups (Tables VIg and VIh). Difference between the 6 and 12- month FEV1% was significant only in the medical group of CRS with polyposis (P<0.05) (Tables Vim and VIn). The same group also differed significantly from its corresponding surgical group (P<0.05) (Tables VIk and VII). Differences between CRS without and with polyposis within each treatment were statistically insignificant (P>0.05). Figure VII.4 and VII.5 illustrate changes in the mean FEV1% over the 12-month follow-up period.

3,2.3g P E F Despite the fact that there was an improvement in PEF of all groups in the follow-up settings, this reached statistical significance only in the medical groups of CRS and CRS without polyposis (Tables VII and VIj). No significant difference was found between the 6 and 12-month PEF (P > 0.05) (Tables Vim and VIn). Differences between the surgical and medical groups

122 as well as between CRS without and with polyposis within each treatment were statistically insignificant (P > 0.05) (Tables VIk and VII). Figure VII.6 and VIL7 illustrate changes in the mean PEF over the 12-month follow-up period.

123 3.3 Nasal nitric oxide

3.3.1 NO and CT score Baseline NO levels correlated significantly with CT scores (P<0.001). The correlation coefficient was -0.483 (Kendall’s tau-b). Furthermore, CT scores were categorised into three grades according to the severity of the changes: grade 1 (0-4), grade 2 (5-8) and grade 3 (9-12). The mean NO levels for the three grades were 537 ± 202, 362 ±188 and 165 ±151 ppb respectively. The differences in baseline NO amongst the groups were statistically significant (P<0.001, Kruskal-Wallis test). The differences between the individual groups were statistically significant as well (P<0.001, Mann-Whitney test). Figure VIII.l shows boxplots of the baseline NO levels versus CT score grades.

3.3.2 NO and SCI Because of the inability to detect SCT, seventeen and twenty-one patients were excluded from the 6 and 12-month analysis respectively. Only one patient showed inability to taste saccharine. Changes in NO concentrations correlated significantly with SCT changes (P<0.001). The Correlation coefficients were -0.676 (Kendall’s tau-b) in the 6 and -0.693 (Kendall’s tau- b) in the 12-month measurements. Figures VIIL2 and Vni.3 demonstrate the negative correlation between the changes in NO and SCT, the equation of simple linear regression and the R-square values. The Equations of simple linear regression were:

6-month SCT improvement (expressed in folds o f the baseline) = 0.92 + {-0.94 X Log 6-month NO improvement (expressed in folds of the baseline)}.

124 12-month SCT improvement (expressed in folds o f the baseline) = 0.92 + {-0.96 X Log 12-month NO improvement (expressed in folds of the baseline)}.

3.3.3 NO and VAS Changes in NO levels correlated significantly (P<0.001) with changes in VAS. The correlation coefficients were -0.298 (KendalTs tau-b) for the 6- month measurements and -0.362 (KendalTs tau-b) for the 12-month measurements. NO changes also correlated significantly with all individual scores (P<0.01) except pain and headache (P>0.05). The sensitivity of NO measurements to detect VAS changes was 98.6%, whereas the specificity was 81.8% for the 6-month results. On the other hand, the sensitivity and the specificity in the 12-month setting were 98.6% and 88.9% respectively. Figures VIIL4 and VIII.5 show scatterplots of NO changes versus VAS changes.

3.3.4 NO and endoscopic score NO changes correlated significantly (P<0.001) with endoscopic score changes. The correlation coefficients were -0.368 (KendalTs tau-b) for the 6- month and -0.317 (KendalTs tau-b) for the 12-month measurements. The endoscopic score changes were recoded into three categories: worse or no change (0 to 50%), mild to moderate improvement (-1 to -70%) and marked improvement (-71 to -100%). The mean percentage NO changes for the three groups were -7 ± 22, 95 ± 123 and 175 ± 225 for the 6-month and 13 ± 16, 107 ± 140 and 168 ± 219 for the 12-month measurements respectively {Figures VIIL6 and VII1.7). The differences in NO changes amongst the groups were statistically significant (P<0.01, Kruskal-Wallis test). The differences in NO changes between each two groups were statistically significant (P<0.01, Mann-Whitney test).

125 3.3.5 NO and nasal polyposis NO changes correlated significantly with the 6-month (P<0.05) and 12-month (P<0.01) polyp grade changes for the 6-month and for the 12-month changes). The correlation coefficients were -0.209 and -0.292 (Kendall's tau-b) respectively. The differences in NO changes amongst the groups were statistically significant (P<0.05, Kruskal-Wallis test). The differences in NO changes between the individual groups did not reach statistical significance (P>0.05, Mann-Whitney test) except when the no change group was included in one side of the equation. Figures VTIL8 and VIII.9 show boxplots of NO changes in relation to polyp grade changes.

3 J.6 NO and surgical score NO changes correlated significantly with surgical score (P<0.01). The correlation coefficients were 0.291 (Kendall's tau-b) and 0.265 (Kendall's tau-b) for the 6 and 12-month measurements respectively. According to the surgical score, patients were divided into two groups; group 1 (score 0-4) and group 2 (score 5-7). The difference in NO changes between the two groups was statistically significant (P<0.01,Mann-Whitney test). Figures VIII.IO and V III.ll illustrate boxplots of NO changes in the surgical score groups.

3.3.7 NO and age No statistical correlation was found between NO changes and age (P>0.05, Pearson’s test). Figures VIII.12 and VIII.13 show scatterplots ofNO changes versus age.

3.3.8 NO and sex Males tended to have a higher degree of NO improvement. The 6 and 12- month mean percentage improvement were 112 ± 113 and 121 ±116 in the male group versus 90 ± 179 and 103 ± 191 in the female group. However, this did not reach any statistical significance (P>0.05, Mann-Whitney test). Figures VIII.14 and VIII.15 show boxplots of NO changes in the two groups.

126 3.3.9 NO and smoking Non-smokers had a higher degree of NO improvement. The 6 and 12-month mean percentage improvement were 109 ± 158 and 120 ± 167 in non-smokers versus 53 ± 57 and 67 ± 55 smokers. However, the difference did not reach statistical significance (P>0.05, Mann-Whitney test). Correlations between number of cigarettes per day and NO changes also failed to attain statistical significance (P>0.05). Figures VIII.16 and VIII.17 show boxplots of NO changes in smokers and non-smokers.

3.3.10 NO and allergy Patients with positive SPT, positive grass pollen sensitivity or positive family history of allergy showed a slightly higher mean NO percentage improvement. However, no statistical significance for this difference could be detected (P>0.05, Mann-Whitney test). Figures VIII.18-23 show boxplots of NO changes in the different groups.

127 4 - Discussion

Contents Page

4.1 Treatment of chronic rhinosinusitis 129

4.2 Effect of treatment of chronic rhinosinusitis upon 140 concomitant asthma

4.3 Nasal nitric oxide 146

4.4 Conclusions 149

128 4.1 Treatment of chronic rhinosinusitis

Developments in medicine and surgery had taken place for centuries without any randomised controlled studies as this type of trial has only been in existence since the late 1940s and only in the last 30 years has it gained a wide spread acceptance and became the recognised standard for conduct of clinical research. The purposes of such randomisation are to avoid bias and to provide a basis for the standard methods of statistical analysis such as significance tests. In non-human experiments, the researcher often has all his experimental units available at once and can maintain tight control over the experiment so that randomisation can usually be implemented with only minor inconvenience. However, this situation is very different for a clinical trial in which the experimental units are patients. The idea that the patient should be randomly assigned to one or other form of treatment is not intuitively accepted by both the clinician and the patient especially when the treatment is a surgical procedure. Likewise, surgical treatment of chronic rhinosinusitis has been traditionally developed over the years as the main therapy without any randomised controlled trial to assess its superiority over medical treatment. Whilst three randomised controlled studies have investigated this issue in nasal polyposis (Lildholdt et al, 1988;Lildholdt et al, 1997;Blomqvist et al, 2001), none has specifically dealt with chronic rhinosinusitis. Therefore, the present study has been designed in a prospective, randomised, controlled fashion to evaluate and compare the surgical and medical treatment of chronic rhinosinusitis.

Three main difficulties were faced in planning and conducting this study. The first was the choice of the antimicrobial therapy, since there is no generally accepted consensus on the microbiology of chronic rhinosinusitis. Microbiologie studies have provided extremely varying results. The variations seem to depend on the sampling technique, the transport system and the specimen processing. Differences amongst the studied population also appear

129 to influence the results, since prior sinus surgery, use of systemic corticosteroids and nasal irrigation have been associated with significantly higher Gram-negative rods (GNRs) and Pseudomonas aeruginosa (Nadel et al, 1998;Brook & Frazier, 2001). Even the presentation and interpretation of the results add more confusion to the situation. Some studies have been presented in terms of percentages of the isolates (Doyle & Woodham, 1991;Biel et al, 1998), whereas others have been reported in percentages of the cultures (Ramadan, 1995;Nadel et al, 1998). Another confiising factor is the lack of correlation between the maxillary, ethmoid and middle meatal cultures. Jiang et al. (1997) described no correlation in 72.5% of the cases between the ho mo lateral ethmoid and maxillary sinuses in the same patients. Similarly, other studies have demonstrated different antral and middle meatal microbiological profiles in the same patients (Karma et al, 1979;Su et al, 1983). In contrast, Klossek et al. (1998) reported an agreement between samples from the middle meatus and the corresponding maxillary sinus cavity in 74% of a selected group (65 cases) of the total 394 CRS patients. However, it should be noted that the selection of this group was not randomised and that identical pathogens were only sampled from 44% of the selected group, whereas the remaining 30% agreed in either having commensals or being sterile. Furthermore, it is still debatable whether most of the isolated organisms represent contaminants from nasal flora and skin or even reflect the commensal flora of the middle meatus and sinuses. Cultures from the middle meatus of normal asymptomatic adults have provided a close match to the most common organisms described in chronic rhinosinusitis studies (Chow et al, 1993;Klossek et al, 1996;Nadel et al, 1999). Busch et al. (1984) also described that the concentration of anaerobic bacteria in the healthy upper airway mucosa can reach 10^* organisms per ml fluid. Therefore, isolation of anaerobic bacteria in chronic rhinosinusitis, in which the mucociliary clearance is impaired, does not necessarily mean that they are the primary cause of the disease. Recently, Kremer et al. (2001) conducted a qualitative and semi-quantitative bacteriological study in patients with chronic

130 rhinosinusitis. Based on their bacteriological findings, a differentiation between patients and control group was not possible. Hence, they concluded that the clinical value of bacteriological examinations of nasal and paranasal mucosa is doubtful in patients with chronic rhinosinusitis. The second difficulty was to determine the duration of the antimicrobial therapy. Short­ term courses of antibiotics have failed to control chronic rhinosinusitis and although the Rhinosinusitis Task Force Committee meeting has suggested 4-6 weeks as a recommended duration of antibiotic treatment for chronic rhinosinusitis, this was not evidence-based, since no studies were performed to determine the optimal length of treatment (Benninger et al, 1997). However, based on previous clinical experience as well as the unique anti­ inflammatory and immunomodulatory actions of macrolides antibiotics such as erythromycin, a 12-week course of erythromycin has been chosen as the antimicrobial agent. The third difficulty was to convince patients to participate in a randomised trial especially when courses of medical treatment had been tried before. This difficulty can be appreciated by considering that of 327 consecutive patients, with whom the study was discussed, 196 (59.9%) refused to take part in such a randomised study and that the recruitment process took place over two years.

In the present study, the medical regimen; 12-week course of low-dose erythromycin, alkaline nasal douche, topical corticosteroids and short courses of oral corticosteroids, when indicated, seems to be an effective, well- tolerated therapy for CRS closing the gap that has been claimed to persist over the past years between the surgical and medical treatment of CRS. Total VAS and individual symptom scores did not show any significant difference between the surgical and medical groups. Quality of life measurements behaved the same way. Likewise, no significant difference was found between the surgical and medical groups in the objective measurements except for total nasal volume in CRS and CRS without polyposis groups in which surgical treatment demonstrated greater changes. Previous studies on CRS with

131 polyposis reported no significant difference between snare polypectomy and a depot injection of 14 mg betamethasone (Lildholdt et al, 1988;Lildholdt et al, 1997). A temporary statistically significant difference was even reported in favour of systemic steroids (Lildholdt et al, 1988). On the other hand, Blomqvist et al. (2001) studied the additive effect of endoscopic sinus surgery for CRS with polyposis over topical steroids after treating all patients with oral prednisolone for 10 days. They claimed an additional effect of surgery on nasal obstmction but not on sense of smell, although a significant worsening in nasal obstruction scores was experienced between the third and sixth months postoperatively. Twenty five percent of the patients were willing to undergo endoscopic sinus surgery on the unoperated side at the end of the study.

Endoscopic sinus surgery significantly improved the subjective symptoms, quality of life and objective measurements, except for SF36 physical functioning domain in all groups and minimum cross-sectional area in the surgical groups CRS without polyposis. No significant difference was found between the 6 and 12-month measurements except for improvement of the SF36 energy domain. Other studies described similar improvement in the subjective (Schaefer, 1989;Levine, 1990;Stammberger, 1991c;Schaitkin et al, 1993;Lund & Mackay, 1994;Senior et al, 1998;Jiang & Hsu, 2000;Kennedy et al, 2000), quality of life (Gliklich & Hi!inski, 1995;Gliklich & Metson, 1997;Metson & Gliklich, 1998;Winstead & Barnett, 1998;Jones et al, 1998;Gosepath et al, 2000;Damm et al, 2002) and objective (Waguespack, 1995;Lund & Scadding, 1994;Abdel-Hak et al, 1998) measurements following endoscopic sinus surgery. The present trial also confirms the low complications profile of endoscopic sinus surgery reported in previous studies (Stammberger & Wolf, 1988;Stankiewicz, 1989;May et al, 1994;Danielsen & Olofsson, 1996;Seniorgr u/, 199 8 ; Jakob sen & Svendstrup, 2000).

132 The medical treatment, similarly, improved the subjective, quality of life and objective measurements significantly, except for the SF36 physical functioning domain in all groups and total nasal volume and MCA in CRS without polyposis. No significant difference was found between the 6 and 12- month measurements except for improvement of the SF36 energy domain in all groups and SNOT, SCT and nasal NO in CRS with polyposis. The efficacy of long-term macrolide antibiotics in the treatment of chronic rhinosinusitis has been noted in previous non-randomised non-controlled studies. Clarithromycin, 400 mg per day for 8-12 weeks, was effective in management of 45 cases of chronic rhinosinusitis refractory to other medical and surgical therapy (Hashiba & Baba, 1996). Using a qualitative score, an overall good response was obtained in 71.1% of the cases with an improvement of rhinorrhoea in 66.7%, postnasal drip in 61.5%, nasal obstmction in 51.4%, quantity of nasal secretions in 55.6%, viscosity of nasal secretions in 63.6% and mucosal oedema in 19.5% of the patients. Although, the effect on oedema or swelling of the mucosa was limited, nasal polyps were reduced, though not eliminated, in many cases. The clinical efficacy of clarithromycin was dependent on the duration of the course and no significant side effects were noted during the 12 weeks (Hashiba & Baba, 1996). In another study, clarithromycin, in the same dose and duration, reduced the size of nasal polyps in 40% of the cases. Control of the size of nasal polyps was correlated to the reduction of interleukin 8 levels in the nasal lavage (Yamada et al, 2000). Roxithromycin, 150 mg per day for at least 8 weeks, induced an overall improvement of 52% in CRS with polyposis (Ichimura et al, 1996). In another study, 12 weeks of 150 mg roxithromycin significantly improved all subjective and objective findings, except for the sensation of foul odour, in patients with chronic rhinosinusitis (Kimura et al, 1997).

The impressive efficacy of long-term low-dose macrolides cannot be attributed only to their antibacterial action since erythromycin and its derivatives have been found to be beneficial even for patients infected with

133 erythromycin-resistant organisms such as Pseudomonas aeruginosa (Fujii ei al, 1995) and Haemophilus influenzae (Kimura et al, 1997). The possible mechanisms of action of the long-term low-dose erythromycin in chronic rhinosinusitis can be explained by the following: 1. Antibacterial actions: a. Bacteriostatic and bactericidal actions Erythromycin exhibits good activity against Gram-positive aerobes, some Grame-negative aerobes, some anerobes and atypical pathogens (Williams & Sefton, 1993). b. Accumulation in tissues and host defence cells Macrolides are lipophilic in nature and have a low degree of ionisation. This allows extensive accumulation in tissues in concentrations higher than concurrent serum levels. They also enter host defence cells, particularly macrophages and polymorphonuclear leucocytes (Zhanel et al, 2001). This is thought to be the mechanism by which macrolides, in concentration less than the minimum inhibitory concentrations, produce antipseudomonal bactericidal activity (Tateda et al, 1996). c. Reduction o f bacterial virulence and suppression o f bacterial toxins Erythromycin has been shown to reduce the virulence of Pseudomonas aeruginosa and suppress the toxic lactins, pro teases and haemolysins (Sofer et u/, 1999 ;K itae/u/, 1991). d. Disruption o f bacterial carbohydrate metabolism and reduction o f biofilm formation Some bacteria such as Pseudomonas aeruginosa produce extracellular polysaccharide biofilm to protect them from phagocytes and antibiotics. This biofilm is also useful in strengthening the bacterial attachment to the mucosal surfaces. Macrolides have been shown to inhibit the carbohydrate metabolism

134 and the biofilm formation in Pseudomonas aeruginosa (Ozeki et al, 1996;Ichimiya e/ al, 1996).

2. Anti-inflammatory and immunomodulatory actions: а. Downregulation o f proinflammatory cytokines and reactive oxygen species Erythromycin and its derivatives has been shown to inhibit gene expression of IL-1 beta (Miyanohara et al, 2000), IL-2 (Konno et al, 1992), IL-5 (Konno et al, 1993), IL6 (Takizawa et al, 1995), IL-8 (Takizawa et al, 1997), endothelin- 1 (Takizawa et al, 1998), and iNOS (Tamaoki et al, 1999). This may be due to inhibition of transcription factors such as Nuclear Factor Kappa B and activator protein-1 (Aoki & Kao, 1999;Abe et al, 2000;Desaki et al, 2000). Activated Nuclear Factor Kappa B increases the gene expression of IL-2, EL- б, EL-8, iNOS, tumour necrosis factor alpha, intercellular adhesion molecule-1 and granulocyte-macrophage colony-stimulating factor (Baeuerle & Henkel, 1994). Pseudomonas aeruginosa (DiMango et al, 1998), haemophilus influenzae (Miyanohara et al, 2000), rhino virus (Papi & Johnston, 1999)and respiratory syncytial virus (Bitko et al, 1997) are known to activate Nuclear Factor Kappa B. Activator protein-1, on the other hand, appears to be the main regulator of EL-8 (Abe et al, 2000).

Macrolides have also been reported to block transforming growth factor betal receptors (Wang et al, 1994). Transforming growth factor beta 1 gene has been found to be expressed by eosinophils in chronically inflamed upper airway tissues, where it has been suggested that it plays a role in chronic inflammatory reaction, proliferation of nasal polyp fibroblasts, and prolonged survival of eosinophils(Ohno et al, 1992;Elovic et al, 1994;Coste et al, 1998). h. Protection from bioactive phospholipids Bioactive phospholipids are derivatives of arachidonic acid metabolism that cause damage to the ciliated airway epithelium both directly and indirectly through phagocyte-derived reactive oxidants. Macrolides have been shown to

135 have a membrane-stabilising effect on neutrophils inhibiting their de granulation and preventing the release of cytotoxic substances (Anderson et al, 1996;Feldman et al, 1997). c. Reduction o f the number o f leucocytes Macrolides have been reported to reduce number of neutrophils without affecting neutrophil infiltration or function through induction of neutrophil apoptosis (Aoshiba et al, 1995;Chin et al, 1998)and reduction of neutrophil chemotactic activity (Oda et al, 1994). It has also been suggested that macrolides may decrease the number of eosinophils via suppression of eosinophil chemotactic factors (Erger & Casale, 1995;Sato et al, 2001) and blockage of transforming growth factor betal receptors, which prolongs eosinophil survival (Coste et al, 1998). Erythromycin was also reported to inhibit proliferation of lympocytes (Keicho et al, 1993;Noma et al, 2001). Reduction of the number of the inflammatory cells may prevent fiirther amplification of inflammatory injury. d. Acceleration o f mucociliary clearance Macrolides have been noted to increase mucociliary clearance (Sugiura et al, 1997;Nakano et al, 1998). This may be a result of reduced inflammation, decreased goblet cell hypersecretion (Goswami et al, 1990;Tamaoki et al, 1997) and changed biophysical properties of mucus (Rhee etal, 2000).

3. Glucocorticoid-sparing action: Erythromycin was reported to reduce total body clearance, decrease apparent volume of distribution and increase half-life of glucocorticoids (LaForce et al, 1983;Spahn et al, 2001), probably through inactivation of one of the cytochrome P-450 enzymes (Periti et al, 1992).

Nasal douching holds a central place among the adjunctive treatments of chronic sinonasal diseases. Various studies have reported its effectiveness in

136 improving mucociliary clearance, subjective manifestations and nasal endoscopic appearance (Homer et al, 1999;Taccariello et al, 1999;Homer et al, 2000;Bachmann et al, 2000).

Corticosteroids are considered by clinicians among the most useful medications in chronic rhinosinusitis, since chronic rhinosinusitis is increasingly appreciated as an immunologically complex inflammatory disease rather than a simple infective process. Corticosteroids are potent anti­ inflammatory and immunomodulatory agents that exert their action through reducing the number of inflammatory cells with a special effect on eosinophils and T lymphocytes and downregulating a wide range of proinflammatory cytokines and mediators (Kamada & Szefler, 1995;Bames et al, 1998). Although there is a strong physiological basis to support the use of corticosteroids in chronic rhinosinusitis, only four studies have investigated the effect of topical but not systemic corticosteroids in chronic rhinosinusitis. Results of these studies appears to be very conRising with two studies showing significant improvement as compared to placebo (Sykes et al, 1986;Cuenant et al, 1986), whereas the other two reported no significant difference (Qvamberg et al, 1992;Parikh et al, 2001). In contrast, topical corticosteroid treatment is the best documented therapy of CRS with polyposis. Generally speaking, all topical corticosteroid preparations have proved effective in reducing polyp size and controlling most patient symptoms. Fluticasone propionate is one of the potent corticosteroids with a proven efficacy in treatment of rhinitis (Nathan et al, 1991;Scadding et al, 1995c) and nasal polyposis (Hobnberg et al, 1997;Lund et al, 1998), with a faster onset of action than beclomethasone dipropionate aqueous nasal spray (Holmberg et al, 1997). Corticosteroid drop formulation has been shown to facilitate mucosal distribution better than corticosteroid sprays (Hardy et al, 1985), with a more potent efficacy in the head down and forwards position (Lund, 1995). Fluticasone propionate nasal drops have been introduced to overcome the potential systemic side effects and the non-metered doses of the

137 conventional betamethasone drops. The mean absolute bioavailabilities for doses of 800 micro gram per day of fluticasone drops and spray were estimated to be 0.06% (drops) and 0.51% (spray) (Daley-Yates & Baker, 2001). Two large studies have reported the efficacy and tolerability of fluticasone propionate drops in CRS with polyposis. Keith et al. (2000) reported that a 12- week course 400 micrograms once daily fluticasone propionate nasal drops showed an improvement in polyp size (27% of patients) and investigator’s assessment of nasal blockage (55% of patients). No significant differences were found between the active treatment and placebo in the number of patients who demonstrated improvement in polyp size and clinical assessment of rhinitis and olfaction, whereas a significant difference was reported in investigator’s assessment of nasal blockage and peak nasal inspiratory flow. Penttila et al. (2000) demonstrated that fluticasone drops, 400 micro gram twice daily for 12 weeks, were significantly more effective in controlling polyp size (41% of patients) compared with 400 micrograms once daily of fluticasone drops (24% of patients) and placebo (15% of patients). Both doses were significantly better than placebo in improving nasal blockage (23% placebo, 52% fluticasone once daily, 41% fluticasone twice daily) and olfaction as measured by a modified University of Pennsylvania Smell Identification Test.

Systemic corticosteroid therapy is known to be very effective in controlling rhinitis symptoms and polyp size. It is even more effective than topical steroids and surgey in improving the sense of smell (Lildholdt et al, 1988;Lildholdt etal, 1997;van Camp & Clement, 1994). Short courses of oral prednisolone are not known to have significant adverse effects in well- selected patients. However, systemic corticosteroid therapy is not a substitute for topical corticosteroids since its effect in controlling symptoms is transient (van Camp & Clement, 1994) and patients need to continue with intranasal corticosteroids to avoid recurrences. In the present study, a short course of oral prednisolone proved effective as a salvage therapy for CRS with

138 polyposis, being used in three patients of CRS with polyposis after failure of erythromycin and fluticasone drops to control their manifestations. Two of these patients were able to defer surgical intervention during the trial. No side effects were reported in these three patients.

It has been suggested that nasal polyposis (Kennedy, 1992;King et al, 1994;Sobol et al, 1998) and asthma (Lawson, 1991 ;Kennedy, 1992;Sobol et al, 1998) serve as poor prognostic factors for the efficacy of the surgical therapy to control CRS manifestations. The present study does not support this issue since almost all the subjective and objective parameters of CRS improved significantly in the surgical and medical groups of CRS with polyposis and asthma, with no significant difference between the corresponding surgical and medical groups. In the previous studies authors reached that conclusion through comparing CRS with polyposis to CRS without polyposis and asthmatics to non-asthmatics. This comparison certainly gave non-valid statistical information since the baseline data, as documented by CT scans in this study as well as in Kennedy trial (1992), was significantly more extensive in CRS with polyposis and asthmatics than CRS without polyposis and non-asthmatics respectively.

Finally, it has to be mentioned that double blind placebo-controlled trials are needed to investigate the possibility that the improvement in the groups may be affected by the natural history of CRS, a placebo effect or even the impact of long-tem topical corticosteroids, which have been used in the surgical and medical groups.

139 4.2 Effect of treatment of chronic rhinosinusitis upon concomitant asthma

The relationship between the upper and lower airways, including chronic rhinosinusitis and asthma, has been noted as far back as the early Christian era. Direct evidence that chronic rhinosinusitis can aggravate or induce asthma has not been proven. However, indirect evidence, including that concerning the potential effect of therapy for chronic rhinosinusitis upon concomitant asthma, has been accumulating in the literature over the years. The currently available studies are unsatisfactory, since none of them meets the accepted standards for clinical trials to provide evidence for therapy. Table Ib shows an analysis of the trials discussing the effect of sinus surgery for CRS on asthma. There is considerable confusion concerning the effect of the surgical treatment of chronic rhinosinusitis upon the lower airways. On the other hand, few, if any, adult studies have considered the effect of medical treatment of CRS on asthma. The increasing awareness of asthma as an inflammatory disease has emphasised the need to document studies investigating asthma with a sensitive inflammatory marker. Exhaled NO has been shown to be a sensitive non-invasive test for the inflammatory asthmatic response increasing during exacerbation and decreasing during recovery and in response to anti-asthmatic anti-inflammatory treatments (Massaro et al, 1995;Lundberg et al, 1996b;Kharitonov et al, 1996b;Kobayashi et al, 1999;Bisgaard et al, 1999;Bratton et al, 1999). Therefore, this study was designed in a prospective randomised fashion considering the effect of both medical and surgical treatment for chronic rhinosinusitis on asthma, applying a range of subjective and objective parameters, which included exhaled nitric oxide as a non-invasive and sensitive detector of asthmatic inflammation.

About 31% of CRS patients, with whom the study was discussed, suffered from asthma. Annesi-Maesano (1999) reported a 34 % prevalence of asthma in CRS patients. Out of the 43 asthmatics who were enrolled in the study, 24 developed asthma before and 19 after CRS. Seventeen (70.8%) of those who

140 had asthma before CRS, reported that their asthma had been worsened by CRS. Similarly, 16 (84.2%) of those who developed asthma after CRS reported that when their CRS got worse, their asthma got worse as well. Eight (42.1%) of them described that their first attack of asthma was linked to an exacerbation of CRS. Scadding (1999) showed that 88.8% (8 out of 9 asthmatics) of her patients developed worse chest symptoms when their sinus symptoms worsened. These figures suggest a potential role of rhinosinusitis in triggering or exacerbating asthma.

In the present study, the surgical groups showed a general trend for improvement in the subjective and objective lower airway measurements. This reached a statistical significance for all parameters of CRS except for chest score, use of corticosteroid inhalers and PEF. On the other hand, the subjective and objective measurements in CRS without and with polyposis failed to attain any statistical significance. Likewise, no significant difference was found between CRS without and with polyposis. Previous studies showed that sinus surgery induced subjective improvement in 80 - 91% of asthmatics (Slavin, 1982;English, 1986;Stammberger, 1991a;Jankowski et al, 1992;Nishioka et al, 1994a;Rosen et al, 1996;Senior & Kennedy, 1996;Dinis & Gomes, 1997;Park et al, 1998;Senior et al, 1999;Nakamura et al, 1999). Few studies have reported improvement of respiratory function tests (Juntunen et al, 1984;Mings et al, 1988;McFadden et al, 1990;Stammberger, 1991 a;l 992;Nakamura et al, 1999) and bronchial hyperreactivity (1992). Conversely, surgery appears to have a negative impact on asthma in a subgroup of CRS patients. This study included two patients (8.7%) whose lower airway manifestations got worse after surgery: a patient of CRS without polyposis who developed asthma for the first time three months after surgery and another patient of CRS with polyposis whose asthmatic manifestations were worse after surgery than any time before. Both patients showed subjective worsening asthma, increased use of medication, elevated exhaled NO levels and reduced FEV1% and PEF. Some authors have reported 18-46

141 % subjective worsening in asthma (Francis, 1929;Weille, 1933;Weille & Richards, 1951 ;Schenck, 1974;Moloney, 1977;Dinis & Gomes, 1997), whereas others have described precipitation of the first attack of asthma (Samter & Lederer, 1958m;Samter & Beers, Jr., 1967;synder & Seigel, 1967;Saberman & Ross, 1973;Moloney, 1977) after sinus surgery. Some authors have suggested CRS with polyposis to be the group that suffers lower airway problems following sinus surgery. Francis (1929) described worsening of asthma in 46 % of 24 patients who underwent sinonasal surgery for CRS with polyposis. Samter and Lederer (1958) reported an increase in bronchial reactivity in 17 patients of CRS with polyposis who underwent sinonasal surgery. Recently, Lamblin et al. (2000) demonstrated an irreversible increase in bronchial hyperresponsiveness and a slight, but significant, drop in spirometric measurements in topical steroid non-responders undergoing sinonasal surgery for CRS with polyposis. The present study does not support this finding, since: first, there was a general subjective and objective tendency for asthma improvement, although not significant, in the surgical group of CRS with polyposis; second, the effect of surgical treatment of CRS upon asthma did not show any significant subjective or objective difference between the groups of CRS without and with polyposis; third, the only patient who developed the first attack of asthma after surgery belonged to the group of CRS without polyposis; fourth, there was no significant difference between the pre and postoperative lower airway measurements in the non-asthmatic surgical group of CRS with polyposis, and fifth, the effect of surgical treatment of CRS upon the lower airways did not show any significant subjective or objective difference between the non-asthmatic groups of CRS without and with polyposis. Dunlop et al. (1999) demonstrated no major differences for outcomes between CRS without and with polyposis. Other studies have reported improved respiratory ftinction tests (Nakamura et al, 1999) and bronchial reactivity (Jankowski et al, 1992) after surgery for CRS with polyposis. However, the present study suggests that surgery for CRS plays a less effective role in the control of asthma in patients of CRS with

142 polyposis, since lower airway measurements in the asthmatic surgical group of CRS without polyposis and medical group of CRS with polyposis showed higher improvement values than the asthmatic surgical group of CRS with polyposis. A significant difference was also shown in exhaled NO and FEV1% measurement between the asthmatic medical and surgical groups of CRS with polyposis. It may be possible that CRS with polyposis exhibits a different profile of inflammatory mediators, cytokines and cells, which supports a more intimate link with the lower airways, with the efficacy of surgery and postoperative topical corticosteroids being limited to control such an inflammatory profile. On the other hand, it is worth mentioning that the negative effect of surgery upon lower airways in some patients seems to be independent of the degree of success of surgery to control CRS. Both patients, who reported worsening of their lower airway symptoms in this study, showed an excellent subjective and objective improvement in their CRS manifestations. It is possible that surgical trauma may induce a change in the cytokine profile of the upper airways, which has the ability to trigger or aggravate asthma in a special subgroup of CRS patients. Recently, Bo lard et al. (2001) demonstrated that microscopic intranasal sphenoethmoidectomy for CRS with polyposis altered the cytokine profile in nasal secretions with significantly higher levels of IL-8, IL-IO and EL-I beta than the medically treated or untreated groups. The relevance of this change in the cytokine profile and the characteristics of the patients who are susceptible to develop or suffer an aggravation of asthma after surgery are still to be investigated.

Likewise, the medical groups showed a general tendency for subjective and objective improvement, but with higher significance values than the corresponding surgical groups. The difference between the medical and surgical groups was significant in exhaled NO and FEVI% measurements in CRS with polyposis. The medical groups improved significantly in all parameters except for use of corticosteroid inhalers in CRS, all subjective parameters in CRS without polyposis and chest score, use of corticosteroid

143 inhalers and PEF in CRS with polyposis. No significant difference was found between CRS without and with polyposis. This impressive response of asthmatics to medical treatment of CRS can be explained by: 1. Indirect effect The combined use of long-term erythromycin and glucocorticoids seems to provide an excellent control of the inflammatory reaction in CRS through decreasing the microbiological load (Williams & Sefton, 1993;Tateda et al, 1996;Kita et al, 1991 ;Ichimiya et al, 1996), reduction of the number of leucocytes (Chin et al, 1998;Sato et al, 2001;Noma et al, 2001) and downregulation of a wide range of cytokines and inflammatory mediators (Miyanohara et al, 2000;Konno et al, 1992;Konno et al, 1993;Takizawa et al, 1995;Takizawa et al, 1997;Takizawa et al, 1998;Tamaoki et al, 1999). Rhinosinusitis has been postulated to trigger or aggravate asthma through failure of nasal functions, enhancement of beta adrenergic blockade, stimulation of a rhinosinobronchial reflex, sinopulmonary deposition of inflammatory product-rich secretions, enhancing systemic airway inflammatory responses and and modulation of nitric oxide levels.

2. Direct effect on the lower airways Macrolides have been suggested to play a role in control of asthma through their antibacterial, anti-inflammatory, and glucocorticoid-sparing properties. The antibacterial properties of erythromycin were reported to cover a broad spectrum of bacteria including atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae, which have been incriminated in the pathogenesis of asthma (Martin et al, 2001). The anti-inflammatory properties of erythromycin were suggested to play the main role in control of the asthmatic inflammatory response especially through inhibiting eosinophilic response (Erger & Casale, 1995;Sato et al, 2001;Coste et al, 1998)and reducing levels of cytokines and reactive oxygen species (Miyanohara et al, 2000;Konno et al, 1992;Konno et al, 1993;Takizawa et al, 1995;Takizawa et al, 1997;Takizawa et al, 1998;Tamaoki et al, 1999). Erythromycin was also

144 reported to attenuate bronchial hyperresponsiveness in patients with bronchial asthma, probably through its inhibitory action on superoxide production and chemotaxis of neutrophils as well as mixed lymphocytic reaction (Miyatake et al, 1991). Erythromycin may also be helpful in asthma management through protecting the ciliated airway epithelium from the action of bioactive phospholipids (Feldman et al, 1997), reducing mucus production (Tamaoki et al, 1997) and improving mucus biophysical properties (Rhee et al, 2000). Finally, it has been suggested that erythromycin inhibits glucocorticoid clearance and enhances the effect of steroid therapy on asthma (LaForce et al, 1983 ;Spahn et al, 2001 ).

145 4.3 Nasal nitric oxide

Nitric oxide is a fairly stable gas, which is secreted in the upper and lower airways. In the upper airways, the human paranasal sinuses are the major source of NO production that floods through sinus ostia and makes a large contribution to the levels of NO found in the nasal cavity (Lundberg et al, 1994b;Lundberg et al, 1995a). On the other hand, patency of sinus ostia plays a pivotal role in maintaining normal sinus physiology and its disruption can lead to the development of chronic rhinosinusitis. Lindberg et al. (1997b) showed that patients with chronic rhinosinusitis had lower nasal NO levels than healthy controls. Conversely, Amal et al. (1999) found no significant difference in nasal NO levels between patients with chronic rhinosinusitis and controls. However, the latter study could not definitively conclude that CRS does not alter nasal NO levels since the degree of paranasal sinus alteration on CT scans was milder in the CRS group. Therefore, this study was designed prospectively to study the effect of therapy for chronic rhinosinusitis upon nasal NO levels and to investigate the value of nasal NO as an objective indicator of the effect of therapy on chronic rhinosinusitis.

In the present study, nasal NO increased significantly with medical and surgical treatment of CRS, with higher levels, although not significant, in the surgical than the medical groups. This supports the previous report that nasal NO levels are low in CRS (Lindberg et al, 1997b). Theoretically, nasal NO levels have been postulated to depend mainly on the amount of NO produced by the ciliated epithelium of the paranasal sinuses and the size of the paranasal sinus ostia (Lindberg et al, 1997b). The results of this study fit well with this theoretical explanation, since it could be anticipated that treatment of CRS resulted in recovery of the ciliated epithelium of the paranasal sinuses, which regained its normal ability to express iNOS and produce NO that passed through the sinus ostia and increased nasal NO levels. The higher levels of nasal NO improvement in the surgical rather than in the medical groups may

146 reflect the role of the paranasal sinus ostial size. However, failure to show any significant difference between the surgical and medical groups demonstrates that the condition of the ciliated epithelium of the paranasal sinuses is more relevant than the actual size of the paranasal sinus ostia. Amal et al. (1999) reported that patients with Kartagner’s syndrome had very low nasal NO levels, despite the presence of patent paranasal sinuses on CT scans.

Attempts at objective documentation of the impact of therapy in chronic rhinosinusitis have been tried over the years. However, no single test has proved to be the objective measurement of choice. Many authors have speculated that nasal NO might provide such a genuine objective test to quantify and objectively document the results of different treatments for chronic rhinosinusitis. However, this has not been proven. In the present study, nasal NO changes correlated inversely (P<0.001) with symptom score changes, with excellent sensitivity (98.6%) and specificity (88.9%). This demonstrated that the subjective improvement reflected a genuine physiological recovery of the nose and paranasal sinuses. On the other hand, studies in animals (Runer et al, 1998) and healthy human sinus mucosa (Kim et al, 2001;Runer & Lindberg, 1998) have indicated NO to be a regulator of mucociliary activity in the upper respiratory tract. Lindberg et al. (1997a) studied a cohort of 12 patients reporting that low levels of nasal NO correlated with impaired mucociliary activity. In the present study, the correlation between the dynamic changes in nasal NO and SCT as a result of therapy for CRS were studied in the 73 and 69 patients who detected saccharine in the 6 and 12-month settings respectively. Nasal NO changes strongly correlated with SCT changes providing further support to the previous studies that nasal NO levels reflect the state of sinonasal mucociliary function. The in vivo SCT was preferred to the in vitro ciliary beat frequency (CBF), since it would seem more appropriate to study both mucociliary activity and nasal NO in the same environment and SCT measures the whole mucociliary system, whereas CBF looks only at ciliry activity. Lindberg et al. (1994) showed that the in vivo

147 mucociliary wave frequency did not correlate with the in vitro CBF. The more or less .fixed equations of simple linear regression in the 6 and 12-month settings reflect the accuracy of SCT measurements in the present study. Furthermore, the present study showed an inverse correlation between nasal NO levels and the extent of sinus disease as documented by CT scans, endoscopic score and polyp grades. Amal et al. (1999) reported that nasal NO levels were inversely correlated with the extent of sinus opacification on CT scans in patients with CRS with polyposis. Taking into consideration that postoperative sinus CT scans are generally considered non-ethical due to hazards of radiation, it would seem logical that nasal NO measurement could serve as an excellent alternative to postoperative sinus CT scans, since elevation of nasal NO levels following treatment of CRS does reflect not only recovery of sinus epithelium but also patency of sinus ostia and the ostiomeatal complexes. Finally, NO changes did not correlate with any of the following parameters; age, sex, smoking, skin prick test positivity, grass pollen sensitivity and family history of allergy. It is worth mentioning that patients with positive SPT, positive grass pollen sensitivity or a positive family history of allergy tended to show higher mean NO percentage improvements than patients with negative SPT, negative grass pollen sensitivity or a negative family history of allergy. Amal et al. (1999) reported that allergic patients with polyposis had a significantly higher nasal NO levels than non-allergic patients with polyposis. However, failure of the present study to show a significant difference between allergic and non-allergic patients may be related to the efficacy of intranasal corticosteroids to control the allergic manifestations during the recruitment period of the study. Studies in both adults (Kharitonov et al, 1997b) and children (Baraldi et al, 1998) showed that topical nasal glucocorticoids significantly lowered the elevated nasal NO levels in patients with seasonal and perennial allergic rhinitis.

148 4.4 Conclusions

1. CRS study provides evidence that chronic rhinosinusitis should be targeted with maximal medical therapy in the first instance, with surgical treatment being reserved for cases refractory to medical therapy. The medical regimen used in this study is encouraging. Neither presence of nasal polyps nor asthma serves as a poor prognostic factor for the efficacy of CRS therapy, either medical or surgical.

2. Although the nature of the relation between the upper and lower airways remains controversial, the evidence for its existence is compelling. This study provides comprehensive subjective and objective evidence that both medical and surgical therapy of CRS improves the clinical course of asthma. It also provides conclusive evidence for the superiority of the medical treatment, especially in cases of CRS with polyposis. In addition, it seems that sinus surgery can occasionally trigger or aggravate asthma in a small subgroup of CRS patients. This is related neither to the success of the surgery nor to the presence of nasal polyps. However, it may be related to a surgery-induced change in upper airways cytokine profile. The nature of this triggering cytokine profile and the characteristics of the CRS subgroup are still to be investigated.

3. Nasal NO is a valuable objective measurement in monitoring medical and surgical therapy for CRS. Nasal NO levels increase with treatment of CRS, reflecting not only the physiological recovery of paranasal sinus epithelium and mucociliary activity, but also the anatomical improvement in terms of patency of sinus ostia and ostiomeatal complexes. The correlation between nasal NO changes and the patient’s own perception of clinical improvement seems to be associated with excellent sensitivity and specificity. However, in the clinical application of nasal NO measurement

149 in monitoring CRS therapy, it seems more useful if the pre-treatment NO level of each patient serves as his own control, since the absolute nasal NO values, apart from the extremes of the range, do not reflect extent of sinus disease. It is also worth mentioning that the excellent correlation between nasal NO changes and SCT changes strongly suggests potential use of NO in diagnosis and even in therapy of diseases affecting sinonasal mucociliary function. Finally, NO measurement is non-invasive, quick and easy, even in children. The chemiluminescence analysers are sensitive, accurate and reproducible. However, they are still expensive and this limits the application ofNO in daily clinical practice.

150 5. Future work

1. Although the anti-inflammatory and immunomodulatory actions of the macrolides has been reported in the literature, the exact mechanisms by which the macro lides exert these actions are not fully understood and further studies are required to identify the nature of these mechanisms.

2. The changes in cytokine profiles following endoscopic sinus surgery for CRS without and with polyposis and the implications of such changes in asthma development need further investigations. The role of various patients’ characteristics such as age, sex, allergy, aspirin intolerance and presence of nasal polyps in inducing these changes also needs to be explored.

3. Having established that nasal nitric oxide is truly useful as an objective measurement for the efficacy of CRS therapy, it would be instructive to examine a large rhino logy clinic population investigating and correlating nasal nitric oxide levels with the success of different therapies in controlling various rhino logy problems.

4. Nitric oxide is known to play a role in host defence through being toxic for micro-organisms and contributing to local host defence by stimulating ciliary motility. Hence, speculation can be made that low NO levels may play a role in the development of chronic rhinosinusitis. Further studies are required to establish this role.

5. Nitric oxide has very valuable physiological characteristics such as mucociliary regulation and bronchodilatation. A lot of work has to be done

151 to benefit from these characteristics in treatment of upper and lower airway diseases such as Primary Ciliary Dyskinesia and asthma respectively.

6. Nitric oxide measurement is increasingly appreciated as an efficient diagnostic and treatment-monitoring tool. However, the heavy and expensive nitric oxide analysers still prevent its widespread use in the daily clinical practice. Moreover, an international consensus on the technique is not yet well developed. Further work is still needed to develop portable and cheaper nitric oxide analysers as well as to agree on definitive recommendations for exhaled and nasal nitric oxide measurements.

152 6. Summary

1. Chronic rhinosinusitis (CRS) is a prevalent disease that has marked effects on the society. Its definition, pathophysiology, microbiology and treatment are still a source of debate. Likewise, there is still considerable confusion in the literature concerning the relationship and the effect of therapy of CRS upon the concomitant asthma. On the other hand, nitric oxide is a fairly stable gas that is secreted in the upper and lower airways and its measurements excite considerable interest as it provides a simple non- invasive means of measuring airway inflammation, even in children.

2. The aims of the thesis were: to conduct the first prospective randomised controlled trial, evaluating and comparing the medical and surgical treatment of CRS and its subgroups; to study whether the presence of nasal polyps serves as a poor prognostic factor for the efficacy of CRS therapy; to study whether asthma serves as a poor prognostic factor for the efficacy of CRS therapy; to elucidate the relationship between upper and lower airway diseases, considering specifically the relationship between CRS and asthma; to conduct the first prospective randomised study evaluating and comparing the effect of the medical and surgical treatment of CRS and its subgroups upon asthma, applying a range of subjective and objective parameters, and including exhaled NO as an easy and sensitive detector of inflammation; to study whether the presence of nasal polyps serves as a poor prognostic factor for asthma control in CRS patients; to study the effect of medical and surgical therapy of CRS upon nasal NO levels; to investigate the value of nasal NO as an objective indicator of the effect of therapy on CRS.

153 3. Patients were recruited from the Rhinology Clinics of the Royal National Throat, Nose and Ear Hospital, London. The process of recruitment took place over two years. They were 90 patients with CRS, of whom 43 were asthmatics. The study comprised 45 males and 45 females, with a mean age ± (SD) of 43 ± (13) and a range from 24 to 71 years. Patients were equally randomised to either medical or surgical therapy of CRS. All patients underwent pre and post-treatment assessments of visual analogue score (VAS), chest score, overall asthma control score, use of anti-asthma medication, hospitalisation for asthma, the Sinonasal Outcome Test-20 (SNOT-20), the Short Form 36 Health Survey (SF-36) nitric oxide (NO), acoustic rhino me try, saccharine clearance time (SCT), spirometry and nasal examination including anterior rhinoscopy and endoscopy.

4. Both the medical and surgical treatment of CRS significantly improved all the subjective and objective parameters of CRS (P<0.01) except for SF-36 physical functioning domain in all groups (P>0.05), total nasal volume (P>0.05) in the medical group of CRS without polyposis and minimum cross-sectional area (P>0.05) in the medical and surgical groups CRS without polyposis. No significant difference was found between the medical and surgical groups (P>0.05) except for total nasal volume in CRS (P<0.01) and CRS without polyposis (P<0.01) groups in which surgical treatment demonstrated greater changes.

5. Both the medical and surgical treatment significantly improved all the subjective (P<0.01 in total groups and <0.05 in subgroups) and objective parameters (P<0.01 in total groups and <0.05 in subgroups) of CRS in asthmatic patients except for SF-36 physical functioning domain in all groups and total nasal volume and MCA in CRS without polyposis. No significant difference was found between the surgical and medical groups.

154 6. About thirty one percent of CRS patients with whom the study was discussed, suffered from asthma. Out of the 43 asthmatics who were enrolled in the study, 24 developed asthma before and 19 after CRS. Seventeen (70.8%) of those who had asthma before CRS, reported that their asthma had been worsened by CRS. On the other hand, 16 (84.2%) of those who developed asthma after CRS reported that when their CRS got worse, their asthma got worse as well. Eight (42.1%) of them described that their first attack of asthma was linked to an exaggeration of CRS.

7. The asthmatic surgical groups showed a general trend for improvement in the subjective and objective lower airway measurements. However, this did not reach a statistical significance except for use of bronchodilator inhalers (P<0.05), use of oral corticosteroids (P<0.05), hospitalisation (P<0.05), Overall asthma control score (P<0.05), exhaled NO (P<0.05) and FEV1% (P<0.05) in the total surgical group of CRS. This study showed two patients (8.7%) whose lower airway manifestations got worse after surgery: a patient of CRS without polyposis who developed asthma for the first time three months after surgery and another patient of CRS with polyposis whose asthma got worse after surgery than any time before. On the other hand, the medical groups showed higher significance values than the corresponding surgical groups. However, the difference between the medical and surgical groups did not reach a statistical significance except for exhaled NO (P<0.05) and FEV1% (P<0.05) measurements in CRS with polyposis. On the other hand, no significant difference was found between the surgical groups of CRS without and with polyposis, although CRS without polyposis tended to show higher improvement percentage values in the subjective and objective lower airway measurements.

8. Lower airway measurements in the asthmatic surgical group of CRS without polyposis and medical group of CRS with polyposis showed

155 higher improvement values than the asthmatic surgical group of CRS with polyposis. Notably, a significant difference was reached in exhaled NO and FEV1% measurement between the asthmatic medical and surgical groups of CRS with polyposis.

9. Nasal NO increased significantly upon medical (P<0.01) and surgical (P<0.01) treatment of CRS, with higher levels, although not significant (P>0.05), in the surgical than the medical groups. Nasal NO correlated inversely with VAS (P<0.001), SCT (P<0.001), endoscopic score (P<0.001), polyp grades (P<0.01) and CT score (P<0.001). Finally, NO changes did not correlate (P>0.05) with any of the following parameters: age, sex, smoking, skin prick test positivity, grass pollen sensitivity and family history of allergy.

10. Both medical and surgical treatment of CRS are effective in controlling the manifestations of CRS. Therefore, chronic rhinosinusitis should be targeted with maximal medical therapy in the first instance, with surgical treatment being reserved for cases refractory to medical therapy. Neither the presence of nasal polyps nor asthma serves as a poor prognostic factor for the efficacy of CRS therapy, either medical or surgical.

11. Evidence of a link between CRS and asthma is too striking to be denied. Both medical and surgical therapy of CRS improved the clinical course of asthma, with the medical treatment being superior to the surgical, especially in CRS with polyposis. On the other hand, it seems that sinus surgery can occasionally trigger or aggravate asthma in a subgroup of CRS patients. This is related neither to the success of surgery nor to the presence of nasal polyps. However, it may be related to a surgery-induced change in upper airways cytokine profile. The nature of this triggering

156 cytokine profile and the characteristics of the CRS subgroup are still to be investigated.

12. Nasal NO measurement is non-invasive, quick and easy, even in children and represents a valuable objective measurement in monitoring medical and surgical therapy for CRS. The chemiluminescence analysers are sensitive, accurate and reproducible. However, they are still expensive and this limits the application of NO in daily clinical practice.

157 7 - Appendices

Contents Page

Appendix I Main data collection sheets 159

Appendix II Baseline data tables 169

Appendix III Baseline data figures 174

Appendix IV CRS study tables 190

Appendix V CRS study figures 208

Appendix VI Asthma study tables 231

Appendix VII Asthma study figures 245

Appendix VIII Nitric oxide study figures 249

158 Appendix I Main data collection sheets

Cover sheet

Surname

Forenames

Age

Date of birth

Sex

Occupation

Address

Phone:

E-MAIL( if present)

Hospital number

Trial number

Date

Visit number

159 Nasal symptom score

0 = none 10 = greatest severity

1- NASAL BLOCKAGE

10

2- NASAL DISCHARGE

10

3- PROBLEMS WITH SENSE OF SMELL

10

4- FACIAL PAIN

10

5- HEADACHES

10

6- OVERALL DISCOMFORT

10

160 Asthma symptom score

0 : No symptoms. 1 : Symptoms present but causing little or no discomfort. 2 ; Symptoms present and troublesome but not causing interference with either daily activities or with sleep. 3 ; Symptoms present, troublesome and interfering with either daily activities or with sleep. 4 : Symptoms intolerable.

Overall asthma control score

0 : Not controlled . 1 : slightly controlled. 2 : Adequately controlled. 3 : Well controlled. 4 : very well controlled.

161 Objective measurements

Parameter Right Left

Endoscopic score (0-2)

Polyps

Edema

Discharge

Scarring

Crusting

Total points for each side Polyp grades (0-3)

SCT

Nasal volume

MCA

Nasal NO

Exhaled NO

FEV1% (% of predicted value)

PEE (% of predicted value)

162 Surgical score

NO = 0 YES = 1

Procedure Right Left

Uncioectomy

Middle meatal antrostomy Anterior ethmoidectomy Posterior ethmoidectomy Sphenoidectomy

Frontal recess surgery

Reduction of middle turbinate Total points for each ' side Total points for both sides

163 THE SHORT FORM 36 HEALTH SURVEY QUESTIONNAIRE (SF-Sô***)

The following questions ask for your views about your health, how you fed and how well you are able to do your usual activities. If you are unsure about how to answer any questions please give the best answer you can and make any of your own comments if you like. Do not spend too much time in answering as your immediate response is likely to be the most accurate.

1. In general, would you say your health is;

{Plimt tick ont box)

Excellent J

Very good ^

Good ^ J f» [ ]

Poor ^ J

2. Compared to one year ago, how would you rate your health in general now?

iPlease lick one box)

Much beoer than one year ago ^

Somewhat better than one year ago

About the same

' Somewhat worse now than one year ago ^

Much worse now than one year ago

164 3. HEALTH AND DAILY ACTIVTnES

The following questions are about activities you tnight do during a typical day. Does your health limit you in these activities? If so, how much? (Please lick one box on each line)

Y e s, Yes, No, not l im ite d limited limited a lo t a little at all a) Vigorous activities, such as running, lifting heavy objects, r —i participating in strenuous sports L J [ ] n b) M oderate activities, such as moving a table, pushing a r —i vacuum, bowling or playing golf L _J [ ] [ ] ' ■ c) Lifting or carrying groceries [ ] [ ] d ) Climbing several flights of stairs ^ [ ] [ ] e) Climbing one flight of stairs [ ] [ ] f) Bending, kneeling or stooping [j H [ ] [ ] g) Walking more than a mile ^ [ ] [ ] h) Walking half a mile ^ ^ [ ] [ ] i) W alking 100 yartis ^ ^ [ ] [ ] j) Bathing and dressing yourself ^ L J [ ]

4. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a rM ult of your physical health? (Please answer Yes or No to each question)

Y e s N o

a) Cut down on the amount of time you spent r on work or other activities L [ ] b ) .Accomplished less than you would like ^ C ] c) Were limited in the kind of work or other activities C ] d ) Had difficulty performing the work or other ^ activities (eg it took more effort) [ ]

165 5. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of any em otiooal problem s (such as feeling depressed or anxious)? (Please answer Yes or No to each question}

Y es No a) Cut down on the amount of time you spent on work or i 1 i------1 other activities L J L J

Accomplished less than you would like 1 C J

Didn't do work or other activities as carefully as usual ^ ^ ____ J

6. During the past 4 weeks, to what extent have your physical health or emotional problems interfered with your normal social activities with family, hiends, neighbours or groups? (Please tick one box)

Not at ail 1^ j

Slightly ]

Moderately ^

Quite a bit J

Extremely ^ ____J

7. How much bodily paio have you had during the past 4 weeks? (Please rick one bos)

N one j

Very mild J M ild [ ] M oderate [ ] Severe [ 3 Very Severe J

During the past 4 weeks how much did pain interfere with your normal work (including work both outside the home and housework)? (Please tick one box)

N ot at all [ ~

A little bit [ :

M oderately [ :

Quite a bit [ :

Extrem ely r ■

166 YOUR FEELINGS

9. These questions arc about how you feel and how things have been with you during the past month. (For each question, please indicate the one answer that comes closest to the way you have been feeling).

(^Please tick one box on each line)

How much time during All Most A good Some A little N one the last month: of the of the bit of of the o f the o f th e time time the time time tim e tim e

Did you feel full of life? a) ] [ ] n [ [] LJ Have you been a very nervous ^ b) ] [ ] [ ] [ □ [ ] person? [ □

Have you felt so down in the p c) dumps that nothing could cheer you L ][][][ ] [] [ J up?

Have you felt calm and peaceful? ^ d) ][][][ ][] [ □ Did you have a lot of energy? Q 0 ][][][ ] [ ] [ □ Have you felt downhearted and | 0 low? ^][][][ ] [ ] [ □ Did you feel worn out? g) ][][][ ] [ ] [ ] Have you been a happy person? h) ][][][ ] [ ][ ] Did you feel tired? Q i) ][][][][ ] [ ] Has your health limited your p j) social activities (like visiting L ][][][ ] [ ] [ ] friends or close relatives)?

HEALTH IN GENERAL

10. Please choose the answer that best describes how true or false each of the ‘ following statements is for you.

(Please tick one box on each line)

Definitely Mostly Not M ostly Definitely | true true sure false false a) I seem to get ill more easily than other people n [ ] n LJ LJ b ) I am as healthy as anybody I know [ ] [ ] [ ] C] [ ] ; c ) I expect my health to gel worse [ ] [ ] [ ] [ ][ ] d ) . My health is excellent C ] LJ LJ LJ []

SF36 is a trade mark o f the Medical Outcomes Trttst

167 The Sinonasal Outcome test-20

[.D.: Sr^o-N.ASAL O inroivrE T e s t f S N O T - 2 0 )

Below you will find a list of symptoms and social/emotional consequences of your rhmosinusitis. We would like to know more about these problems and would appreciate your answering the following questions to the best of your ability. There are no nght or wrong answers, and only you can provide us with this information. Please rate your problems as they have been over the past rwn weeks. Thank you fur your participation. Do not hesitate to ask for assistance if necessary.

------

2 2 1 I f S 1 1 i 2. 1. Considering how severe the problem is when you 3 . s 3 Ô experience it and how frequently it happens, f E 1 S please rate each item below on how "bad" it is by Î i 1 circling the number that corresponds with how g Î s 1 you feel using (his scale: -+ 3 Z s.- i I

I. Need to blow nose 0 1 2 3 4 5 0

2. S n e e z in g 0 1 2 3 4 5 0

3. R u n n y n o se Q 1 %' 3 4 5 0

4. C o u g h 0 1 2 3 4 5 o

5. Post-oasaldiacharge 0 1 2 3 4 5 0

6. Thick nasal discharge 0 1 2 3 4 5 0 -o'" % 1 1 æ 8. D izz in ess 0 1 2 3 4 5 0

9. E a r p a in - ' - C ; - . S .t ; m 1 ’ % % 'o '; 10. Facial pain/pressure 0 1 2 3 4 5 0 11. Difflcnlty M ing asleep , ^ "y':' # :•ï ' ^ m # 12 . W ake np at night 0 1 2 3 4 5 0 13. a " - "iT • # w - 3 - - 0 14. W ake up tired 0 1 2 3 4 5 0

15. F a tig u e 0 1 2 1 3 4 S 0

16. Reduced productirity 0 1 2 3 4 5 0

17. Reduced concentratioa 0 1 2 3 4 5 0

IS Frustrated/restlesa/irri table 0 1 2 3 4 5 0

19 S a d % # ' ^ - 0 ' . 1 4 - 'A 0

20 Embarrassed 0 1 2 4 5 0

2. Please mark the most important items affecting your health (maximum of 5 itcms)_

Copyright ® 1996 by Jay F. Piccirillo, M.D.

168 Appendix II Baseline data tables

Table Ila Characteristics of the surgical and medical groups of CRS

Characteristics Surgical group Medical group Number 45 45 Age (mean ± SD) 42 ±13 years 45 ±13 years Age (range) 24-71 years 26-70 years Male 44.4% 55.6% Female 55.6% 44.4% CRS without polyposis 57.8% 64.4% CRS with polyposis 42.2% 35.6% Asthma 51.1% 44.4% Non-asthma 48.9% 55.6%

Table Ilb Characteristics of the surgical and medical groups of CRS without polyposis

Characteristics Surgical group Medical group Number 26 29

Age (mean ± SD) 41 ±13 years 43 ±13 years Age (range) 24-71 years 26-67 years Male 30.8% 51.7% Female 69.2% 48.3% Asthma 42.3% 34.5% Non-asthma 57.7% 65.5%

169 T able I le Characteristics of the surgical and medical groups of CRS with polyposis

Characteristics Surgical group Medical group Number 19 16 Age (mean ± SD) 43 ±12 years 48 ±14 years Age (range) 27-71 years 28-70 years Male 63.2% 62.5% Female 36.8% 37.5% Asthma 63.2% 62.5% Non-asthma 36.8% 37.5%

T able I ld Baseline VAS

Diagnosis Descriptive Surgical group Medical group statistics

CRS Mean ± SD 4 0 ± 11 38 ± 9 Range 21-60 22-53 CRS without Mean ± SD 4 0 ± 11 4 0 ± 10 polyposis Range 24-60 21-56 CRS with Mean ± SD 38 ± 9 38 ± 8 polyposis Range 22-53 25-53

170 Table Ile Baseline SCT

Diagnosis Descriptive Surgical group Medical group statistics

CRS Mean ± SD 23.9 ± 12 minutes 20.8 ± 9 minutes Range 8-59 minutes 7-47 minutes CRS without Mean ± SD 19.7 ± 7.9 19 ± 7 minutes polyposis minutes Range 8-33 minutes 7-35 minutes CRS with Mean ± SD 30.4 ± 14.5 24.8 ± 11.5 polyposis minutes minutes Range 14-59 minutes 12-47 minutes

Table I l f Baseline total nasal nitric oxide levels

Diagnosis Descriptive Surgical group Medical group statistics

CRS Mean ± SD 723 ± 486 ppb 773 ± 426 ppb Range 41-1964 ppb 82-1738 ppb CRS without Mean ± SD 918 ± 477 ppb 976 ± 350 ppb polyposis Range 179-1964 ppb 402-1738 ppb

CRS with Mean ± SD 468 ± 373 ppb 405 ± 283 ppb polyposis Range 41-1250 ppb 82-1105 ppb

171 Table Hg Baseline total nasal volume

Diagnosis Descriptive Surgical group Medical group statistics CRS Mean ± SD 15.78 ±6.13 cm' 15.99 ±6.39 cm' Range 3.42-30.6 cm' 3.44-34.8 cm'

CRS without Mean ± SD 17.66 ±5.70 cm' 18.6 ± 6.08 cm' polyposis Range 9.29-30.6 cm' 8.95-34.8 cm'

CRS with Mean ± SD 13.31 ±5.94 cm' 11.24 ±3.6 cm' polyposis Range 3.42-28.38 cm' 3.44-19.5 cm'

Table Ilh Baseline total nasal minimum cross-sectional area.

Diagnosis Descriptive Surgical group Medical group statistics CRS Mean ± SD 0.93 ±0.43 cm" 0.87 ±0.35 cm" Range 0.2-2.02 cm" 0.19-1.78 cm" CRS without Mean ± SD 1.04 ± 0.43 cm" 1.01 ± 0.34 cm" polyposis Range 0.49-2.02 cm" 0.47-1.78 cm"

CRS with Mean ± SD 0.80 ±0.41 cm^ 0.62 ±0.22 cm" polyposis Range 0.2-1.89 cm" 0.19-1.01 cm"

172 Table III Baseline endoscopic score

Diagnosis Descriptive Surgical group Medical group statistics CRS Mean ± SD 5.6 ± 1.8 6 ± 1.7 Range 2-10 3-10 CRS without Mean ± SD 5 ±1.5 5.5 ± 1.4 polyposis Range 2-8 3-8 CRS with Mean ± SD 6.3 ± 2 7.2 ± 1.6 polyposis Range 4-10 4-10

Table I lj CT score

Diagnosis Descriptive Surgical group Medical group statistics CRS Mean ± SD 1 3 ± 5 12 ± 4 Range 4-24 5-22

CRS without Mean ± SD 1 0 ± 3 9 ± 2 polyposis Range 4-20 5-15 CRS with Mean ± SD 1 8 ± 5 16± 5 polyposis Range 9-24 7-22

173 Appendix III Baseline data figures

Figure ffl.l The demographic characteristics of the surgical and medical groups

male female asthma non-asthma CRS without CRS with ■ Surgical polyposis polyposis H M edical intervention

174 Figure 111.2 The characteristics of the surgical and medical groups of CRS without polyposis

70.00% 1

60.00%

o 50.00% O) 2 40.00%

Ü 30.00% o Q. 20.00%

10.00%

0 .00%# lale Female Asthma Non-asthm a Surgical group Medical group Intervention

Figure III.3 The characteristics of the surgical and medical groups of CRS with polyposis

70.00%

60.00%

Q) 50.00% O) 03 ■4~> c 40.00% 0) e 30.00% Q) 0_ 2 0 .00%

10.00%

0 .00% Male Female Asthma Non-asthma 1 Surgical group Intervention 1 Medical group

175 Figure HI.4 Box plots of VAS of the surgical and medical groups of CRS

60.DÛ-

50 0 0 - (/) S

C 40 0 0 - 0) m

3 0 .0 0 - S i S i

20.00 4 Surgical group Medical group

Intervention

Filiure III.5 Box plots of VAS of the surgical and medical groups of CRS without polyposis

eo ÛÛ-J

5 0 .0 0 - (/) g

30 00

20 0 0 - Surgical group Medical group

Intervention

76 Figure III.6 Box plots of VAS of the surgical and medical groups of CRS with polyposis

60 00

50 00 sin at . E 40.00 D w g m g n) m

30.00 -

2 0 .0 0 -

Surgical group Medical group

Intervention

Figure III.7 Bar chart of baseline VAS and individual symptom mean scores of the surgical and medical groups of CRS

60

50

(U 0) O) > S u c m o j = Surgical u U ■ e .i5 2 3 I Medical Q O i T3

177 Figure II/.8 Bar chart of baseline VAS and individual syniptoni mean scores of the surgical and medical groups of CRS without polyposis

Surgical Medical

Figure III.9 Bar chart of baseline VAS and individual symptom mean scores of the surgical and medical groups of CRS with polyposis

Surgical Medical

78 Figure III.10 Bar chart of the baseline mean scores of the SNOT of the surgical and medical groups of CBS.

I Surgical SNOT most important 5 I Medical items

Figure III.II Bar chart of the baseline mean scores of the SNOT of the surgical and medical groups of CRS without polyposis

■ Surgical SNOT most important 5 items 11 Medical

179 Fifjure 111.12 Bar chart of the baseline mean scores of the SNOT of the surgical and medical groups of CRS with polyposis

1 Surgical

I Medical must impuitant 5 Items

Figure H I.13 Bar chart of the baseline mean scores of the SF-36 of the surgical and medical groups ofCRS without polyposis

RP RE SF MH EV I Surgical (Medical

80 Figure III. 14 Bar chart of the baseline mean scores of the SF-36 of the surgical and medical groups of CRS without polyposis

Surgical Medical

Figure 111.15 Bar chart of the baseline mean scores of the SF-36 of the surgical and medical groups of CRS with polyposis

Surgical Medical

18 Figure 111.16 Box plots of baseline SCT of the surgical and medical groups of CRS

60 0 0 - 4) £

Surgical group Mgdical group Intervention

Figure IIL17 Box plots of baseline SCT of the surgical and medical groups of CRS without polyposis

60.00 -

4) E a, 50.00' o § rt 4» 40.00' 4) C Î5 30.00' so : V rt w 2 0 .0 0 - 4»

W4) W m 10.00'

Surgical group Medical group

Intervention 82 Figure IH.IH Box plots of baseline SCT of the surgical and medical groups of CRS with polyposis

t.û û -

£ 'Zj

c "C p* 30.00 - x: o o mp% o> 2 0 .0 0 - c U «A rs CO 1 0 .0 0 -1

Surgical group Medical group

Intervention

Figure IIL19 Box plots of baseline total nitric oxide levels of the surgical and medical groups of CRS

2000 .00 -

M W cp* 1000.00 B o ■ * -» 55

0.00 - 1------1------Surgical group Medical group 83 Intervention Figure 111.20 Box plots of baseline total nitric oxide levels of the surgical and medical groups of CRS without polyposis

2Û0Û .0Û -

0) 2 X o 1500 .00 -

w 1 0 0 0 .0 0 -

Î o -t-f .r'.knl. <0 .5 500.00 U) rt jCI

0 .00 - 1------Surgical group kkdical group Intervention

Figure II 1.21 Box plots of baseline total nitric oxide levels of the surgical and medical groups of CRS with polyposis

2ÛÛÛ.0D

2 X o 1500.00 ■

w tn crt 1000.00-

2o V . £ 500.00 (fl41 rt

0.00 -

Surgical group totedical group

Intervention 84 Figure 111.22 Box plots of baseline total nasal volumes of the surgical and medical groups of CRS

^ 3 0 .0 0 E _3 O > U) rt c 2 0 .0 0 - 2 O

4) _C "3 U) 1 0 .0 0 - « m

Surgical group Medical group

Intervention

Figure 111.23 Box plots of baseline total nasal volumes of the surgical and medical groups of CRS without polyposis

3 0 .0 0 ' 2E o > 13 u> c 20.00' 3 o (V _c

W 10.00' m

Surgical group futedlcal group

Intervention 85 Figure 111.24 Box plots of baseline total nasal volumes of the surgical and medical groups of CRS with polyposis

3 0 .0 0 ' E 3 o > 15 19in c 20.00'

2O 0) _c "3 in 10 00 A/ w - CO

Surgical group Medical group

Intervention

Figure III.25 Box plots of baseline MCA of the surgical and medical groups of CRS

rt 2.00 c o o 4) ? % 1.50 ' O V 3£ £ c 1.00 E 15 19in C 15 0 .5 0 ' o

"oi in (9 Surgical group lutedical group m Intervention 86 Figure 111.26 Box plots of baseline MCA of the surgical and medical groups of CRS without polyposis

n

1 3 2 .0 0 - c o *3O 0> U) u> U) 1 . 5 0 - o

3E E "c 1.0 0 - E 15w c 15 0 . 5 0 - -t-l o 4-> c<0 n U) « Surgical group Medical group ID Intervention

Figure 111.27 Box plots of baseline MCA of the surgical and medical groups of CRS with polyposis

01 rt 15 2 . 0 0 - c o ■*3 o 0> (n J i (A 1 .5 0 - o &_ o E 3 E ‘c 1 .0 0 - £ 15 U) (0 ÉMiteswi c 15 0 . 5 0 - * -> o Of c U w p) Surgical group Medical group CD 187 Intervention Fi<*iire III.28 Box plots of CT scores of the surgical and medical groups of CRS

20.00 1

4) &_ oO 0» 1 5 .0 0 ■ 0 1 1 0 .0 0 -

5 . 0 0 -

Surgical group Medical group

Intervention

Fi}»iire 111.29 Box plots of CT scores of the surgical and medical groups of CRS without polyposis.

20 .00 -

o W* 15 .00 • o s o 10 .0 0 -

5 0 0 -

Surglcal group Medical group

Intervention Figure 111.30 Box plots of CT scores of the surgical and medical groups of CRS with polyposis

20.00 -

1 0 .0 0 -

5 .00 -

Surgical group Kitedical group Intervention

89 Appendix IV CRS study tables

Table IVa Baseline and 6-month VAS of the surgical and medical groups of CRS Baseline 6-month Paired VAS VAS t test Group Mean SD Mean SD P value

Surgical CRS 40 11 20 12 <0 .001 group (n = 44) (n = 43)

CRS 40 11 21 12 <0 .001 without polyposis (n =25) (n = 24) CRS 40 10 19 13 <0.001 with polyposis (n=19) (n = 19) Medical CRS 38 9 20 11 <0.001 group (n = 45) (n = 41)

CRS 38 9 22 12 <0.001 without polyposis (n = 29) (n = 26)

CRS 38 8 18 8 <0 .001 with polyposis (n = 16) (n = 15) Logarithmic transformation was applied

190 Table IVb Baseline and 12-month VAS of the surgical and medical groups of CRS

Baseline 12-month Paired VAS VAS t test Group

Mean SD M ean SD P value

Surgical CRS 40 11 19 12 <0.001 group (n = 44) (n = 40)

CRS 40 11 20 11 <0.001 without polyposis (n =25) (n = 21) CRS 40 10 18 14 <0.001 with polyposis (n=19) (n = 19) Medical CRS 38 9 18 12 <0 .001 group (n = 45) (n = 38)

CRS 38 9 21 13 <0.001 without polyposis (n = 29) (n = 25) CRS 38 8 14 7 <0.001 with polyposis (n = 16) (n= 13) Logarithmic transformation was applied

191 Table IVc Baseline and 6-month SCT of the surgical and medical groups of CRS

Baseline 6-month Paired SCT SCT t test G roup Mean SD M ean SD P value (minutes) (minutes)

Surgical CRS 23.9 12 14.9 6.6 <0.00 r group (n = 38) (n = 40)

CRS 19.7 7.9 13.6 5.7 <0 .001 without polyposis (n =23) (n = 21) CRS 30.4 14.5 16.3 7.4 <0.001 with polyposis (n = 15) (n = 1 9 ) M edical CRS 20.8 9 14.9 6.4 <0.001 group (n = 42) (n = 39)

CRS 19 7.1 15 6.8 <0.001 ^ without polyposis (n = 29) (n = 26) CRS 24.8 11.5 14.8 5.9 <0 .001 with polyposis (n = 13) (n = 13) ~W =Wilcoxon signed ranks test

192 Table IVd Baseline and 12-month SCT of the surgical and medical groups of CRS

Baseline 12-month Paired SCT SCT t test G roup Mean SD M ean SD P value (minutes) (minutes)

Surgical CRS 23.9 12 14.3 6.7 < 0.001 group (n = 38) (n = 38)

CRS 19.7 7.9 12.8 5.8 <0.001 without polyposis (n =23) (n = 20) CRS 30.4 14.5 15.9 7.4 <0.001 with polyposis (n= 15) (n = 18) M edical CRS 20.8 9 13.8 6 <0 .001 ^ group (n = 42) (n = 37)

CRS 19 7.1 13.8 6.3 <0.001 without polyposis (n = 29) (n = 25) CRS 24.8 11.5 13.8 5.7 <0.001 with polyposis (n= 13) (n = 12) w =Wilcoxon signed ranks test

193 Table IVe Baseline and 6-month total nasal NO of the surgical and medical groups of CRS

Baseline 6-month Paired total nasal NO total nasal NO t test Group

Mean SD Mean SD P value

(PPb) (PPb) Surgical CRS 724 486 1137 547 <0 .001 group (n = 44) (n = 42)

CRS 918 477 1277 511 <0 .001 without polyposis (n =25) (n = 23) CRS 468 373 969 553 <0.001 with polyposis (n= 19) (n = 19) M edical CRS 773 426 1129 496 <0.001 group (n = 45) (n = 41 )

CRS 976 350 1266 417 <0 .001 without polyposis (n = 29) (n = 26)

CRS 405 283 892 545 <0 .001 with polyposis (n = 16) (n = 15)

194 Table IV f Baseline and 12-month total nasal NO of the surgical and medical groups of CRS

Baseline 12-month Paired total nasal NO total nasal NO t test Group Mean SD Mean SD P value

(PPb) (PPb) Surgical CRS 724 486 1173 524 <0.001 group (n = 44) (n = 40)

CRS 918 477 1336 437 <0.001 without polyposis (n=25) (n = 21) CRS 468 373 994 564 <0.001 with polyposis (n = 19) (n = 19) Medical CRS 773 426 1240 531 <0 .001 group (n = 45) (n = 38)

CRS 976 350 1334 460 <0.001 without polyposis (n = 29) (n = 25) CRS 405 283 1058 625 <0.001 with polyposis (n = 16) (n = 13)

195 Table IVg Baseline and 6-month total nasal volume of the surgical and medical groups of CRS

Baseline 6-month Paired total nasal total nasal t test Group volume volume

Mean SD Mean SD P value (cm^) (crn)

Surgical CRS 15.8 6.1 20.7 7.2 <0 .001 group (n = 44) (n = 42)

CRS 17.7 5.7 21.3 6.4 <0 .01 without polyposis (n =25) (n = 23) CRS 13.3 5.9 20 8.1 <0.001 with polyposis (n = 19) (n= 19) Medical CRS 16 6.4 17.9 6.5 <0.01'" group (n = 45) (n = 41) CRS 18.6 6.1 19.3 6.3 >0 .05 without polyposis (n = 29) (n = 26) CRS 11.2 3.6 15.4 62 <0 .01 with polyposis (n = 16) (n= 15) w =Wilcoxon signed ranks test

196 Table IVh Baseline and 12-month total nasal volume of the surgical and medical groups of CRS

Baseline 12-month Paired total nasal total nasal t test Group volume volume

Mean SD Mean SD P value (crn) (crn)

Surgical CRS 15.8 6.1 20.6 7.2 <0.001 group (n = 44) (n = 40)

CRS 17.7 5.7 20.9 6.6 <0.01 without polyposis (n =25) (n = 21)

CRS 13.3 5.9 20.3 8 <0.001 with polyposis (n= 19) (n = 19) Medical CRS 16 6.4 19.2 7.2 <0 .01 group (n = 45) (n = 38)

CRS 18.6 6.1 20.5 7.1 >0.05^^ without polyposis (n = 29) (n = 25) CRS 11.2 3.6 16.7 7.1 <0.01 with polyposis (n = 16) (n= 13)

=Wilcoxon signed ranks test

197 Table IVi Baseline and 6-month total nasal MCA of the surgical and medical groups of CRS

Baseline 6-month Paired total nasal MCA total nasal MCA t test Group

Mean SD Mean SD P value (crn) (crn) Surgical CRS 0.93 0.44 1.15 0.39 <0 .01 group (n = 44) (n = 42)

CRS 1.03 0.43 1.08 0.38 >0 .05 without polyposis (n =25) (n = 23) CRS 0.8 0.41 1.23 0.4 <0.001 with polyposis (n = 19) (n = 1 9 ) Medical CRS 0.88 0.37 1 0.3 <0.01 group (n = 45) (n = 41)

CRS 1.02 0.35 1.06 0.31 >0 .05 without polyposis (n = 29) (n = 26) CRS 0.62 0.22 0.9 0.27 <0 .001 with polyposis (n = 16) (n= 15)

198 Table IV] Baseline and 12-month total nasal MCA of the surgical and medical groups of CRS

Baseline 12-month Paired total nasal MCA total nasal MCA t test Group

M ean SD M ean SD P value

(crn) (crn )

Surgical CRS 0.93 0.44 1.13 036 <0.01 group (n = 44) (n = 40)

CRS 1.03 0.43 1.1 0.35 >0 .05

without

polyposis (n =25) (n = 21)

CRS 0.8 0.41 1.17 0.39 <0.01

with

polyposis (n= 19) (n = 19)

Medical CRS OjW 0.37 1.07 029 <0 .001 group (n = 45) (n = 38)

CRS 1.02 0.35 1.11 0.31 >0 .05

without

polyposis (n = 29) (n = 25)

CRS 0.62 0.22 1 0.25 <0.001

with

polyposis (n = 16) (n = 13)

199 Table IVk Baseline and 6-month total endoscopic score of the surgical and medical groups of CRS

Baseline 6-month Paired total endoscopic total endoscopic t test Group score score

Mean SD Mean SD P value

Surgical CRS 6 2 2 2 <0 .001 group (n = 44) (n = 43)

CRS 5 2 2 2 <0 .001* without polyposis ^ = 2 5 ) (n = 24)

CRS 6 2 2 2 <0.001 with polyposis (n = 19) (n = 1 9 ) Medical CRS 6 2 3 2 <0.001'^ group (n = 45) (n = 41)

CRS 5 1 3 2 <0 .001 without polyposis (n = 29) (n = 26) CRS 7 2 3 1 <0 .001^ with polyposis (n = 16) (n= 15)

=Wilcoxon signed ranks test

200 Table IVl Baseline and 12-month total endoscopic score of the surgical and medical groups of CRS

Baseline 12-month Paired total endoscopic total endoscopic t test Group score score

Mean SD M ean SD P value

Surgical CRS 6 2 2 2 <0.001 'V group (n = 44) (n = 40)

CRS 5 2 2 2 <0.001* without polyposis (n =25) (n = 21) CRS 6 2 2 2 <0.001 * with polyposis (n=19) (n = 19) Medical CRS 6 2 2 2 <0 .001* group (n = 45) (n = 38)

CRS 5 1 2 2 <0.001 without polyposis (n = 29) (n = 25) CRS 7 2 3 1 <0.001* with polyposis (n = 16) (n= 13)

=Wilcoxon signed ranks test

201 Table IVm 6 and 12-month percentage change of VAS of the surgical and medical groups of CRS

Parameter Group Surgical group Medical group Two % change from % change from samples t baseline baseline test

Mean SD M ean SD P value

6-month % change

VAS CRS 49.7 27.9. 45.3 2&9 >0.05 (n = 43) (n = 41)

CRS 46.6 30.5 40.9 30.2 >0.05 yviihout (n = 24) (n = 26) polyposis

CRS 53.7 24.4 52.7 18.3 >0.05 with (n = 19) (n= 15) polyposis

12-month % change

VAS CRS 51.6 30 50.4 29 >0.05 (n = 40) (n = 38)

CRS 48.7 32.7 44.8 31.9 >0.05 without (n = 21) (n = 25) polyposis

CRS 54.7 27.3 612 19.1 >0.05 with (n = 19) (n = 13) polyposis

Square transformation was applied.

202 Table IVn 6 and 12-month percentage changes of VAS of the surgical

Parameter Group 6-month 12-month Paired t % change from % change from test baseline baseline Mean SD Mean SD P value VAS CRS 49.7 27.9 51.6 30 > 0.05 " (n = 43) (n = 40) CRS 46.6 30.5 48.7 3Z7 > 0.05 " without (n = 24) (n = 21) polyposis CRS 53.7 24.4 54.7 27.3 >0.05 with (n=19) (n = 1 9 ) polyposis

Table IVo 6 and 12-month percentage changes of VAS of the medical groups of CRS

Parameter Group 6-month 12-month Paired t % change from % change from test baseline baseline Mean SD Mean SD P value VAS CRS 45.3 26.9 50.4 29 > 0.05 (n = 41) (n = 38) CRS 40.9 30.2 44.8 31.9 > 0.05 without (n = 26) 01 = 25) polyposis CRS 52.7 18.3 61.2 19.1 >0.05 with (n= 15) (n= 13) polyposis

203 Table IVp 6-month percentage change of the objective measurements of

Parameter Group Surgical group Medical group Two % change from % change from samples t baseline baseline test Mean SD Mean SD P value SCT CRS 30.1 20.3 26a 21.5 >0.05 (n =35) (n = 38) CRS 24.1 15.8 20.1 20.9 >0.05 without (n = 20) (n = 26) polyposis CRS 38 23.4 41.3 15.3 >0.05 with (n= 15) (n= 12) polyposis Total nasal CRS 117 172.7 80.1 110.7 >0.05 NO (n = 42) (n = 41) CRS 56 60.1 40.4 533 > 0.05 without (n = 23) (n = 26) polyposis CRS 190.9 230 149.1 147.9 >0.05 with (n = 19) (n= 15) polyposis Total nasal CRS 3T9 35 17.3 324 <0.01 volume (n = 42) (n = 41) CRS 21.8 23 3.2 11.9 <0.01 without (n = 23) (n = 26) polyposis CRS with 57.3 37.6 41.8 42.8 > 0 4 5 ^ ^ polyposis (n=19) (n = 15) Total nasal CRS 43.7 78.1 25.4 51 > 0.05 *** MCA (n = 42) (n = 41) CRS 8.5 30.4 5.8 16.5 >0.05 without (n = 23) (n = 26) polyposis CRS 86.1 96J 59.2 70.9 > 0 4 5 " ^ with (n = 19) (n= 15) polyposis Total CRS 58.7 32.1 562 26.4 >0.05^'^ endoscopic (n = 43) (n = 41) score CRS 54.8 38 52a 30.2 >0.05 without (n = 24) (n = 26) polyposis CRS 63J 2Z7 62 17.8 >0.05 with (n= 19) (n= 15) polyposis

204 Table IVq 12-month percentage change of the objective measurements of

Parameter Group Surgical group Medical group Two % change from % change from samples t baseline baseline test M ean SD M ean SD P value SCT CRS 312 19.8 30.6 21.8 >0.05 (n =33) (n = 36) CRS 2&6 17.6 24.2 20.5 >0.05 yviihout (n=19) (n = 25) polyposis CRS 37.2 22 45 18 >0.05 with (n = 14) (n= 11) polyposis Total nasal CRS 129.4 180 92.7 127.6 > 0.05 NO (n = 40) (n = 38) CRS 613 63.1 46.5 52.4 > 0 4 5 " * without (n = 21) (n = 25) polyposis CRS 198 2313 181.5 178.2 >0.05 with (n=19) (n= 13) polyposis Total nasal CRS 37.5 35.9 20 38.1 <0.01^'^ volume (n = 40) (n = 38) CRS 18.1 15.8 4.3 14.1 <0.01 without (n = 21) (n = 25) polyposis CRS with 5&8 40 50.3 50.7 > & 05^ * polyposis (n = 19) (n= 13) Total nasal CRS 42.4 79 29.8 61.1 > 0.05 '"'V MCA (n = 40) (n = 38) CRS 10.3 24.1 5.7 16.6 >0.05 without (n = 21) (n = 25) polyposis CRS 77.9 101.6 76.1 86.2 >0.05 with (n =19) (n= 13) polyposis Total CRS 616 333 60.7 263 > 0 .0 5 " * endoscopic (n = 40) (n = 38) score CRS 613 39.1 583 30.1 > 0.05 "* without (n = 21) (n = 25) polyposis CRS 619 26.6 65.2 16.8 > 0.05 " * with (n = 19) (n= 13) polyposis i-Whitney test

205 Table IVr 6 and 12-month percentage change of the objective

Parameter Group 6-month% 12-month®/© Paired t change from change from test baseline baseline Mean SD Mean SD P value SCT CRS 30.1 20.3 32.2 19.8 >0.05 (n =35) (n =33) CRS 24.1 15.8 28.6 17.6 >0.05 without (n = 20) (n = 1 9 ) polyposis CRS 38 23.4 37.2 22 >0.05 with (n= 15) (n = 14) polyposis Total nasal CRS 117 172.7 129.4 180 > 0.05 NO (n = 42) (n = 40) CRS 56 60.1 673 63.1 > 0.05 without (n = 23) (n = 21) polyposis CRS 190.9 230 198 237.3 >0.05 with (n = 19) (n = 19) polyposis Total nasal CRS 374 35 37.5 35.9 > 0.05 'v volume (n = 42) (n = 40) CRS 21.8 23 18.1 15.8 > 0 4 5 * without (n = 23) (n = 21) polyposis CRS with 57.3 37.6 58.8 40 >0.05 polyposis (n = 19) (n = 19) Total nasal CRS 43.7 78.1 42.4 79 > 0 .0 5 * MCA (n = 42) (n = 40) CRS 8.5 30.4 10.3 24.1 > 0 .0 5 * without (n = 23) (n = 21) polyposis CRS 86.1 96.5 77.9 101.6 >0.05 with (n = 19) (n = 19) polyposis Total CRS 58.7 32.1 62^ 333 > 0.05 * endoscopie (n = 43) (n = 40) score CRS 54.8 38 623 39.1 > 0.05 * without (n = 24) (n = 21) polyposis CRS 63 J 22.7 624 2&6 > 0 .0 5 * with (n = 19) (n = 19) polyposis

206 Table IVs 6 and 12-month percentage change of the objective measurements of the medical groups Parameter Group 6-month% 12-month% Paired t change from change from test baseline baseline Mean SD Mean SD P value SCT CRS 2&8 21.5 306 21.8 >(105 (n = 38) (n = 36) CRS 20.1 20.9 24.2 20.5 >0.05 without (n = 26) (n = 25) polyposis CRS 41.3 15.3 45 18 <0.05 with (n = 12) (n = 11) polyposis Total nasal CRS 80.1 110.7 922 127.6 >(105 NO (n = 41) (n = 38) CRS 40.4 532 46.5 52.4 >0.05 without (n = 26) (n = 25) polyposis CRS 149.1 147.9 181.5 178.2 <0.01 with (n = 15) (n = 13) polyposis Total nasal CRS 17.3 329 20 38.1 > 0.05 volume (n = 41) (n = 38) CRS 3.2 11.9 4.3 14.1 > 0.05 without (n = 26) (n = 25) polyposis CRS with 41.8 42.8 50.3 50.7 > 0 2 5 " polyposis (n = 15) (n = 13) Total nasal CRS 25.4 51 292 61.1 > 0.05 " MCA (n = 41) (n = 38) CRS 5.8 16.5 5.7 16.6 > 0.05 " without (n = 26) (n = 25) polyposis CRS 592 70.9 76.1 86.2 >0.05 with (n= 15) (n= 13) polyposis Total CRS 562 26.4 60.7 262 > 0.05 " endoscopic (n = 41) (n = 38) score CRS 52^ 302 582 30.1 > 0.05 " without (n = 26) (n = 25) polyposis CRS 62 17.8 652 16.8 > 0.05 with (n= 15) (n= 13) polyposis test

207 Appendix V CRS study figures

F igure V .l Flow chart of chronic rhinosinusitis trial stages

Assessed for eligibility (n=327)

Excluded (n=237) ’“Not meeting inclusion criteria (n=34) ’“Refused to participate (n=196) ’“Lost (n=7)

Randomised (n=90)

Allocated to Allocated to medical treatment surgical treatment (n=45) (n=45) ’“Received the ’“Received the treatment (n=45) treatment (n=44) ’“Did not receive the ’“Did not receive the treatment (n=0) treatment (n=l): Patient unavailable

6-month follow- 6-month follow- up up *Lost to follow-up ’“Lost to follow-up (n=4); patients (n=l): patien t unavailable. unavailable. ’“Discontinued ’“Discontinued treatment (n=0) treatment (n=0) ’“Analysed (n=41) ’“Analysed (n=43)

r r 12-month follow- 12-month follow- up up ’“Lost to follow-up (n=7): patients ’“Lost to follow- unavailable. up (n=4); patien ts ’“Discontinued unavailable. treatment (n=0) ’“Discontinued 208 ’“Analysed (n=38) treatment (n=0) ’“Analysed (n=40) Figure V.2 Changes in the mean VAS scores of the surgical groups

45 n

40 -

35 -

30 -

25 -

20 -

- # " CRS baseline after 6 after 12 □ ------CRS without polyposis months m onths — A — CRS with polyposis

F igure V.3 Changes in the mean VAS scores of the medical groups

45 ■ # " CRS — O — CRS without polyposis 40 — -A — CRS with polyposis

35

0) 30 8 ^ 25 \V I. s s 15

10

5

0 baseline after 6 after 12 months months

209 Figure V.4 Changes in the mean nasal blockage scores of the surgical groups

10 n ■ CRS — □ ------CRS without polyposis — -A — CRS with polyposis

O)

baseline after 6 after 12 months m onths

F igure V.S Changes in the mean nasal blockage scores of the medical groups

10 -1 CRS CRS without polyposis ^ ■ " ■ C R S with polyposis

O)

- 0

baseline after 6 after 12 months m onths

210 Figure V.6 Changes in the mean nasal discharge scores of the surgical groups

10 CRS 9 -C R S without polyposis 8 ■CRS with polyposis 7

6 5 4 3 2 1 0 baseline after 6 after 12 months months

F igure V.7 Changes in the mean nasal discharge scores of the medical groups

1 0 -I CRS CRS without polyposis 'CRS with polyposis

O)

-a

baseline after 6 after 12 m onths m onths

211 Figure V.8 Changes in the mean olfactory disturbance scores of the surgical groups

10 -1 CRS CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 months months

F igure V.9 Changes in the mean olfactory disturbance scores of the medical groups

10 1 # " CRS CRS without polyposis ■CRS with polyposis

baseline after 6 after 12 months months

212 Figure V.IO Changes in the mean pain scores of the surgical groups

1 0 -I « - CRS CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 months months

Figure V,ll Changes in the mean pain scores of the medical groups

CRS CRS without polyposis 'CRS with polyposis

O.

- 0

baseline after 6 after 12 months months

213 Figure V.12 Changes in the mean headache scores of the surgical groups

10 -, # - CRS CRS without polyposis 'CRS with polyposis

T3

baseline after 6 after 12 months m onths

Figure V.13 Changes in the mean headache scores of the medical groups

1 0 -I # " CRS CRS without polyposis 'CRS with polyposis

T3

baseline after 6 after 12 months m onths

214 Figure V.14 Changes in the mean overall discomfort scores of the surgical groups

10 -1 # - CRS CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 months m onths

Figure V.15 Changes in the mean overall discomfort scores of the medical groups

10 -1

CRS without polyposis 'CRS with polyposis

■o

baseline after 6 after 12 months m onths

215 Figure V.16 Changes in the mean SNOT scores of the surgical groups

2.5 CRS •CRS without polyposis 2 - ■CRS with polyposis uo w 1.5 oI- z cn c 3 0.5

baseline after 6 after 12 months m onths

Figure V.17 Changes in the mean SNOT scores of the medical groups

# - CRS CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 months m onths

216 Figure V.l8 Changes in the mean SNOT most important 5 item scores of the surgical groups

4.5 -, # - CRS If) CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 m onths m onths

Figure V.19 Changes in the mean SNOT most important 5 item scores of the medical groups

CRS in CRS without polyposis 'CRS with polyposis

a

baseline after 6 after 12 months m onths

217 Figure V.20 Changes in the mean PF scores of the surgical groups

100 CRS 90 -CRS without polyposis 80 - •CRS with polyposis 70 - 60 50 40 - 1 30 20 10

baseline after 6 after 12 months m onths

Figure V.21 Changes in the mean PF scores of the medical groups

100 CRS 90 ■CRS without polyposis 80 - "■fi "CRS with polyposis 2 70 uo (4 60 UL 50 QL C 40 3 30 20 4 10

baseline after 6 after 12 m onths m onths

218 Figure V.22 Changes in the mean RP scores of the surgical groups

100 -| CRS 90 - CRS without polyposis 80 - 'CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 months m onths

Figure V.23 Changes in the mean RP scores of the medical groups

100 -] CRS 90 - CRS without polyposis 80 - 'CRS with poiyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

219 Figure V.24 Changes in the mean RE scores of the surgical groups

100 1 # " CRS 90 - CRS without polyposis 80 - 'CRS with polyposis 70 - -O 60 - 50 - 40 - 30 -

20 -

baseline after 6 after 12 m onths m onths

Figure V.25 Changes in the mean RE scores of the medical groups

100 -, CRS 90 - CRS without polyposis 80 - 'CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 - 10 -

baseline after 6 after 12 m onths m onths

220 Figure V.26 Changes in the mean SF scores of the surgical groups

100 n CRS 90 - CRS without polyposis 80 - ‘CRS with polyposis 70 - 60 - ^ 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

Figure V.27 Changes in the mean SF scores of the medical groups

100 - | 90 - g :: U) 60 - # - CRS W 50- CRS without polyposis C 40 - 'CRS with polyposis ra ® 30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

221 Figure V.28 Changes in the mean MH scores of the surgical groups

100 -| CRS 90 - 'CRS without polyposis 80 - 'CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 months m onths

Figure V.29 Changes in the mean MH scores of the medical groups

100 -, 90 -

80 -

70 -

60 - CRS 50 - CRS without polyposis 'CRS with polyposis 40 -

30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

222 Figure V.30 Changes in the mean EV scores of the surgical groups

1 0 0 -I • " CRS 90 - CRS without polyposis 80 - 'CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 months m onths

Figure V.31 Changes in the mean EV scores of the medical groups

100 n 90 - 80 - 70 - 60 - # " CRS 50 - * CRS without polyposis 40 - CRS with polyposis 30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

223 Figure V.32 Changes in the mean P scores of the surgical groups

100 -> CRS 90 - CRS without polyposis 80 - ‘CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baselineafter 6 after 12 months m onths

Figure V.33 Changes in the mean P scores of the medical groups

100 # " CRS 90 - CRS without polyposis 80 - ‘CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 months m onths

224 Figure V.34 Changes in the mean GHP scores of the surgical groups

1 0 0 -I * " CRS 90 - CRS without polyposis 80 - 'CRS with polyposis 70 - 60 - 50 - 40 - 30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

Figure V.35 Changes in the mean GHP scores of the medical groups

100 n CRS 90 - CRS without polyposis

80 - 'CRS with polyposis

70 -

60 -

50 -

40 -

30 -

20 -

10 -

baseline after 6 after 12 m onths m onths

225 Figure V.36 Changes in the mean SCT of the surgical groups

35 1 CRS ■CRS without polyposis "wT 30 - 0) ■CRS with polyposis 3 25 - C E 70 - H- Ü 1b - W c 10 - (U 0) S 5 -

baseline after 6 after 12 months m onths

Figure V.37 Changes in the mean SCT of the medical groups

30 -1 » ■ CRS CRS without polyposis 'CRS with polyposis

10 -

baseline after 6 after 12 m onths m onths

226 Figure V.38 Changes in the mean total NO levels of the surgical groups

1600 -1 CRS CRS without polyposis ^ 1400 - ja 'CRS with polyposis S- 1200 -

1000 - 800 - 600 - 400 - 200

baseline after 6 after 12 months months

Figure V.39 Changes in the mean total NO levels of the medical groups

1600 -I CRS * CRS without polyposis ^ 1400 - Xi ^ ^ “ CRS with polyposis 1200 -

1000 - 800 - 600 - 400 -

200 -

baseline after 6 after 12 months months

227 Figure V.40 Changes in the mean total nasal volumes of the surgical groups

25 -1 CRS CRS without polyposis 'CRS with polyposis

15 -

10 -

baseline after 6 after 12 months m onths

Figure V.41 Changes in the mean total nasal volumes of the medical groups

25 -, # " CRS CRS without polyposis 'CRS with polyposis 20 - O

baseline after 6 after 12 m onths m onths

228 Figure V.42 Changes in the mean total MCA of the surgical groups

1.4 CRS -C R S without polyposis 1 .2 -I ■CRS with polyposis " ue 1 4 < 0.8 O s 0 . 6 4

3 0.4 s 0.2

baseline after 6 after 12 months m onths

Figure V.43 Changes in the mean total MCA of the medical groups

# " CRS CRS without polyposis ‘CRS with polyposis

O 0.6

baseline after 6 after 12 m onths m onths

229 Figure V,44 Changes in the mean endoscopic score of the surgical groups

# - CRS CRS without polyposis 'CRS with polyposis X

■a

baseline after 6 after 12 m onths m onths

Figure V.45 Changes in the mean endoscopic score of the medical groups

CRS CRS without polyposis 'CRS with polyposis

baseline after 6 after 12 m onths m onths

230 Appendix VI Asthma study tables

Table Via Changes in the chest score of the asthma group

G roup Chest Baseline 6-month Sign test 12-month Sign test

score %% P value % P value 0 4.5 9.1 >0.05 9.5 >0.05 1 40.9 50 47.6 on 2 273 18.2 23 j a 3 22.7 18.2 14.3 4 4.5 4.5 4.8

a. 0 10 10 >0.05 11.1 >0.05 3 1.2 &J0 1 40 50 44.4 t ÎI C/) "S 2 20 20 222 *5d ex. 3 30 20 cn U 3 22.2 0 8.3 >0.05 8.3 >0.05 1 41.7 50 50 2 33.3 16.7 25 SI 3 16.7 16.7 8.3 4 8.3 8.3 8.3 1 35 57.9 <0.05 64.7 <0.01 2 45 31.6 29.4 g 3 20 10.5 5.9 Ou 3 1 40 6 6 J >0.05 77.8 >0.05 O -M .52 Oil 2 50 222 11.1 "3 s l | 0 | | 3 10 11.1 11.1 1 .52 1 30 50 >0.05 50 >0.05 "T€ (A 2 40 40 50 eg ^ 6 È 3 30 10

231 Table VIb Use of bronchodilator inhalers in the asthma group

G roup Use of 6-month Sign test 12-month Sign test broncho­ % % dilator

inhalers P value P value (Compared to baseline)

Less 45.5 <0.05 47.6 <0.05 c/5 Same 50 47.6 g More 4.5 4.8 a. ; ^ .2 Less 50 >0.05 55.6 >0.05 5x) Same 50 44.4 u '5d k Ni^ a 3 C/5 Less 41.7 >0.05 41.7 >0.05 Same 50 50 r s g i More 8.3 8.3 47.4 <0.01 c/5 Less 52.9 <0.01 g Same 52.6 47.1 Less 333 >0.05 33.3 >0.05 a -M .a ; Same 66.7 66.7 So e|i ^ a 1 13 Less 60 <0.05 75 <0.05 ^ .a

^ 1CL (/) ^ Same 40 25 o U a-

232 Table Vie Use of corticosteroid inhalers in the asthma group

G roup Use of 6-month Sign test 12-month Sign test cortico­ % % steroid

inhalers P value P value (Compared to baseline)

Less 36.4 >0.05 38.1 >0.05 C/5 Same 54.5 52.4 g More 9.1 9.5 CL Less 40 >0.05 44.4 >0.05 i § ” k, Same 50 44.4 s I 1 ox C/5 "O L. P< CL More 10 11.1 3 u C/5 Less 333 >0.05 333 >0.05 Î a Same 583 58.3 « "o U a More 8.3 8.3 Less 15.8 >0.05 17.6 >0.05 C/5 g Same 84.2 82.4 Less 11.1 >0.05 11.1 >0.05 CL ^ .23 3 O Same 884 884 0Î5 "3 Ml^ CL "3 Less 20 >0.05 25 >0.05 1 6 .ss g 13. c n Same 80 75 O U »•

233 Table VId Changes in the overall asthma control score of the asthma group

G roup Asthma Baseline 6-month Sign test 12-month Sign test

control %% P value % P value score

1 13.6 13.6 <0.01 9.5 <0.05

C/5 2 40.9 18.2 2&6 6 3 31.8 31.8 2&6 4 13.6 36.4 333

Q. 1 10 0 >0.05 0 >0.05 3 2o .2 ^ k c 2 30 40 44.4 o IIcn "o 3 50 10 11.1 'go a 3 U 4 10 50 cn 44.4 1 16.7 25 >0.05 16.7 >0.05 2 50 0 16.7 ^ g. % 3 16.7 50 41.7 g l 4 16.7 25 25 1 10 5.3 <0.01 0 <0.01

cn 2 55 31.6 233 r/ u 3 25 42.1 52.9 4 10 21.1 233 a. 2 60 333 >0.05 11.1 >0.05 3 o 1O .3(A 55.6 5 jd 3 30 77.8 S, 3 I . a C / 2 O 4 10 11.1 11.1 13 C25 a 1 U 1 20 10 <0.05 0 <0.05 -B .22 2 50 30 37.5 o n, 3 20 30 25

it 4 10 30 37.5

234 Table Vie Baseline and 6-month exhaled NO of the asthma group

Baseline 6-month Paired exhaled NO exhaled NO t test G roup Mean SD Mean SD P value

(ppb) (ppb) Surgical CRS 20.13 9.13 15.57 8.59 <0.05 group (n = 22) (n = 21)

CRS 17.90 7.57 12.41 5^8 >0.05 without polyposis (n = 10) (n = 9) CRS 21.99 10.19 17.93 9.73 >0.05 with polyposis (n = 1 2 ) (n = 12) M edical CRS 19.35 7.49 14.37 6.60 <0.01 group (n = 20) (n = 1 9 )

CRS 16.98 5.84 12.28 6.12 <0.05 without polyposis (n = 10) (n = 9) CRS 21.72 8.48 16.25 6.75 < 0.05 with polyposis (n = 10) (n = 10) ~w=Wilcoxon signed ran cs test

235 Table V if Baseline and 12-month exhaled NO of the asthma group

Baseline 12-month Paired exhaled NO exhaled NO t test Group

Mean SD Mean SD P value (ppb) (ppb) Surgical CRS 20.13 9.13 15.18 8.70 <0.05 group (n = 22) (n = 21) CRS 17.90 7.57 11.58 5.56 >0.05 without polyposis (n = 10) (n = 9) CRS 21.99 10.19 17.88 9.82 >0.05 with polyposis (n = 12) (n = 12) M edical CRS 19.35 7.49 12.28 5.47 <0.001 group (n = 20) (n= 17)

CRS 16.98 5.84 11.11 4.91 <0.05 without polyposis (n = 10) (n = 9) CRS 21.72 8.48 13.59 6.09 <0.001 with polyposis (n = 10) (n = 8)

236 Table VIg Baseline and 6-month FEV1% of asthma group

Baseline FEV1% 6-month FEV1% Paired ( percentage of ( percentage of t test G roup predicted value) predicted value)

Mean SD M ean SD P value

Surgical CRS 85.27 . 12.97 8829 13.23 <0.05 group (n = 22) (n = 21) CRS 84.50 12.83 90.22 11.41 >0.05 without polyposis (n = 10) (n = 9) CRS 8542 13.62 86.83 14.78 >0.05 with polyposis (n= 12) (n = 12) Medical CRS 85 9.01 87.58 9.11 <0.01 group (n = 20) (n = 1 9 ) CRS 8 7 j 9.80 91.22 10.17 <0.01 without polyposis (n = 10) (n = 9) CRS 8Z20 7.63 84.30 648 >0.05 with polyposis (n = 10) (n = 10)

237 Table VJh Baseline and 12-month FEV1% of the asthma group

Baseline 12-month Paired FEV1% FEV1% t test Group (% of predicted (% of predicted value) value)

Mean SD Mean SD P value

Surgical CRS 85.27 12.97 8 8 J6 12.80 <0.05 group (n = 22) (n = 21)

CRS 84.50 12.83 90.44 11.08 >0.05 without polyposis (n = 10) (n = 9) CRS 85.92 13.62 87.50 14.31 >0.05 with polyposis (n= 12) (n = 12) M edical CRS 85 9.01 8 9 j# 8.17 <0.001 group (n = 20) (n = 17)

CRS 87.8 9.80 92.89 8.98 <0.01 without polyposis (n = 10) (n = 9) CRS 82.20 7.63 86.50 5.98 <0.01 with polyposis (n = 10) (n = 8)

238 Table VU Baseline and 6-month PEF of asthma group

Baseline 6-month Paired PEF PEF t test Group (% of predicted (% of predicted value) value)

Mean SD Mean SD P value

Surgical CRS 92.18 19.99 95.71 21.06 > 0.05 group (n = 22) (n = 21) CRS 87.20 16.98 93.88 18.80 > 0.05 without polyposis (n = 10) (n = 9) CRS 9633 22.05 97.08 2333 >0.05 with polyposis (n= 12) (n = 12) M edical CRS 87.90 14.92 91.53 15.74 < 0.05 group (n = 20) (n = 1 9 )

CRS 87.30 10.35 94 13.23 < 0.05 without polyposis (n = 10) (n = 9) CRS 8830 19.02 89.30 18.11 > 0.05 with polyposis (n = 10) (n = 10)

=WiIcoxon signed ran ks test

239 Table Vlj Baseline and 12-month PEF of asthma group

Baseline 12-month Paired PEF PEF t test G roup (% of predicted (% of predicted value) value)

Mean SD Mean SD Pvalue

Surgical CRS 92.18 19.99 95.95 21.20 > 0.05 group (n = 22) (n = 21) CRS 87.20 16.98 93.78 18.98 > 0.05 * without polyposis (n = 10) (n = 9) CRS 9633 22.05 97.58 23.42 >0.05 with polyposis (n= 12) (n = 12) M edical CRS 87.90 14.92 95.06 13.83 <0.01 group (n = 20) (n = 17) CRS 87.30 10.35 96.11 13.89 < 0.05 without polyposis (n = 10) (n = 9) CRS 8830 19.02 93 14.60 >0.05 with polyposis (n = 10) (n = 8) w =Wilcoxon signed ran ks test

240 Table Vlk 6-month percentage change of the objective lower airway measurements of the asthma group Param eter Group Surgical group Medical group Two % change from % change from samples t baseline baseline test Mean SD M ean SD P value Exhaled CRS 16.33 40.05 25.16 20.71 > 0.05 NO (n = 21) (n = 19) CRS 23.83 38.14 26.68 19.48 >0.05 without (n = 9) (n = 9) polyposis CRS 10.71 42.16 23.80 22.72 > 0.05 with (n = 12) (n = 10) polyposis FEV1% CRS 3.31 7.9 3.94 4.53 >6:05"" (n = 21) (n = 1 9 )

CRS 6.40 936 5.31 4.69 >0.05 without (n = 9) (n = 9) polyposis CRS 0.99 5.50 2.71 4.23 >0.05 with (n= 12) (n = 10) polyposis

PEF CRS 4.03 12,49 4.59 10.49 > 0 .0 5 " " (n = 21) (n = 19)

CRS 8 j6 15.28 8.06 12.39 > 0 .0 5 " " without (n = 9) (n = 9) polyposis CRS 0.64 920 1.47 7.81 >0.05 with (n= 12) (n = 10) polyposis IMW= Mann-Whitney test

241 Table VU 12-month percentage change of the objective lower airway measurements of the asthma group

Param eter Group Surgical group Medical group Two % change from % change from samples baseline baseline t test

Mean SD Mean SD P value Exhaled CRS 20.05 3332 36.89 18.07 >0.05 NO (n = 21) (n = 17) CRS 28.97 34.80 3230 20.50 >0.05 without (n = 9) (n = 9) polyposis CRS 13.36 31.99 42.06 14.44 <0.05 with (n = 12) (n = 8) polyposis FEV1% CRS 195 7.87 5.88 4.05 > 1 0 5 " * (n = 21) (n = 17)

CRS 6.77 10.13 5.10 3.72 >0.05 " * without (n = 9) (n = 9) polyposis CRS 1.83 5.15 6.76 4.47 <0.05 with (n = 12) (n = 8) polyposis PEF CRS 4.14 12.30 7.59 12 > 0.05"* (n = 21) (n = 17)

CRS 839 15.95 8.87 14.88 >0.05 " * without (n = 9) (n = 9) polyposis CRS 0.96 8.04 6.16 8.49 >0.05 with (n= 12) (n = 8) polyposis 1VTW =Mann-Whitney test

242 Table Vim 6 and 12-month percentage change of the objective lower

P aram eter Group 6-month 12-month Paired % change from % change from t test baseline baseline

Mean SD M ean SD P value Exhaled CRS 16.33 40.05 20.05 3332 > 0.05 NO (n = 21) (n = 21) CRS 23^3 38.14 28.97 34.80 > 0.05 without (n = 9) (n = 9) polyposis CRS 10.71 42.16 13.36 31.99 > 0.05 with (n = 12) (n = 12) polyposis FEV1% CRS 3.31 7.9 3.95 7.87 > 0.05 (n = 21) (n = 21)

CRS 6.40 936 6.77 10.13 > 0.05 without (n = 9) (n = 9) polyposis

CRS 0.99 5.50 1.83 5.15 > 0.05 ^ with (n = 12) (n = 12) polyposis

PEF CRS 4.03 12.49 4.14 12.30 >0.05 (n = 21) (n = 21)

CRS 8 j6 15.28 839 15.95 > 0.05 without (n = 9) (n = 9) polyposis CRS 0.64 9.20 0.96 8.04 >0.05 with (n = 12) (n = 12) polyposis w = Wilcoxon signed ranks test

243 Table Vin 6 and 12-month percentage change of the objective lower

P aram eter Group 6-month 12-month Paired % change from % change from t test baseline baseline

Mean SD M ean SD P value Exhaled CRS 25.16 20.71 3 6 j# 18.07 <0.01'^ NO (n = 19) (n = 17) CRS 26.68 19.48 32.30 20.50 >0.05 without (n = 9) (n = 9) polyposis CRS 23^0 22.72 42.06 14.44 <0.05 with (n = 10) (n = 8) polyposis FEV1% CRS 3.94 4.53 5jW 4.05 >0.05 (n = 19) (n = 17)

CRS 5.31 4.69 5.10 3.72 >0.05 without (n = 9) (n = 9) polyposis

CRS 2.71 4.23 6.76 4.47 <0.05 with (n = 10) (n = 8) polyposis PEF CRS 4.59 10.49 7.59 12 >0.05 (n = 19) (n = 17) CRS 8.06 12.39 8.87 14.88 >0.05 without (n = 9) (n = 9) polyposis CRS 1.47 7.81 6.16 8.49 >0.05 with (n = 10) (n = 8) polyposis IV = Wilcoxon signed ranks test

244 Appendix VII Asthma study figures

Figure VII.l Flow chart of the effect of CRS treatment on asthma trial stages

Assessed for eligibility (n=102)

Excluded (n=59) ""Not meeting inclusion criteria (n=8) ""Refused to participate (n=51) ""Lost (n=0)

Randomised (n=43)

Allocated to Allocated to medical treatment surgical treatment (n=20) (n=23) ""Received the ""Received the treatment (n=20) treatment (n=22) ""Did not receive the ""Did not receive the treatment (n=0) treatment (n=l): Patient unavailable

6-month follow- 6-month follow- up up *Lost to follow-up *Lost to follow-up (n=l); patient (n=0) unavailable. ""Discontinued ""Discontinued treatment (n=0) treatment (n=0) ""Analysed (n=22) * Analysed (n=19)

12-month follow- 12-month up follow-up ""Lost to follow-up ""Lost to follow- (n=3); patients up (n=l): patien t unavailable. unavailable. ""Discontinued ""Discontinued treatment (n=0) treatment (n=0) 245 ""Analysed (n=17) ""Analysed (n=21) Figure VIL2 Changes in the mean exhaled NO of the asthmatic surgical groups

25 -, # - CRS CRS without polyposis 'CRS with polyposis 20 -

■a

Baseline after 6 after12 m onths m onths

Figure VII.3 Changes in the mean exhaled NO of the asthmatic medical groups

25 1 # - CRS CRS without polyposis ‘CRS with polyposis

15 -

Baseline after 6 afterl 2 m onths m onths

246 Figure VIL4 Changes in the mean FEV1% (% of predicted value) of the asthmatic surgical groups

100 -1 •CRS 90 - -C R S without polyposis 80 - ■CRS with polyposis 70 -

60 -

u_ 50 -

40 -

30 -

20 -

Baseline after 6 after 12 months months

Figure VII.5 Changes in the mean FEV1% (% of predicted value) of the asthmatic medical groups

100 1 ■CRS 90 - -C R S without polyposis 80 - ■CRS with polyposis

60 - u. 50 - 40 - 30 -

20 -

10 -

Baseline after 6 after 12 m onths m onths

247 Figure VII.6 Changes in the mean PEF (% of predicted value) of the asthmatic surgical groups

110 •CRS

100 - ■CRS without polyposis ■CRS with polyposis 80 - u_ 70 - LUQ. c 3 50 - s 40 - 30 -

20 -

10 -

Baseline after 6 after 12 months m onths

Figure VII.7 Changes in the mean PEF (% of predicted value) of the asthmatic medical groups

100 1 •CRS

90 - CRS without 80 - polyposis 70 - CRS with 60 - 50 - 40 - 30 -

20 -

10 -

Baseline after 6 after 12 m onths m onths

248 Appendix Vlll Nitric oxide study figures

Figure VIII. 1 Boxplot of baseline nasal NO against CT score grades (n =178,grade! = 56, grade! = 8 3 ,grade3 = 39)

1 Û D Û . D 0 -

■5 X 75Û.DÛ' O o

500.00 rt c a> c

U) 250.00 rt m

0 .0 0 - —r~ —r~ —r~ 1 .0 0 2.00 3.00 CT grades

249 Figure VI1L2 Correlation between 6-month NO and SCT changes (n=73)

Linear Regression

1 5 0 -

o O

c 0 5 0 -

VD

0.00 0 00 0 50 1 0 0 Log 6-month NO improvemem (logno21)

6-month SCT improvement = 0.92 + -0.94 * logno21 R S(|uare = 0.75

Figure VIIIJ Correlation between 12-month NO and SCT changes (n=69)

Linear Regression

1 5 0 -

Ç 0 5 0 - O'ÿ

0.00 0.25 0.50 0.75 hOO Log12-month NO improvement f/ogno,

12-month SCT Im provem ent = 0.92 + -0.96 • logno31 R Square = 0.76 250 Figure V/II.4 Correlation between the 6-month NO and VAS changes (n=83)

Û.ÛO c o ■25 DO E m 5 •50.00 sz c o f e e E -75.00

0 DO 250 00 750 00 1000 00 6-month NO improvement

Figure VIII.5 Correlation between the 12-month NO and VAS changes (n=78)

0.00 c 4» £ 4» > O -25 00 Q. £ (/) o;:. § -60 00 sz c o £ -75 00

- 1 0 0 .0 0

0 00 250.00 500.00 750 00 12-month NO improvement

25 Figure VIII.6 Correlation between the 6-month NO and endoscopic score changes (n=163)

1200 .0 0 - w CD

4-> c o 400.00 - (6

0.00 -

worse or no change marked improvement mild to moderate improvement 6-month endoscopic score changes

Figure VIII.7 Correlation between the 12-month NO and endoscopic score changes (n=154)

1500 .00 -

m 1000 .00 -

z

0 00 -

worse or no change marked improvement mild to moderateimprovement 12-month endoscopic score changes 252 Figure VIll.8 Correlation between the 6-month NO and polyp grade changes(n=68)

1200.00' w 4» 03 C SO 800.00 - o

c 9 400 .00 - E

0 .00 - I I I---- tuio grade improvement no change one grade improvement 6-month polyp grade changes

Figure VIII.9 Correlation between the 6-month NO and polyp grade changes(n=64)

in 4> ^ 1000.00 - rJ JZo O Z

O 500.00 - £

0 0 0 -

three grade improvement one grade improvement two grade improvement no change 12-month polyp grade changes 253 Figure VIII.10 Correlation between the 6-month NO changes and surgical score groups (n=84)

u> 4» Œ rtC sz o 800 0 0 - O z •B c o 400 00 - E (Ô

0.00 ■

group t group 2 Surgical score

Figure VIII.11 Correlation between the 12-month NO changes and surgical score groups (n=80)

1500 .00 -

(n 4) ^ 1000.00 - rt o O

O 500 .00 M

■* V-,

0 .0 0 - — r~ 1--- group group 2 Î54 Surgical score Figure VIII. 12 Correlation between the 6-month NO changes and age ( 11=8 3)

moo 00

c 750.00 E > o

g 500.00 — o z £ Oc 250.00 E (Ô o o o o

0 0 0 -

30 00 40.00 50.00 6 0 .00 70.00 age

Figure VIII. 13 Correlation between the 12-month NO changes and age (n=78)

moo 00

750 00

a.

500.00

250 0 0 -

CM

0.00 0-0

40,0030.00 50 DO 60.00 70.00 age

255 Figure VIII.14 Box plots of the 6-month NO changes versus sex

1000.00

C 7 5 0 .0 0 - E o> > o

0" 500.00 - o Z 5 oc 250.00 E (O

0 .0 0 -

— I— 1--- male female

sex

Figure VIII.15 Box plots of the 12-month NO changes versus sex

1000.0 0 -

c 0) 2 750.00' 0) > o C&_l. — 500.00' O z

c ® 250.00' CM

0.00 -

—r~ — I— male fem ale

sex 256 Figure VHI.16 Boxplots of the 6-month NO changes versus smoking history

1000 00 M

5 7:0.00. E 0) > o

0 " 500.00 O z 5 oc 250 00 E (O

0 00-1

s m o k e rs non-smokers

Smoking

Fi}>ure VIII.17 Boxplots of the 12-month NO changes versus smoking history

1000 0 0 -

c « E 750.00- o> > o

500 00' O z ■£ c o 260 0 0 - E

0 0 0 ' 1 1----- smokers non-smokers

Smoking 257 Figure VIII.18 Boxplots of the 6-month NO changes versus SPT

760.00 -

600.00 -

260.00

0 .0 0 -

negative

Skin Prick Test

Figure VIII.19 Boxplots of the 12-month NO changes versus SPT

1000.0 0 -

c@1 2 760 00' 01 > o k . a. • - 500.00 O z £ c ® 250.00 CM

0 .0 0 -

1— I positive negative

Skin Prick Test

258 Figure VIII.20 Boxplots of the 6-month NO changes versus grass pollen sensitivity

1ÛÛD.0Û-

C 750.00- E 1) > o

^ 500.00 - O z s : oc 250.00 - <£>

0 0 0 -

positive negative

Grass Pollen sensitivity

Figure Vlll.21 Boxplots of the 12-month NO changes versus grass pollen sensitivity

1 0 0 0 .0 0 -

c •V E 750.00- > 2 CL E 500.00 - O

c o 250.00 - E

0 .0 0 -

positlve negative

Grass Pollen sensitivity 259 Figure VIII.22 Boxplots of the 6-month NO changes versus family history of allergy

1 0 0 0 ,0 0 -

c 01 7 50 .0 0 - £ 01 > o C- E 500.00 - O z ■B c o 250.00 E

0 .0 0 - IT

positive negative

Family history

Figure VIII.23 Boxplots of the 12-month NO changes versus family history of allergy

1000.00-

c01 2 750.00 ' 01 > o CL

■— 500 .00 ' o z x: c 260.00 - E (N

0 .0 0 - 1--- p o sitiv e n e g a tiv e

Family history 260 8. Bibliography

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