The extent of endoscopic sinus surgery in patients with severe chronic rhinosinusitis with nasal polyps (AirGOs Operative)*

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the nose and paranasal sinuses characterized by intense inflammation, decreased health-related quality of life (HRQoL), and in severe cases high frequency of co-morbidities and recurrence despite treatment. Conservative treatment consists of nasal lavage, intranasal corticosteroids, and courses of oral corticosteroids, and antibiotics in exacerbations. Endoscopic sinus surgery (ESS) and/or biological therapy is considered if appropriate conservative treatment is not sufficient. The optimal extent of ESS in recalcitrant CRSwNP is not known. The aim of this randomized controlled trial is to evaluate and compare the efficacy and safety of limited ESS with partial ethmoidectomy with extended ESS with total ethmoidectomy in patients with severe CRSwNP. Methods: AirGOs Operative is a randomized controlled trial. It is an investigator-driven multicenter trial led by Helsinki University Hospital. The two surgery arms are compared. The primary outcome is the change in the SNOT-22 score at the 12-month follow-up. Secondary outcomes include the change in the SNOT-22 score at 24-months follow-up, the changes in polyp score, Lund-Mackay (LM) CT score, health-related quality of life (HRQoL), loss of productivity, nasal patency (peak nasal inspiratory flow (PNIF) ± acoustic rhinometry (ARM), olfaction test (Sniffin’ Sticks, identification), lung function (spirometry and PEF) and findings in pathological analysis at 12/24-months follow-up. Discussion: AirGOs Operative trial will lead to a better understanding of the optimal extent of ethmoidectomy in the treatment of recalcitrant severe CRSwNP. Trial registration: ClinicalTrials.gov, NCT03704415. Registered on 8 of October 2018


Introduction
Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses lasting for at least 12 weeks and with an incidence varying between 3-11% (1,2) . CRS is divided into two main phenotypes, CRS with nasal polyps (CRSwNP) and without (CRSsNP). The prevalence of CRSwNP is reported to be between 0,5-4,5% in the general population (3) . CRSwNP is characterized by intense inflammation, decreased health-related quality of life (HRQoL) and in severe cases recurrence despite treatment.
It has a significant impact on airway health, and causes both direct and indirect costs (3,4) . The baseline treatment of CRSwNP contains nasal lavage and intranasal corticosteroids. In addition, courses of oral corticosteroids and antibiotics may be used in uncontrolled and/or exacerbated CRSwNP. Endoscopic sinus for extended approaches lies in revision cases, not in primary surgeries (3) . Browne et al. (2006), in a multicenter cohort study, has concluded that nasal polypectomy with additional surgery seems to have no benefit over simple polypectomy in terms of health-related quality of life (HRQoL) improvement (11) . However, a prospective randomized comparison of limited partial ethmoidectomy and extended functional mucosa sparing ESS in medically recalcitrant CRSwNP is still lacking. A Japanese group showed in a database analysis of 50,734 patients, that the extent of ESS did not significantly affect the overall complication rate (12) . However, extended surgery requires more operating time and is more expensive (12,13) . Potential disadvantages, financial implications, and available hospital resources should be considered when choosing the extent of ESS.
As there are unresolved questions concerning the ideal extent of ESS, the aim of this randomized controlled trial is to evaluate and compare the efficacy and safety of limited ESS with partial ethmoidectomy and extended ESS with total ethmoidectomy in patients with severe CRSwNP. The hypothesis is that extended sinus surgery is superior to limited sinus surgery as measured by validated HRQoL questionnaires, endoscopic nasal polyp score, and CRS and asthma control. In addition, genome-wide molecular factors and microbiome are evaluated from nasal samples.

Primary objective
The primary aim of this study is to evaluate the relative change

AirGOs Operative trial design
AirGOsOperative is a randomized controlled trial. It is an investigator-driven multicenter trial led by Helsinki University

Eligibility criteria
The inclusion criteria for patients evaluated for surgery are: age ≥18 years, total endoscopic nasal polyp score (≥4, bilateral), SNOT-22 ≥30, and Lund-Mackay score of sinus computed tomography or sinus cone beam tomography scans (LM score ≥14). In addition, patients should have a history of at least one of the following: one previous surgery for CRSwNP; one or more oral corticosteroid course(s) during the past two years; three or more antibiotic courses during the past two year. In patients with contraindication/adverse effects for using oral steroids, the additional criteria of oral steroids are not required. All patients should meet the EPOS (European position paper on rhinosinusitis and nasal polyps 2012) criteria for chronic rhinosinusitis (14) . Conservative treatment consists of corticosteroid drops and nasal lavage lasting at least 3 months prior to evaluation.  The study centers will screen all their CRSwNP patients and will document the screening failures to minimize bias in patient selection. Patients meeting inclusion criteria are given detailed oral and written information about the study. Participating patients will be randomized into two surgical arms. Of those declining participation, the age and gender distribution data are used into analyze whether the data is generalizable to the target population.

Randomization
Patients who meet the eligibility criteria are randomized to the two treatment arms with ratio of randomization of 1:1.

Follow-up
Patients are followed every three months for 24 months after surgery. Detailed information on the content of the follow-up is presented in Figure 1.

Definition of CRSwNP and co-morbidities
The CRSwNP phenotype is defined according to EPOS 2020 criteria, by a history of nasal polyps and endoscopic signs of nasal polyps (3) . Clinical data of previous polyp surgery, time of diagnosis of nasal polyposis, allergies, asthma diagnosis, NSAID (non-steroidal anti-inflammatory drug) exacerbated respiratory disease (NERD), profession, work environment, smoking habits, medication and disease history are recorded by the investigator. The diagnosis of asthma is based on typical history, clinical features, and at least one of the following physiologic criteria: (i) a variation of 20% or greater in diurnal peak expiratory flow (PEF) recording (reference to diurnal mean); (ii) an increase of 15% or greater in PEF with β-agonist or (iii) an increase of 12% or greater in forced expiratory volume in 1 second (FEV1) with β-agonist; or (iv) a decrease of 15% or greater in PEF or FEV1 in exercise testing or moderate to severe bronchial hyperresponsiveness. NERD diagnosis is based on a positive history of wheeze/ cough or naso-ocular symptoms after intake of NSAID and/or positive ASA challenge. Allergy is verified with positive history and Skin Prick Test and/or serum allergen-specific IgE against common aeroallergens.

Primary and secondary outcomes
The primary outcome is the change in SNOT-22 score at 12-months follow-up. Secondary outcomes include change in SNOT-22 score at 24-months follow-up, changes in polyp score, LM CT score, HRQoL, loss of productivity, nasal patency (peak nasal inspiratory flow (PNIF) ± acoustic rhinometry (ARM), olfaction test (Sniffin' Sticks, identification), lung function (spirometry, exhaled NO, and PEF) and findings in pathological analysis at 12/24-months follow-up ( Figure 1). Safety (complications, adverse effects), costs and loss of productivity will be compared between the study arms. Also the costs of CRSwNP and asthma treatment one year before and two years after surgery will be compared, taking into account study arms.

Health related quality of life (HRQoL)
Disease-specific quality of life is monitored with the SNOT-22, which is a widely used instrument designed to measure a wide range of consequences of CRS including physical, functional and emotional aspects. It has been shown to be reliable and useful tool to show intervention-related changes (15,16) . Two selfadministered questionnaires of general HRQoL are included: 1. EQ-5D-5L includes fives questions about mobility, self-care, usual activities, pain or discomfort and anxiety or depression. An EQ-5D-5L index is calculated and gives a patient's health status on a scale ranging from 0 (very bad health) to 1 (perfect health).
Patients also rate their overall generic HRQoL using a Visual Analogue Scale (EuroQoL-5D VAS) from 0 (very bad health) to 100 (perfect health). 2. The 15D questionnaire is a standardized, validated HRQoL instrument that can be used both as a profile and a single-index score (17) . The questionnaire consists of 15 dimensions (15D): moving, seeing, hearing, breathing, sleeping, eating, speech, excretion, normal activities, mental functioning, discomfort and symptoms, depression, distress, vitality, and sexual activity. For each dimension, the respondent must choose one of the five levels that best describes her/his state of health at that moment (best level = 1; poorest level = 5). The value of 15D is based on applying the multi-attribute utility theory. The single index score (15D score), representing the overall HRQoL on a scale from 0 to 1 scale (1 = full health, 0 = being dead) and the dimension level values reflecting the goodness of levels relative to no problems along a dimension and to being dead (0) are calculated from the questionnaire using a set of population-based preference or utility weights. Mean dimension level values are used to create 15D profiles for groups. The generic, clinically important minimal difference (MID) in the 15D scores is ±0.015 (18) .

Olfactory function
Olfaction is measured with Sniffing Sticks Identification Test;its twelve pens contain common smells and during the test, one pen is held under the nose for a few seconds at a time. A forced choice out of four options is inquired after explaining that this may well increase the possibility of correct answers by chance.
The score of correct answers per 12 smells is counted.

Nasal patency
Nasal patency is measured by the peak nasal inspiratory flow (PNIF) method using a portable GMI PNIF meter (GM Instruments). A ventilation mask covers the nose firmly and the patient is asked to close the mouth and to inhale through the nose as quickly as possible. The highest inspirations speed (L/min) of three maximal inspirations is accepted for analysis.
Acoustic rhinometry gives an estimate of the cross-sectional diameter of the nasal cavity at each distance, minimal crosssectional areas are recorded. Acoustic rhinometry is performed after an acclimatization period of 15-20 minutes to allow adaptation to the room temperature and humidity. A trained nurse or doctor performs the measurements.

Nasal endoscopy
Modified Lund endoscopy score is used to evaluate polyps, oedema and discharge on a score from 0 to 2 (19) . The polyps are also scored on a four point scale with modified Davos scale from 0 to 4 on each side (score 0: no polyps, score 1: small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, score 2: polyps in the middle meatus reaching below the inferior border of the middle turbinate, score 3: polyps are below the lower border of the middle turbinate and the medial polyps are large or any polyp reaches the lower border of inferior turbinate, score 4: the polyps reach below the lower border of the inferior turbinate) (20) . A total count of the sides is reported.

CRS disease control
CRS control criteria have been defined in EPOS 2012 and 2020 (3,14) . Disease control is defined by the common nasal symptoms and sleep disturbance or fatigue, endoscopy findings and need for systemic corticosteroids or long-term antibiotics during the previous one or three months (14,21) . Control of symptoms is defined as a disease state in which the patients do not report symptoms, or the symptoms are not bothersome.

Asthma control assessed with Asthma Control Test (ACT) and
Mini Asthma Quality of Life Questionnaire (Mini AQLQ). ACT assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily functioning, and overall self-assessment of asthma control.

Productivity, health resource use and costs
The use of resource and the costs of health care utilization, medical costs, and productivity are obtained from hospital databases, intervention reports, medical files and national health records. This data is also collected with the Productivity COST Questionnaire (iPCQ) and Medical Consumption Questionnaire (iMCQ) (22,23) .

Dissemination
The results will be published in international scientific journals.
The outcomes of the trial will be presented in international congresses.

Discussion
There are unresolved questions concerning the ideal extent of ESS in patients with severe CRSwNP. A systemic Cochrane review concluded that there are no trials comparing simple polypectomy and extensive ESS, which would have met their inclusion criteria (24) . This randomized controlled trial compares safety and efficacy of limited and extended ethmoidectomy in the treatment of severe CRSwNP. We will monitor general and disease-spesific HRQoL in CRS and asthma, sense of smell, endoscopic nasal polyp score, lung function, absenteeism and days of decreased productivity during work, as well as the use of treatment resources including their economic aspects in order to assess the rational use of surgical resources. Adverse events of treatments will be monitored throughout the study.

Trial status
The trial started in November 2018. We are currently recruiting patients. The anticipated completion of recruitment is beginning of year 2022.

Authorship contribution
PV is the principal investigator in the Helsinki University Hospital and coordinating investigator with regard to all participating sites. ML, PV and STS prepared the manuscript. All authors read and approved the final manuscript.

Consent for publication
Not applicable.

Availability of data and materials
Not applicable.

Conflict of interest
STS reports consultancies for AstraZeneca, ERT, Novartis, Sanofi Pharma, and Roche Products and a grant of GSK, outside the submitted work. WF reported consultancies for Sanofi and GSK outside the submitted work. JSA reports consultancy for Sanofi outside the submitted work. All other authors declare no conflicts of interest.