Moving Towards Precision Medicine in United Airways Disease: Unraveling Inflammatory Patterns in Asthmatic Patients With or Without Nasal Polyps

Official title

Moving Towards PREcision Medicine In United Airways Disease: Unraveling inflaMmatory Patterns in Asthmatic Patients With or Without Nasal Polyps (PREMIUM) - a Descriptive Pilot Study

Overview

Asthma and chronic rhinosinusitis (CRS) are inflammatory diseases of the respiratory tract, asthma from the lower part, and CRS, from the upper part. In theory, these parts are correlated as if they are one single organ, namely "united airways", which means that if one is affected by any condition, the other might be impacted as well. However, this relationship has not yet been described down to the cellular and molecular levels. By investigating patients that have (1) asthma and CRS with nasal polyp, (2) asthma and CRS without nasal polyp, and (3) just CRS with nasal polyp, we aim to determine the correlation of the upper and lower part of the respiratory tract. At first, the characterization of disease will be determined by established clinical criteria, such as lung function, blood analysis for the presence of eosinophils (a type of white cells), and nasal polyp score. To continue, in-depth analysis of nose, oropharynx, and lung samples will help gain information about the inflammatory profile and local microbiome of the three different groups of patients through molecular and cellular assays. The results of this study will help to describe the hypothesis of the united airways which will provide better guidance for medical treatment of asthma and CRS with or without polyp, thus improving the life quality of patients.

Detailed description

1. Background Both, asthma and chronic rhinosinusitis (CRS) are inflammatory conditions of the airways. The prevalence of asthma - with its cardinal symptoms wheezing, breathlessness, chest tightness, and coughing - has risen over the past decades not only in industrial but also in developing countries. For instance, about 8% of the United States' population and 8.2% of Europeans are diagnosed with asthma. Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) is a condition affecting up to 16% and 11% of the US and European population, respectively3. Both diseases, asthma and CRS, can severely impair quality of life as well as productivity and therefore embody an immense socioeconomic burden.

Despite the distinction of the respiratory tract in the upper and lower airways, both parts are anatomically and immunologically related. This led to the concept of "United airway diseases" assuming that upper and lower airways form a single organ. Consequently, inflammation in the upper affects the lower respiratory tract and vice versa. This concept initially described in the context of allergic respiratory disease can also be extended to the link between sinonasal and lower airway diseases. Accordingly, the association between asthma and CRS prevalence has been unambiguously shown in epidemiological studies: around 20% of CRSsNP patients and around 48% of CRSwNP patients suffer from asthma. Conversely, nasal polyposis is detected in 19 to 25% of asthmatics. In cases of severe asthma, even up to 54% of patients were reported to have a history of nasal polyposis. However, the pathophysiological mechanism underlying the association of asthma and CRS has been poorly investigated so far.

Based on the predominant inflammatory profile, asthma can be separated into T2-high and T2-low endotypes. Thereby, around 60% of severe asthma patients show a T2-high profile. The picture is becoming even more complex regarding classifications of CRS. Phenotypically we distinguish between CRSsNP and CRSwNP. However, up to 10 different endotypes of CRS can be defined based on various different inflammatory markers in nasal polyps or nasal secretions. Approaches to characterize endotypes describing conditions involving both asthma and CRS have barely been made so far.

On a cellular and protein level, it seems that higher concentrations of Staphylococcus enterotoxin-specific IgE, total IgE and eosinophil cationic protein in nasal polyp tissue are indicators for a higher risk of asthma. Furthermore, it was observed that patients with CRS and eosinophilic asthma (as determined by FeNO levels only) show high numbers of eosinophils in their nasal polyps. This nasal polyp eosinophilia was associated with a more severe asthma phenotype as well as larger polyps and a significantly higher nasal polyp recurrence rate compared to non-eosinophilic patients. However, up to this point, no study investigated whether inflammatory profiles in polyps and asthmatic lungs correspond and how inflammatory profiles of patients suffering from asthma with or without polyps may differ.

Novel antibody-based therapies targeting mediators of type 2 immune response are constantly emerging as new treatment options for patients with severe chronic airway diseases. Therapeutic antibodies targeting IgE or IL-4/IL-13, IL-5, or IL-5 receptor-mediated pathways are currently licensed for the treatment of asthma but have also successfully been used to treat CRSwNP to some extent. In this respect, anti-IgE (omalizumab) and anti-IL4α receptor (dupilumab) specific monoclonal antibodies have recently been licensed for the treatment of nasal polyps and CRSwNP respectively. Antibodies targeting molecules further upstream in the inflammatory cascade such as TSLP or IL-33 are currently under development. Anti-TSLP antibodies showed first promising results in clinical trials including patients suffering from uncontrolled asthma. Despite targeting molecular pathways involved in the pathogenesis of both diseases, some monoclonal antibodies such as reslizumab are effective in treating asthma but fail to significantly ameliorate nasal polyposis. Interestingly, a post-hoc responder analysis showed that the group of patients with high baseline IL-5 levels in nasal secretions improved upon reslizumab treatment, while the other patient groups did not. These findings illustrate the urgent need to better understand the pathomechanism and potential links underlying both diseases in order to choose the right therapy for the right patient. 2. Study rationale In this study, we aim to unravel the pathophysiological mechanisms underlying T2-high asthma with or without nasal polyposis. Therefore, we plan to thoroughly examine T2-high asthmatic patients with and without nasal polyposis at the cellular and molecular level and compare them to patients suffering from eosinophilic polyps in the absence of asthma. Deep analysis of nose, oropharynx, and lung samples will yield information on inflammatory patterns at protein and mRNA level, cellular tissue architecture in the different disease subtypes as well as microbiome composition. This pilot study will help to unravel underlying pathomechanisms in these united airway diseases and, therefore, provide a rationale for new therapy approaches including biologicals. 3. Study objectives

In this study we plan to:

* evaluate the inflammatory profile in different sections of the airways; * evaluate the endotype and immunological profile of CRSwNP (when applicable); * determine the microbiome composition in nose, oropharynx, and bronchi in T2-high asthmatic patients with and without CRSwNP, N-ERD compared to patients with CRSwNP in absence of asthma

Interventions

• Procedure Blood sampling
  Blood collection for PBMC isolation, measurement of cytokines in serum, and mass cytometry
• Procedure Nasosorption
  Nasosorptions will be applied for the collection of nasal secretions (Nasosorption FX-I, Hunt Developments (UK) Limited, Midhurst, West Sussex, United Kingdom). Under visualization, the device will be inserted into the nasal cavity and be placed along the lateral wall against the inferior turbinate. The index finger of the patient will be used to press onto the external aspects of the alar and lateral nasal cartilages to hold the device in place. After 1 minute, the devices will be removed.
• Procedure Oral sampling
  For oral sampling, saliva collection devices (SuperSAL or PureSAL, Oasis Diagnostic Corporation, USA) will be applied followed by elution. Then swabs optimized for the collection of specimens will be applied (CLASSIQSwabs, Copan Diagnostics Inc. Murietta, CA, USA) to the dorsum of the tongue.
• Procedure Bronchoscopy
  The bronchoscopy will be performed in the outpatient clinic of the Department of Pulmonology. Bronchial alveolar lavage (BAL): the bronchoscope is wedged in the segmental or subsegmental bronchus of the middle lobe. Up to 300 ml sterile normal saline is injected stepwise via handheld syringe and then gradually withdrawn back into the syringe. BAL fluid (BALF) will be prepared and further analyzed in the lab. Transbronchial biopsy (TBLB): performed by forceps in the lung periphery under fluorosco
• Procedure Nasal biopsy
  Nasal biopsies will be taken during routine endoscopy performed to score CRSwNP. Patients will receive local anesthesia and decongestants prior to obtaining the biopsy. Samples will either be embedded in OCT or processed for cellular analysis
• Procedure Nasal sampling
  Swabs optimized for the collection of specimens will be applied (CLASSIQSwabs, Copan Diagnostics Inc. Murietta, CA, USA) to the anterior naris and middle meatus of each nostril
• Procedure Nasal mucosa mRNA sampling
  Mucosal mRNA sampling will be performed using a 10cm nasal curette (either Rhino-Probe, Arlington Scientific, USA or Cellskim, Hunt Developments, UK). Under direct visualization, the curette will be brought to lie against the mid-inferior portion of the inferior turbinate. The curette will be pressed against the mucosal surface moved outwards 2-3 times. This motion will be repeated 2-3 times to ensure good sample collection. This curette and technique have been shown to cause no significant disc
• Diagnostic test Pregnancy test
  In female patients, pregnancy will be excluded with a standard urine pregnancy test at the beginning of the main visit.
• Other Medical history of patients, demographic data, concomitant medication, questionnaire
  Patients will be asked for their medical history including demographic data and concomitant medication. Details will be noted in the source data file. Furthermore, patients will receive a questionnaire including tools to assess QOL impairment by CRS and asthma
• Diagnostic test UPSIT smell test
  University of Pennsylvania Smell Identification Test (UPSIT) smell test will be performed by the patients during the study. It consists of 40 questions in 4 different booklets. The patient needs to scratch a sniff strip with the microencapsulated odorant using a pencil and mark his choice on four-choice multiple-choice questions. The test is then scored by the study team out of the 40 items.

Primary outcome measures

• Inflammatory profile in different sections of the airways [Time frame: 2 years]

Secondary outcome measures (2)

• Endotype and immunological profile of CRSwNP [Time frame: 2 years]
• Microbiome composition in nose, oropharynx and bronchi in T2-high asthmatic patients with and without CRSwNP, N-ERD compared to patients with CRSwNP in absence of asthma [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

All patients who

• 18-99 years of age
• have a recorded clinical diagnosis of asthma (ICD-10 Code: J45)
• undergo moderate-serve asthma treatment according to GINA/DAL treatment step 4 or step 5 without oral corticosteroid or monoclonal antibody therapy
• Asthma treatment for a minimum of 12 weeks prior to screening visit

• Group 1 and 2 - T2-high asthma with or without polyps:
• FeNO > 25 ppB
• had either two times >= 250 eosinophils /µl measured in the blood OR one measurement of blood eosinophils >= 250 cells/µl (one of the two measurements at the screening visit) and/or one measurement of sputum eosinophils > 2% within the last 12 months
• Group with polyps: Presence of CRSwNP as confirmed by endoscopy or CT according to the European Position Paper on Rhinosinusitis and CRSwNP Guidelines)

• Group 3 - CRSwNP in absence of asthma:
• Presence of CRSwNP as confirmed by endoscopy or CT according to the European Position Paper on Rhinosinusitis and Nasal Polyps Guidelines
• Evidence of Type 2 inflammation: eosinophils >= 250 cells/µl measured in the blood OR total IgE >100 kU/L at the screening visit
• Absence of asthma and N-ERD
• Patients with a history of treatment with monoclonal antibodies for asthma or polyps will only be included if at least a wash out period of 5 half-lives or at least 3 months have passed

Exclusion criteria

• Pregnancy (as determined by ß-HCG test)
• Patients with severe anatomic variations or deviations that do not allow access to all areas in the nasal cavity
• Patients undergoing chronic oral corticosteroid therapy
• Patients with any other confounding underlying lung disorder including but not limited to:

• Bronchiectasis, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, emphysema, primary ciliary dyskinesia
• Cystic fibrosis, any known parasitic infections, and lung cancer
• Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia including but not limited to: Eosinophilic granulomatosis with polyangiitis (EGPA), allergic bronchopulmonary aspergillus, and hypereosinophilic syndrome
• A mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study
• Patients with clinically meaningful comorbidity as determined by the evaluating committee
• Patients with a history of exacerbation of chronic rhinosinusitis or asthma 4 weeks prior to any visit
• Intake of a burst of systemic corticosteroids 4 weeks prior to any visit.
• Immunosuppressive treatment (e.g. cyclosporine)
• Drug and alcohol abuses
• Current smoker
• Former smoker if stopped smoking <6 months and/or has >10 pack-years

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Screening

Study locations

Austria · 1 center

• Allgemeines Krankenhaus (AKH) Wien — Vienna

Publications

• Stern J, Pier J, Litonjua AA. Asthma epidemiology and risk factors. Semin Immunopathol. 2020 Feb;42(1):5-15. doi: 10.1007/s00281-020-00785-1. Epub 2020 Feb 4. PMID 32020334
• Gibson GJ, Loddenkemper R, Lundback B, Sibille Y. Respiratory health and disease in Europe: the new European Lung White Book. Eur Respir J. 2013 Sep;42(3):559-63. doi: 10.1183/09031936.00105513. No abstract available. PMID 24000245
• Hellings PW, Klimek L, Cingi C, Agache I, Akdis C, Bachert C, Bousquet J, Demoly P, Gevaert P, Hox V, Hupin C, Kalogjera L, Manole F, Mosges R, Mullol J, Muluk NB, Muraro A, Papadopoulos N, Pawankar R, Rondon C, Rundenko M, Seys SF, Toskala E, Van Gerven L, Zhang L, Zhang N, Fokkens WJ. Non-allergic rhinitis: Position paper of the European Academy of Allergy and Clinical Immunology. Allergy. 2017 PMID 28474799
• Loftus PA, Wise SK. Epidemiology and economic burden of asthma. Int Forum Allergy Rhinol. 2015 Sep;5 Suppl 1:S7-10. doi: 10.1002/alr.21547. Epub 2015 May 23. PMID 26010063
• Smith KA, Orlandi RR, Rudmik L. Cost of adult chronic rhinosinusitis: A systematic review. Laryngoscope. 2015 Jul;125(7):1547-56. doi: 10.1002/lary.25180. Epub 2015 Jan 30. PMID 25640115
• Giavina-Bianchi P, Aun MV, Takejima P, Kalil J, Agondi RC. United airway disease: current perspectives. J Asthma Allergy. 2016 May 11;9:93-100. doi: 10.2147/JAA.S81541. eCollection 2016. PMID 27257389
• Passalacqua G, Ciprandi G, Canonica GW. United airways disease: therapeutic aspects. Thorax. 2000 Oct;55 Suppl 2(Suppl 2):S26-7. doi: 10.1136/thorax.55.suppl_2.s26. No abstract available. PMID 10992552
• Yii ACA, Tay TR, Choo XN, Koh MSY, Tee AKH, Wang DY. Precision medicine in united airways disease: A "treatable traits" approach. Allergy. 2018 Oct;73(10):1964-1978. doi: 10.1111/all.13496. Epub 2018 Jul 10. PMID 29869791

Identifiers

NCT: NCT05009758 · PREMIUM2021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗