Non-Type 2 and Mixed Inflammation in Chronic Rhinosinusitis and Lower Airway Disease.

OBJECTIVE: The aim was to discuss the role of non-type 2 inflammation in patients diagnosed with chronic rhinosinusitis (CRS) and comorbid lower airway disease. DATA SOURCES: Medline, Embase, National Institute for Health and Care Excellence, TRIP Database, ProQuest, Clinicaltrials.gov, Cochrane Central Registry of Controlled Trials, Web of Science, government and health organizations, and graduate-level theses. REVIEW METHODS: This scoping review followed PRISMA-ScR guidelines. Search strategy was peer-reviewed by medical librarians. Studies were included if they utilized airway sampling, non-type 2 cytokines, and patients with CRS and lower airway disease. RESULTS: Twenty-seven from 7060 articles were included. In patients with CRS and comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and chronic obstructive pulmonary disease (COPD)/bronchiectasis, 60% (n = 12), 33% (n = 2), and 100% (n = 1), respectively, demonstrated mixed or non-type 2 endotypes. Comorbid CRS and asthma produced type 1 (n = 1.5), type 2 (n = 8), type 3 (n = 1), mixed type 1/2 (n = 1), and mixed type 1/2/3 (n = 8.5) endotype shifts. AERD demonstrated type 2 (n = 4), mixed type 2/3 (n = 1), and mixed type 1/2/3 (n = 1) endotype shifts. CRS with COPD or bronchiectasis demonstrated a mixed 1/2 (n = 1) endotype shift. CONCLUSION: Type 2 disease has been extensively reviewed due to advent biologics targeting type 2 inflammation, but outcomes may be suboptimal due to the presence of non-type 2 inflammation. A proportion of patients with CRS and comorbid lower airway disease demonstrated mixed and non-type 2 endotype shifts. This emphasizes that patients with unified airway disease may have forms of inflammation beyond classical type 2 disease which could inform biologic development. Laryngoscope, 134:1005-1013, 2024.

Unified Airway Disease: Environmental Factors.

The unified airway is in constant exposure to environmental factors that promote inflammation and disease. Environmental allergens, including house dust mites, pets, pollens, and molds, are strongly linked with development and exacerbation of upper airway disease with nonlinear dose-dependent relationships. Occupational triggers, including combat exposures and construction workers, are associated with the development of both upper and lower airway disease resulting in a "healthy worker effect" where many people leave jobs due to significant morbidity..

Unified Airway Disease: Medical Management.

Concurrent chronic rhinosinusitis with nasal polyps (CRSwNP) in the upper airway, and asthma in the lower airway, often have a shared underlying pathophysiology, namely type 2 inflammation; hence, the term "unified airway disease." The combination of CRSwNP and asthma is associated with uncontrolled disease. The range of treatment of CRSwNP includes intranasal corticosteroids, nasal saline irrigation, oral corticosteroids, antibiotics, and biologics. A combined clinical algorithm for the management of the upper and lower airways in type 2 inflammation will be beneficial, especially for patients with uncontrolled disease who may benefit from biologics.

Sex Differences in Airway Diseases.

It is evident that sex and gender differences impact pathophysiology, disease burden, and treatment outcomes for a variety of systems and major illnesses including those affecting the unified airway. Important male-female differences in unified airway disease are driven by various intrinsic and extrinsic mechanisms including anatomic, morphometric, hormonal, genetic (and epigenetic), environmental, psycho-social, and comorbidity-related factors. This review highlights current knowledge of how patient sex influences epidemiology, diagnosis, treatment, and outcomes for diseases affecting the unified airway.

Unified Airway Disease: Diagnosis and Subtyping.

The concept of a unified airway posits that pathology affects the respiratory tract in a continuum and that disease in one part of the respiratory tract may be associated with or directly or indirectly affect the function of a different part. Transcriptomic analysis has shown 91% homology between the genes expressed in the upper and the lower airway. Approaching inflammatory airway disorders using the unified airway hypothesis allows for a better clarification of disease process and provides a detailed and a high-level overview of dysfunction. There are several tools available to the clinician to use to subtype and diagnose accurately the abnormal pathways operating in inflammatory airway disorders. These tools include clinical history, physical examination findings, imaging (computed tomography and MRI), allergy and laboratory testing, pulmonary function testing (PFT), and tissue histopathology. Tests can be categorized based on platform, by specimen, or the marker being studied.

Unified Airway Disease: Future Directions.

Unified airway disease describes the shared epidemiologic and pathophysiologic relationship among the chronic inflammatory diseases of the upper and lower airways including allergic rhinitis, chronic rhinosinusitis, asthma, and chronic otitis media. This concept proposes that these diseases are manifestations of a single inflammatory process and require an integrated diagnostic and therapeutic approach to achieve global disease control. Future directions to further establish this entity should focus on pathophysiology, diagnostic markers, flora microbes with particular emphasis on fungi, the role of type 3 inflammation, and targeted therapeutics including biologics, JAK inhibitors, and synthetic peptides.

A Comparative Study of Symptoms, Nasal Eosinophilia and Pulmonary Function Tests Before and After Short Term Treatment with Corticosteroid Nasal Spray in Patients with Allergic Rhinitis.

Allergic rhinitis has been on the rise because of urbanization and major population shift in addition to changes in the particulate matter in the atmosphere. Intranasal corticosteroid sprays are recommended as first-line prescription treatment in all cases of allergic rhinitis. The propensity of co-existing non-apparent lower airway hyper-responsiveness is also on the rise and must be evaluated. The aim of this study is to compare the symptomatic improvement, changes in nasal eosinophilia and asymptomatic airway hyper responsiveness before and after short term treatment with steroid nasal spray. Fifty patients meeting the inclusion criteria for allergic rhinitis with no symptoms of asthma underwent pulmonary function tests and assessment of symptoms before and after one-month treatment with inhalational steroid nasal spray (Fluticasone Furoate), in the standard adult dosage. Based on TNSS (Total nasal symptom score) and TOSS (Total ocular symptom score), all 50 patients showed significant improvement after treatment. Among 20 patients with > 50 eosinophils per high power field, 80% had 0-10 eosinophils per high power field on nasal smear after treatment. Among 40 patients with mild large airway obstruction, 37 showed significant improvement in FEV1 data. Also FEV1/FVC data showed significant improvement. Significant improvement (FEF25-75 > 50%) was also noticed in small airway disease after treatment among the 5 patients. The study showed that lower airway hyper responsiveness coexists with allergic rhinitis and treating allergic rhinitis with just steroid nasal spray assists in reducing the former, supporting the concept of Unified Airway Disease (UAD).

Chronic Rhino-Sinusitis and Asthma: Concept of Unified Airway Disease (UAD) and its Impact in Otolaryngology.

The aim of our study is to understand the concept of unified airway disease, to know the advantage of this concept in the diagnosis and treatment of allergic rhinitis, chronic rhino-sinusitis and asthma, to know its impact on practice of otolaryngologists, to motivate the otorhinolaryngologist to apply this concept in diagnosis and treatment. This article is based on our experience on (20 cases) chronic rhino-sinusitis and asthma, and observations and results from various literatures. Implement of the concept of unified airway disease and ability to translate its principles into successful diagnostic and treatment strategies can enhance the practice of otolaryngology. The end result is the potential for improved patient care. In our study 80% cases have reduced frequency of symptoms and all (100%) cases having improved night time symptoms thus the use of short-acting beta2 agonist to control the asthma symptoms decreases.