Is endoscopic sinus surgery sufficient to modify the evolution of adult AERD? Aspirin desensitization as a maintenance factor: systematic review.

Introduction: Aspirin desensitization (AD) and aspirin therapy after desensitization (ATAD) are therapeutic interventions for patients with aspirin-exacerbated respiratory disease (AERD). Our aim is to investigate whether its addition to endoscopic sinus surgery (ESS) improves the overall prognosis of the disease. Methods: A systematic review of the current literature including adult patients with a positive diagnosis of AERD undergoing endoscopic sinus surgery (ESS) in the context or in absence of upper airway comorbidity, prior to AD + ATAD. Conclusion: This review concludes that the surgical approach is beneficial in AERD, but its effects are short-lived. Surgery should be considered initially with subsequent AD + ATAD in AERD patients, due to the sustained improvement achieved compared to those receiving ESS alone.

A EUFOREA comment on a lost comorbidity of asthma.

"Epidemiology of comorbidities and their association with asthma control" (Tomisa, G., Horváth, A., Sánta, B. et al. Epidemiology of comorbidities and their association with asthma control. Allergy Asthma Clin Immunol 17, 95 (2021). https://doi.org/10.1186/s13223-021-00598-3 ) is an interesting paper reflecting data collection from more than 12,000 asthmatic patients in Hungary regarding their condition and associated comorbidities. We found it valuable that the paper provides an overview of asthma comorbidities not usually considered in similar reports. Nevertheless, we believe that chronic rhinosinusitis (CRS) with or without nasal polyps (CRSwNP or CRSsNP) should have been listed due to its high incidence and prevalence, its association with asthma which is also endorsed in both GINA and EPOS, as well as in several peer-reviewed scientific papers, and to reflect the role of this comorbidity in poor control and a most severe presentation of asthma for the patient. Consequently, several targeted therapies (especially monoclonal antibodies) used for several years in severe forms of asthma are now indicated also for the effective treatment of nasal polyps.

WAO-ARIA consensus on chronic cough - Part III: Management strategies in primary and cough-specialty care. Updates in COVID-19.

Background: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. Objectives: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. Outcomes: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.

Epidemiology of Chronic Rhinosinusitis: Prevalence and Risk Factors.

Knowledge of chronic rhinosinusitis (CRS) epidemiology may directly impact patient care: aiding patient identification and establishing accurate diagnosis as well as informing treatment decisions. The objective of this review is to summarize the current evidence on the epidemiology of CRS, with a focus on prevalence and risk factors. Although the presence of either symptoms or objective findings alone have yielded CRS prevalence estimates of over 10%, the presence of both-consistent with guideline-based diagnostic criteria for CRS-has suggested that the true prevalence of CRS is consistently less than 5%, with approximately one-third of patients with CRS having nasal polyps, in epidemiologic studies from around the world. In comparison, the prevalence of CRS endotypes-pathophysiologic subclassification of CRS most commonly as related to type 2 or non-type 2 inflammation-has been found to vary significantly by region. The epidemiology of CRS is modified and ultimately determined by risk factors: genetic/hereditary, demographic, environmental, and imparted by predictive pre-/comorbid disease. The understanding of these epidemiologic relationships may help the provider to optimally identify and understand each individual's CRS disease process, thereby improving both diagnosis and treatment.

A retrospective study on long-term efficacy of intranasal lysine-aspirin in controlling NSAID-exacerbated respiratory disease.

PURPOSE: Aspirin treatment after desensitization (ATAD) represents an effective therapeutic option suitable for NSAID-exacerbated respiratory disease (N-ERD) patients with recalcitrant disease. Intranasal administration of lysine-aspirin (LAS) has been suggested as a safer and faster route than oral ATAD but evidence for its use is less strong. We investigated nasal LAS therapy long-term efficacy based on objective outcomes, smell function, polyp recurrence and need for surgery or rescue therapy. Clinical biomarkers predicting response to intranasal LAS, long-term side effects and consequences of discontinuing treatment have been evaluated. METHODS: A retrospective analysis of a database of 60 N-ERD patients seen between 2012 and 2020 was performed in March 2021. They were followed up at 3-months, 1-, 2- and 3-years with upper and lower airway functions assessed at each follow-up. RESULTS: Higher nasal airflow and smell scores were found at each follow-up in patients taking LAS (p < 0.001 and p = 0.048 respectively). No influence of LAS on pulmonary function measurements was observed. Patient on intranasal LAS showed a lower rate of revision sinus surgery when compared to those who discontinued the treatment (p < 0.001). None of the variables studied was found to influence LAS treatment response. CONCLUSION: Our study demonstrates the clinical effectiveness of long-term intranasal LAS in the management of N-ERD in terms of improved nasal airflow and olfaction and a reduced need for revision sinus surgery. Intranasal LAS is safe, being associated with a lower rate of side effects when compared to oral ATAD. However, discontinuation of the treatment at any stage is associated with a loss of clinical benefit.

Innate and adaptive immunity in allergic airway disease.

PURPOSE OF REVIEW: This article explores recent findings on the involvement of innate immunity in allergic airways disease, concentrating on allergic rhinitis. RECENT FINDINGS: We speculate on the ways in which environmental influences act to initiate inflammation and on how these may have altered in recent decades. Improved understanding of the mechanisms involved may reveal future possibilities for therapy. SUMMARY: The complex nature of immunity - both innate and acquired - in airways disease has implications for prevention and for therapy and requires further elucidation.

WAO-ARIA consensus on chronic cough - Part 1: Role of TRP channels in neurogenic inflammation of cough neuronal pathways.

BACKGROUND: Cough features a complex peripheral and central neuronal network. The function of the chemosensitive and stretch (afferent) cough receptors is well described but partly understood. It is speculated that chronic cough reflects a neurogenic inflammation of the cough reflex, which becomes hypersensitive. This is mediated by neuromediators, cytokines, inflammatory cells, and a differential expression of neuronal (chemo/stretch) receptors, such as transient receptor potential (TRP) and purinergic P2X ion channels; yet the overall interaction of these mediators in neurogenic inflammation of cough pathways remains unclear. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on neuroanatomy and pathophysiology of chronic cough. The role of TRP ion channels in pathogenic mechanisms of the hypersensitive cough reflex was also examined. OUTCOMES: Chemoreceptors are better studied in cough neuronal pathways compared to stretch receptors, likely due to their anatomical overabundance in the respiratory tract, but also their distinctive functional properties. Central pathways are important in suppressive mechanisms and behavioral/affective aspects of chronic cough. Current evidence strongly suggests neurogenic inflammation induces a hypersensitive cough reflex marked by increased expression of neuromediators, mast cells, and eosinophils, among others. TRP ion channels, mainly TRP V1/A1, are important in the pathogenesis of chronic cough due to their role in mediating chemosensitivity to various endogenous and exogenous triggers, as well as a crosstalk between neurogenic and inflammatory pathways in cough-associated airways diseases.

WAO-ARIA consensus on chronic cough - Part II: Phenotypes and mechanisms of abnormal cough presentation - Updates in COVID-19.

BACKGROUND: Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed. OUTCOMES: Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.

A multicenter real-life study on the multiple reasons for uncontrolled allergic rhinitis.

BACKGROUND: Recent data show uncontrolled disease in 35% of allergic rhinitis (AR) patients on medical treatment. The reasons for uncontrolled disease can arbitrarily be divided into disease-related, diagnosis-related, treatment-related, and patient-related factors. However, the relative importance of these factors in uncontrolled disease remains speculative. This explorative study aimed at determining the factors causing uncontrolled AR on four different continents worldwide, identifying the most common reasons for uncontrolled disease in AR. METHODS: Patients with uncontrolled AR (n = 430) were asked to fill out a questionnaire and underwent a clinical examination at the outpatient clinic in five university outpatient clinics (Leuven [Belgium], Beijing [China], Kinshasa [Congo], Bangalore [India], and Philadelphia [US]). Two independent physicians evaluated the reason or multiple reasons for uncontrolled disease. The study was coordinated from the University Hospital of Leuven. RESULTS: In uncontrolled AR patients, 76% of patients showed two or more reasons for uncontrolled disease according to the physicians' evaluation. Disease-related factors (64%) were considered most often the reason for uncontrolled disease, followed by treatment- (56%), patient- (54%), and diagnosis-related (47%) factors. There is limited variability in observations across different centers worldwide. CONCLUSION: We here define the multiple reasons for uncontrolled AR across different continents, with disease-related factors being most frequently associated with uncontrolled disease. A better understanding of uncontrolled disease will guide us in defining strategies to improve AR care.

Burden of allergic rhinitis and impact of MP-AzeFlu from the patient perspective: pan European patient survey.

OBJECTIVE: The aims of this survey were to (1) assess the burden of allergic rhinitis (AR) from the patient perspective, (2) investigate MP-AzeFlu use in real life and its impact on patients' lives and (3) explore factors associated with treatment satisfaction. METHODS: A cross-sectional, quantitative, online, questionnaire-based survey was conducted in seven European countries (March-June 2019). Questions explored AR burden and treatment satisfaction. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication 9-item (TSQM-9; max score = 100). Participants (aged ≥18 years) had a doctor/healthcare provider confirmed AR diagnosis and used MP-AzeFlu within the last year. RESULTS: Pre-MP-AzeFlu treatment, participants (n = 1004) reported an average of 3.3 (SD:3.5) doctor visits/year, 8.1 (SD:11.0) days/year absenteeism and 15.8 (SD:18.9) days/year presenteeism due to AR. Only 48% of participants used MP-AzeFlu twice/day as recommended. Post-MP-AzeFlu 57% of participants reported better QoL, 47% reported fewer doctor visits and 52% discontinued polypharmacy. Absenteeism and presenteeism were reduced by 2.5 (SD 10.0) and 7.3 (SD:16.0) days/year, respectively. 70% of participants were more/much more satisfied with MP-AzeFlu versus previous AR treatment(s), and ≥70% were satisfied/extremely satisfied with its ability to prevent/treat AR, relieve symptoms and with its onset of action. Mean global, effectiveness and convenience TSQM-9 scores were 70.0 (SD:19.8), 68.3 (SD:21.6) and 72.7 (SD:20.4), respectively. Treatment satisfaction and effectiveness were significantly improved when MP-AzeFlu was taken as recommended. CONCLUSIONS: The impact of AR on patients' lives remains high. Real-life use of MP-AzeFlu reduces that impact and is associated with a high level of effectiveness, convenience and global satisfaction.

Heterogeneity of the pharmacologic treatment of allergic rhinitis in Europe based on MIDAS and OTCims platforms.

BACKGROUND: The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems. To understand these differences and their implications, the rhinitis market was studied in some of the EU countries. METHODS: We conducted a pharmaco-epidemiological database analysis to assess the medications that were being prescribed for allergic rhinitis in the years 2016, 2017 and 2018. We used the IQVIA platforms for prescribed medicines (MIDAS®- Meaningful Integration of Data, Analytics and Services) and for OTC medicines (OTC International Market Tracking-OTCims). We selected the five most important markets in the EU (France, Germany, Italy, Poland and Spain). RESULTS: Intranasal decongestants were excluded from the analyses because they are rarely prescribed for allergic rhinitis. For both Standard Units (SU) and costs, France is leading the other countries. In terms of SU, the four other countries are similar. For costs, Poland is lower than the three others. However, medication use differs largely. For 2018, in SU, intranasal corticosteroid is the first treatment in Poland (70.0%), France (51.3%), Spain (51.1%) and Germany (50.3%), whereas the Italian market is dominated by systemic antihistamines (41.4%) followed by intranasal corticosteroids (30.1%). Results of other years were similar. DISCUSSION: There are major differences between countries in terms of rhinoconjunctivitis medication usage.

Innate and Adaptive Immunity: ILC2 and Th2 Cells in Upper and Lower Airway Allergic Diseases.

Advances in our understanding of the immune system, with the recent discovery of a parallel set of innate T lymphocytes, the innate lymphocytes (ILCs), have led to a reassessment of the pathogenesis of allergic and eosinophilic airway disorders, including allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps. We review current understanding of both elements of type-2 inflammatory responses and their relative influence in these common conditions and consider possible impacts of this on treatment selection.

Pathophysiological and Clinical Aspects of Chronic Rhinosinusitis: Current Concepts.

Adult chronic rhinosinusitis (CRS) is a chronic inflammation of the mucosa of the nose and paranasal sinuses. According to the latest EPOS guidelines CRS should be regarded as primary or secondary with distinction between diffuse and localized disease. Further pathophysiologic research identified different inflammatory patterns leading to the term "endotyping of CRS." The primary focus of endotyping is to define a dominant inflammatory type allowing for better orientation of therapy. The current approach proposes the differentiation between type 2 (eosinophilic) and non-type 2 inflammatory responses. In this review pathophysiological concepts of CRS will be discussed, focusing on the different inflammatory endotypes of T cells with special attention to the eosinophilic type 2 inflammatory response. The contribution of innate and adaptive immune system responses is presented. The possibility of endotyping based on sinonasal secretions sampling is brought to attention because it is indicative of corticosteroid responsiveness and available to most ENT surgeons. Furthermore, the clinical aspects of the three distinct phenotypes are analyzed in view of their characteristics, the related endoscopic findings, typical radiological imaging, histopathology findings, their relation toward allergy and obvious therapeutical implications. This overview will enable clinicians to relate pathophysiological patterns with clinical observations by explaining the different inflammatory mechanisms, hence providing a better understanding of therapy.

Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.