EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

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.

Monoclonal antibody or aspirin desensitization in NSAID-exacerbated respiratory disease (N-ERD)?

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a clinical syndrome characterized by nasal polyposis, asthma, and intolerance to aspirin/NSAID. It affects approximately 15% cases of severe asthma, 10% of nasal polyps and 9% of rhinosinusitis. N-ERD results in associated asthma exacerbations, oral corticosteroids bursts, corticosteroid-dependent disease, and multiple endoscopic sinus surgeries. Unknown influences cause polyp epithelium to release alarmins, such as IL-33 and TSLP. These cytokines activate lymphoid cells, both Th2 and ILC2, to release cytokines such as IL5, IL4 and IL13, resulting in complex type 2 inflammation involving mast cells, eosinophils and platelets. Arachidonic acid released from such cells is metabolized into mediators. N-ERD is characterized by an imbalance in eicosanoid levels, especially CysLTs, PDG and PGE2. Patients with N-ERD present nasal symptoms (congestion, hyposmia/anosmia, nasal discharge) and lower airways symptoms (cough, sneezing, shortness of breath, chest tightness), anosmia, severe hyposmia as well as severe asthma which impacts the quality of life in this disease and leads to safety concerns in patients daily lives. Despite the variety of treatment strategies, the likelihood of recurrence of symptoms is high in patients with N-ERD. The most important strategies for treating N-ERD are listed as following: drug therapies, aspirin desensitization, monoclonal antibodies and other therapies associated. N-ERD treatment remains a major challenge in the current situation. Selecting the appropriate patient for aspirin desensitization, monoclonal antibodies or both is essential. This review provides an overview on aspirin desensitization and biologics in N-ERD and might help in decision making from both the perspective of the physician and patient. Patient characteristics, safety, efficacy, health care costs, but also patient preferences are all factors to take into account when it comes to a choice between biologics or aspirin desensitization.

European Academy of Allergy and Clinical Immunology position paper on endoscopic scoring of nasal polyposis.

Nasal endoscopy is not only used for the diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), but also for monitoring the response to therapy playing an important role in both daily practice and research. In contrast to patient-reported outcomes, endoscopic nasal polyp scoring by independent blinded readers is an objective measurement, not influenced by the placebo effect. It is safer and cheaper compared with computed tomography imaging and therefore, better suited for regular assessments of the extent of the disease. Since the early 90s, a variety of endoscopic staging methods have been proposed and used in clinical research, making it hard to compare results from different studies. This paper resulted from a task force with experts in the field of CRSwNP, originated by the Ear, Nose and Throat section of the European Academy of Allergy and Clinical Immunology and aims to provide a unified endoscopic NP scoring system that can serve as a reference standard for researchers, but also as a useful tool for practitioners involved in the management of CRSwNP.

Corrigendum on: White paper on European patient needs and suggestions on chronic type 2 inflammation of airways and skin by EUFOREA.

[This corrects the article DOI: 10.3389/falgy.2022.889221.].

White Paper on European Patient Needs and Suggestions on Chronic Type 2 Inflammation of Airways and Skin by EUFOREA.

Background: Type 2 inflammation underlies the chronicity of disease in subgroups of patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and atopic dermatitis (AD), that often co-exist. Although several studies have investigated the unmet needs of asthma, AD and CRSwNP as such, little is known about the similarities and differences in experiences and perspectives of the current management of patients with comorbid Type 2 inflammatory diseases. Aims: To improve insight into the common and organ-specific needs of patients with Type 2 inflammation and comorbidities, allowing the formulation of recommendations to better address these needs in the future. Methodology: This qualitative study was conducted between July 2021 and December 2021 using semi-structured face-to-face or telephone interviews with patients suffering from year-long severe chronic Type 2 inflammation and at least one co-morbid inflammatory condition. Seven participating academic centers in Europe interviewed asthma (Copenhagen and Leuven), CRSwNP (London, Amsterdam and Crete) and/or AD (Oldenburg and Zurich) patients on patient characteristics, disease severity, shortcomings of current care pathways and suggestions for improvement of care. Transcripts were analyzed using an inductive thematic analysis approach. Results: Eighty-one patients with severe Type 2 inflammation and comorbidities were interviewed. Similar needs were recognized by patients with Type 2 inflammation, with both a lack of coordination in care and a lack of a real cure reported as being most frustrating. However, several needs are specific to asthma, CRSwNP and AD. Suggestions for improvement of care were generic across diseases, such as the implementation of a multidisciplinary approach, the improved facilitation of access to better treatments, the increase of general awareness on disease burden, and better educational programs for healthcare providers and patients. Of note, patients with CRSwNP also stated the need for alternatives to sinus surgery, whereas patients with asthma requested better medical care to prevent exacerbations and patients with AD would warmly welcome the reimbursement of emollients. Conclusion: Patients with asthma, CRSwNP and AD have shared unmet needs that need to be addressed by physicians, the academic community and health policy makers. This survey provides unique recommendations made by patients for the implementation of better care.

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.

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.

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.

Evaluating the real-life effect of MP-AzeFlu on asthma outcomes in patients with allergic rhinitis and asthma in UK primary care.

BACKGROUND: MP-AzeFlu (Dymista®; spray of azelastine/fluticasone propionate) is the most effective allergic rhinitis (AR) treatment available. Its effect on asthma outcomes in patients with AR and asthma is unknown. METHODS: This pre-post historical cohort study, using the Optimum Patient Care Research Database, included patients aged ≥12 years, from UK general practice with active asthma (defined as a recorded diagnosis, with ≥1 prescription for reliever or controller inhaler) in the year before or at the initiation date. The primary study outcome was change in number of acute respiratory events (i.e. exacerbation or antibiotic course for a respiratory event) between baseline and outcome years. The effect size of MP-AzeFlu was quantified as the difference in % of patients that improved and worsened. RESULTS: Of the 1,188 patients with AR and asthma included, many had a record of irreversible obstruction (67%), and uncontrolled asthma (70.4%), despite high mean daily doses of reliever/controller therapy and acute oral corticosteroid use, in the year pre-MP-AzeFlu initiation. MP-AzeFlu initiation was associated with fewer acute respiratory events (effect size (e) = 5.8%, p = 0.0129) and a reduction in daily use of short-acting ß2-agonists, with fewer patients requiring >2 SABA puffs/week (e = 7.7% p < 0.0001). More patients had well-controlled asthma 1-year post-MP-AzeFlu initiation (e = 4.1%; p = 0.0037), despite a reduction in inhaled corticosteroids (e = 4.8%; p = 0.0078). CONCLUSIONS: This study provides the first direct evidence of the beneficial effect of MP-AzeFlu on asthma outcomes in co-morbid patients in primary care in the United Kingdom. TRIAL REGISTRATION: EUPAS30940. Registered August 13, 2019.

Cluster Analysis of Chronic Rhinosinusitis Suggests Gender-Based Differences.

PURPOSE: We aimed to evaluate the interaction between the overall severity of chronic rhinosinusitis (CRS) before treatment and subjective improvement following surgical or medical treatment. PROCEDURES: A group of 97 patients with CRS completed the visual analog scale (VAS) symptom score and the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire in the moment of their sinus computerized tomography (CT) scan. Data were analyzed via a 2-step cluster analysis based on gender, polyp presence, CT scan, and VAS scores for symptoms. RESULTS: There were 3 clusters: the first cluster comprised 37 female patients with CRS without nasal polyps (CRSsNP), the second cluster comprised 30 patients with CRS and NP (CRSwNP; 15 males and 15 females); and third cluster had 30 male patients with CRS without NP (CRSsNP). Different symptom patterns between clusters were identified. After adjustment for polyp presence, gender, eosinophilia (p = 0.021), and the SNOT-22 score (p = 0.005) were found to be better outcome predictors than the CT score (p = 0.26). CONCLUSION: Long-term patient satisfaction is significantly associated with the subjective symptom severity prior to treatment, i.e., postnasal drip and overall disease severity (SNOT-22 score), but not with the objective severity of the disease (CT score and inflammation).

Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper.

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.

Chronic Rhinosinusitis-Could Phenotyping or Endotyping Aid Therapy?

OBJECTIVES: We reviewed the phenotyping and endotyping of chronic rhinosinusitis (CRS) and treatment options. METHODS: We searched PubMed, Google, Google Scholar, and the Proquest Central Database of the Kirikkale University Library. RESULTS: Phenotypes are observable properties of an organism produced by the environment acting upon the genotype, that is, patients with a particular disorder are subgrouped according to common characteristics. Currently, CRS is usually phenotyped as being with (CRSwNP) or without (CRSsNP) nasal polyps. However, this is not immutable as some individuals progress from nonpolyp to polypoid CRS over time. Phenotypes of CRS are also based on inflammatory patterns, generally CRSwNP is eosinophilic, CRSsNP neutrophilic; but there is a spectrum, rather than a clear-cut division into 2 types. An endotype is a subtype of a condition defined by a distinct functional or pathobiological mechanism. Endotypes of CRS can be (1) nontype Th2, (2) moderate type Th2, and (3) severe type Th2 immune reactions, based on cytokines and mediators such as IL4, 5, 13. CRS endotyping can also include a (1) type 2 cytokine-based approach, (2) eosinophil-mediated approach, (3) immunoglobulin E-based approach, and (4) cysteinyl leukotriene-based approach. Subdivisions of CRSwNP can be made into nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, allergic fungal sinusitis, and eosinophil pauci-granulomatous arteritis by testing. General treatment for all CRS is nasal douching. The place of surgery needs careful reconsideration. Endotype-directed therapies include glucocorticosteroids, antibiotics, aspirin, antifungals, anticytokines, and immunoglobulin replacement. The recognition of united airways and the co-occurrence of CRSwNPs and severe asthma should lead to common endotyping of both upper and lower airways in order to better direct therapy. CONCLUSION: Endotyping can allow for the identification of groups of patients with CRS with a high likelihood of successful treatment, such as patients with a moderate type 2 immune reaction or those with acquired immune deficiency.