The Effectiveness of Biological Agents on Chronic Rhinosinusitis with Nasal Polyposis in Patients with Comorbid Asthma: A Multicenter Real-Life Study from Türkiye.

Background and Objectives: Real-life data on the efficacy of biologic agents (BAs) on asthma-comorbid CRSwNP are needed. Our primary goal is to investigate the effects of BAs on CRSwNP symptoms, as well as endoscopic and tomography scores. Our secondary goal is to show a reduction in the frequency of acute sinusitis exacerbations and the need for surgery. Materials and Methods: We conducted a multicenter, retrospective, real-life study. We screened the patients with asthma-comorbid CRSwNP treated with omalizumab or mepolizumab. A total of 69 patients (40 F/29 M; omalizumab n = 55, mepolizumab n = 14) were enrolled. We compared the visual analog scale (VAS), sinonasal outcome test-22 (SNOT-22), nasal congestion score (NCS), Lund-Mackay computed tomography score (LMS), and total endoscopic polyp scores (TPS) before and after BAs. We evaluated the endoscopic sinus surgery (ESS) and acute exacerbations of chronic rhinosinusitis (AECRS) frequencies separately, according to the BAs. Results: The overall median (min-max) age was 43 (21-69) years. The median (min-max) of biologic therapy duration was 35 (4-113) months for omalizumab and 13.5 (6-32) for mepolizumab. Significant improvements were seen in VAS, SNOT-22, and NCS with omalizumab and mepolizumab. A significant decrease was observed in TPS with omalizumab [95% CI: 0-4] (p < 0.001), but not with mepolizumab [95% CI: -0.5-2] (p = 0.335). The frequency of ESS and AECRS were significantly reduced with omalizumab [95% CI: 2-3] (p < 0.001) and [95% CI: 2-5] (p < 0.001); and mepolizumab [95% CI: 0-2] (p = 0.002) and [95% CI: 2-8.5] (p < 0.001), respectively. There was no significant difference in LMS with either of the BAs. Conclusions: Omalizumab and mepolizumab can provide a significant improvement in the sinonasal symptom scores. BAs are promising agents for CRSwNP patients with frequent exacerbations and multiple surgeries.

Doxycycline may be more clinically effective in type 2 chronic rhinosinusitis nasal polyp comorbid with asthma.

OBJECTIVE: Chronic rhinosinusitis with nasal polyp (CRSwNP) is one of the major phenotypes of chronic rhinosinusitis (CRS) with a high symptom burden. Doxycycline can be used as add-on therapy in CRSwNP. We aimed to evaluate short-term efficacy of oral doxycycline on visual analog scale (VAS) and SNOT-22 (Sino-nasal outcome test) score for CRSwNP. METHODS: Visual analog score (VAS) for nasal symptoms and total SNOT-22 scores of 28 patients who applied with the diagnosis of CRSwNP and received 100 mg doxycycline for 21 days were analyzed in this retrospective cohort study. Doxycycline efficacy was also evaluated in subgroups determined according to asthma, presence of atopy, total IgE and eosinophil levels. RESULTS: After 21-day doxycycline treatment, there was a significant improvement in VAS score for post-nasal drip, nasal discharge, nasal congestion, and sneeze, and total SNOT-22 score (p = 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). No significant improvement was observed in VAS score for the loss of smell (p = 0.18). In the asthmatic subgroup, there were significant improvements in all VAS scores and total SNOT-22 score after doxycycline. In the non-asthmatic subgroup, there was no significant change in any of the VAS scores, but total SNOT-22 score was significantly improved (42 [21-78] vs. 18 [9-33]; p = 0.043). Improvement in VAS score for loss of smell is significant in only some subgroups like asthmatic patients, non-atopic patients, and patients with eosinophil >300 cell/µL. CONCLUSIONS: Doxycycline can be considered as an add-on treatment for symptom control in patients especially with CRSwNP comorbid with asthma.

Stepwise Approach in Asthma Revisited 2023: Expert Panel Opinion of Turkish Guideline of Asthma Diagnosis and Management Group.

Introduction of inhaled corticosteroids (ICS) has been the cornerstone of the long-term management of asthma. ICSs either alone or in combination with long-acting beta-2 agonists have been shown to be associated with favorable asthma outcomes. However, asthma control is still reported to be below expectations all around the world. Research in the last decades focusing on the use of ICS/formoterol both as maintenance and as needed (maintenance and reliever therapy approach) showed improved asthma outcomes. As a result of recent developments, Turkish Asthma Guidelines group aimed to revise asthma treatment recommendations. In general, we recommend physicians to consider the risk factors for poor asthma outcomes, patients' compliance and expectations and then to determine "a personalized treatment plan." Importantly, the use of short-acting beta-2 agonists alone as a symptom reliever in asthma patients not using regular ICS is no longer recommended. In stepwise treatment approach, we primarily recommend to use ICS-based controllers and initiate ICS as soon as possible. We define 2 different treatment tracks in stepwise approaches as maintenance and reliever therapy or fixed-dose therapy and equally recommend each track depending on the patient's risks as well as decision of physicians in a personalized manner. For both tracks, a strong recommendation was made in favor of using add-on treatments before initiating phenotype-specific treatment in step 5. A strong recommendation was also made in favor of using biologic agents and/or aspirin treatment after desensitization in severe asthma when indicated.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

[Biologics for the treatment of severe asthma: Current status report 2023]. / Agir astim tedavisinde biyolojikler: Güncel durum raporu 2023.

Severe asthma is associated with increased use of healthcare services, significant deterioration in the quality of life, and high disease and economic burden on patients and societies. Additional treatments are required for severe forms of asthma. Biological agents are recommended for the treatment of severe asthma. In this current status report, we aimed to evaluate the efficacy, effectiveness, and safety data of approved biologics; omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab, in the treatment of severe asthma and appropriate patient profiles for these biologics. Pubmed and Cochrane databases based on randomized controlled trials, posthoc analyses, meta-analyses, and real-life studies examining the efficacy and effectiveness of biologics in severe asthma were searched, and the results of these studies on important asthma outcomes were reviewed. Existing studies have shown that all the approved biologic agents targeting cells, receptors, and mediators involved in type 2 inflammation in the bronchial wall in severe asthma significantly reduce asthma exacerbations, reduce the need for oral corticosteroids, and improve asthma control, quality of life, and pulmonary functions. Characterizing the asthma endotype and phenotype in patients with severe asthma and determining which treatment would be more appropriate for a particular patient is an essential step in personalized treatment.

Picturing asthma in Turkey: results from the Turkish adult asthma registry.

INTRODUCTION: National data on asthma characteristics and the factors associated with uncontrolled asthma seem to be necessary for every country. For this purpose, we developed the Turkish Adult Asthma Registry for patients with asthma aiming to take a snapshot of our patients, thereby assigning the unmet needs and niche areas of intervention. METHODS: Case entries were performed between March 2018 and March 2022. A web-based application was used to record data. Study outcomes were demographic features, disease characteristics, asthma control levels, and phenotypes. RESULTS: The registry included 2053 patients from 36 study centers in Turkey. Female subjects dominated the group (n = 1535, 74.8%). The majority of the patients had allergic (n = 1158, 65.3%) and eosinophilic (n = 1174, 57.2%) asthma. Six hundred nineteen (32.2%) of the patients had obese asthma. Severe asthma existed in 670 (32.6%) patients. Majority of cases were on step 3-5 treatment (n: 1525; 88.1%). Uncontrolled asthma was associated with low educational level, severe asthma attacks in the last year, low FEV1, existence of chronic rhinosinusitis and living in particular regions. CONCLUSION: The picture of this registry showed a dominancy of middle-aged obese women with moderate-to-severe asthma. We also determined particular strategic targets such as low educational level, severe asthma attacks, low FEV1, and chronic rhinosinusitis to decrease uncontrolled asthma in our country. Moreover, some regional strategies may also be needed as uncontrolled asthma is higher in certain regions. We believe that these data will guide authorities to reestablish national asthma programs to improve asthma service delivery.

Biological therapy management from the initial selection of biologics to switching between biologics in severe asthma.

The aim of this review is to elaborate the management of biologic therapy from initial selection to switching biologics in severe asthma. A nonsystematic review was performed for biological therapy management in severe asthma. Depending on clinical characteristics and biomarkers, selecting the preferred biologic based on super-responder criteria from previous studies may result in adequate clinical efficacy in most patients. On the other hand, no matter how carefully the choice is made, in some patients, it may be necessary to discontinue the drug due to suboptimal clinical response or even no response. This may result in the need to switch to a different biological therapy. How long the biological treatment of patients whose asthma is controlled with biologics will be continued and according to which criteria they will be terminated remains unclear. It has been shown that in patients with a long history of good response to biologics, asthma control may be impaired when biologics are discontinued, while it may persist in others. Therefore, discontinuation of biologics may be a viable strategy in a particular patient group. Clinicians should make the best use of all predictive factors to identify patients who will most benefit from each biologic. Patients who do not meet a predefined response criterion after sufficient time for response evaluation and who are eligible for one or more alternative biological agents should be offered the opportunity to switch to another biologic. There is no consensus on when the biologics used in severe asthma that produce favorable results should be discontinued. In our opinion, treatment should continue for at least five years, as premature termination may potentially deteriorate asthma control.

Stable and exacerbation period serum cytokine and periostin levels of the five distinct phenotypes of severe asthma.

BACKGROUND: The differences in molecular mechanisms during a stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different predefined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. METHODS: Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. RESULTS: Serum IL-13, IL-25, TSLP, and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients, and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p = 0.05] and periostin levels were much lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p = 0.022]. DISCUSSION: Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long-term systemic steroid use.

Venom immunotherapy and difficulties encountered before and during immunotherapy: Double sensitization, systemic reactions, treatment with omalizumab, and high dose VIT.

BACKGROUND: Venom immunotherapy (VIT) is the most effective treatment method to prevent recurrent systemic reactions to Hymenoptera stings. In this study, the demographic characteristics of VIT patients, the success rates of VIT, the difficulties we encountered during VIT, and solutions for these difficulties in our clinic were presented. METHODS: We retrospectively analyzed patients with venom allergy who applied venom immunotherapy between 2013- 2020. Data on age, gender, Hymenoptera species with the first reaction, grade of the reaction, beekeeping history, skin prick and specific IgE and component results, double sensitization, blood groups, and reactions with VIT and/or sting during built-up and maintenance periods were recorded. RESULTS: A total of 73 patients were enrolled in the study. The median time from the first sting reaction to the application to the allergy outpatient clinic was 12 (0.5-24) months. The first sting reaction of 38 (52.1%) of the patients was with honey bees, and 24 (32.9%) were with wasps. Double positivity was present in 29 (40%) of the patients in prick results and 26 (36%) serologically. There was no correlation between the severity of first reactions and Apis Mellifera or Vespula prick diameters (p = 0.643; r = -0.056; p = 0.462; r = 0.089, respectively). High-dose VIT was administered to 4 patients. Omalizumab has been used as an alternative agent to achieve the maintenance dose in 2 patients with frequent systemic reactions during VIT. DISCUSSION: Most patients were able to tolerate VIT. Double positivity is one of the most common difficulties before VIT. In patients who develop systemic reactions in the VIT maintenance phase, a maintenance dose increase should be considered in the maintenance phase. Adding omalizumab does not seem to be a permanent solution in patients who develop a severe systemic reaction.

Discontinuing Omalizumab Treatment in Super-Responder Patients with Allergic Severe Asthma: Can the Baseline Total IgE Level Be Used as a Biological Marker to Decide Discontinuing Omalizumab Treatment?

BACKGROUND: Although there are many studies presenting the efficacy of omalizumab in severe asthma, the data about the optimal treatment duration are still debated. OBJECTIVE: In this study, we aimed to investigate the clinical effects of omalizumab discontinuation after 5 years of treatment in patients with omalizumab super-responders, the persistence of response and to compare the features of patients, whose symptoms are still well controlled and those who relapsed and re-treated with omalizumab. METHODS: Clinical and laboratory data of 100 adult patients diagnosed with allergic severe asthma and treated with omalizumab between 2008 and 2020 were evaluated retrospectively. Demographic, clinical, functional, and laboratory parameters of the patients who were re-treated with omalizumab and those who did not need to be re-treated were compared. RESULTS: There were 14 super-responder patients, who were treated with omalizumab for 5 years, and the treatment was discontinued then. Omalizumab was not restarted in 9 patients (64%) and was restarted in 5 (36%) patients. No significant difference was presented between these two groups in terms of demographic, clinical, functional, and laboratory parameters. The baseline total IgE levels of patients, who were re-treated with omalizumab, was found to be higher than those who were not, but this difference was not statistically significant (440 [229-864] IU/mL vs. 164 [85-293] IU/mL; p = 0.053, respectively). CONCLUSION: One of 3 patients was re-treated with omalizumab due to loss of asthma control after discontinuation of the treatment. Therefore, omalizumab's immunomodulatory effect may seem to persist in a majority of cases after discontinuation. Also, higher baseline total IgE levels might help to predict the cases that need re-treatment after discontinuation.

The External Exposome and Allergies: From the Perspective of the Epithelial Barrier Hypothesis.

Introduction: In the last decades, we have seen a rapid increase in the prevalence of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergies. The environmental changes caused by industrialization, urbanization and modernization, including dramatic increases in air pollutants such as particulate matter (PM), diesel exhaust, nitrogen dioxide (NO2), ozone (O3), alarming effects of global warming, change and loss of biodiversity, affect both human health and the entire ecosystem. Objective: In this review, we aimed to discuss the effects of the external exposome on epithelial barriers and its relationship with the development of allergic diseases by considering the changes in all stakeholders of the outer exposome together, in the light of the recently proposed epithelial barrier hypothesis. Method: To reach current, prominent, and comprehensive studies on the subject, PubMed databases were searched. We included the more resounding articles with reliable and strong results. Results: Exposure to altered environmental factors such as increased pollution, microplastics, nanoparticles, tobacco smoke, food emulsifiers, detergents, and household cleaners, and climate change, loss and change in microbial biodiversity, modifications in the consumption of dietary fatty acids, the use of emulsifiers, preservatives and the decrease in the antioxidant content of the widely consumed western diet may disrupt the epithelial barriers of the skin, respiratory and gastrointestinal tracts, making us more vulnerable to exogeneous allergens and microbes. Epithelial cell activation, microbial dysbiosis and bacterial translocation disrupt the immune balance and a chronic Th2 inflammation ensues. Conclusion: Dramatic increases in air pollution, worrisome effects of global warming, dysbiosis, changing dietary habits and the complex interactions of all these factors affect the epithelial barriers and local and systemic inflammation. We want to draw attention to the emerging health effects of environmental changes and to motivate the public to influence government policies for the well-being of humans and the nature of the earth and the well-being of future generations.

The adequacy of current diagnostic criteria for making a diagnosis of ABPA.

Introduction: Currently, there are four different diagnostic criteria systems for allergic bronchopulmonary aspergillosis (ABPA): The Rosenberg-Patterson, Seropositive ABPA (ABPA-S), Central Bronchiectasis and ABPA (ABPA-CB), and the International Society for Human and Animal Mycology (ISHAM) ABPA study group criteria. This study aims to retrospectively compare these four diagnostic criteria in ABPA patients. Materials and Methods: Patients who were followed up with the diagnosis of ABPA were retrospectively re-evaluated using these four diagnostic criteria, and the superiority of these criteria to each other was determined. Result: A total of 10 ABPA patients were included in the study. Seven patients were diagnosed according to ISHAM ABPA study group diagnostic criteria and six patients according to the Rosenberg-Patterson diagnostic criteria. None of the patients fulfilled the criteria when evaluated individually with ABPA-S and ABPA-CB. Of patients diagnosed by ISHAM, five had a total IgE level above 1000 IU/mL and two had below 1000 IU/mL. Conclusions: We demonstrated that the diagnostic criteria developed by the ISHAM ABPA study group were superior to the others in diagnosing ABPA in cases with a total IgE level above 1000 IU/mL. However, all these criteria seem to be sufficient to diagnose ABPA in patients with a total IgE below 1000 IU/mL. We believe the necessity to demonstrate presence of Aspergillus fumigatus precipitating antibodies or specific IgG positivity should be questioned particularly in patients with radiologic findings compatible with ABPA and a total IgE level below 1000 IU/mL.

Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease.

Environmental exposure plays a major role in the development of allergic diseases. The exposome can be classified into internal (e.g., aging, hormones, and metabolic processes), specific external (e.g., chemical pollutants or lifestyle factors), and general external (e.g., broader socioeconomic and psychological contexts) domains, all of which are interrelated. All the factors we are exposed to, from the moment of conception to death, are part of the external exposome. Several hundreds of thousands of new chemicals have been introduced in modern life without our having a full understanding of their toxic health effects and ways to mitigate these effects. Climate change, air pollution, microplastics, tobacco smoke, changes and loss of biodiversity, alterations in dietary habits, and the microbiome due to modernization, urbanization, and globalization constitute our surrounding environment and external exposome. Some of these factors disrupt the epithelial barriers of the skin and mucosal surfaces, and these disruptions have been linked in the last few decades to the increasing prevalence and severity of allergic and inflammatory diseases such as atopic dermatitis, food allergy, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, and asthma. The epithelial barrier hypothesis provides a mechanistic explanation of how these factors can explain the rapid increase in allergic and autoimmune diseases. In this review, we discuss factors affecting the planet's health in the context of the 'epithelial barrier hypothesis,' including climate change, pollution, changes and loss of biodiversity, and emphasize the changes in the external exposome in the last few decades and their effects on allergic diseases. In addition, the roles of increased dietary fatty acid consumption and environmental substances (detergents, airborne pollen, ozone, microplastics, nanoparticles, and tobacco) affecting epithelial barriers are discussed. Considering the emerging data from recent studies, we suggest stringent governmental regulations, global policy adjustments, patient education, and the establishment of individualized control measures to mitigate environmental threats and decrease allergic disease.

A prospective observational evaluation of treatment outcomes of patients with chronic obstructive pulmonary disease and peripheral blood eosinophilia.

INTRODUCTION: This study aimed to compare two groups of patients with Chronic Obstructive Lung Disease (COPD) and blood eosinophil values of ≥300 cells/ µL. The patients were followed up for one year in two groups, one receiving inhaled corticosteroids (ICS) and the other not receiving ICS in terms of exacerbation rates, the incidence of pneumonia, mortality rates, FEV1, FVC and FEF25-75 changes, the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scores. MATERIALS AND METHODS: Stable patients, who presented to the University Medical Faculty Chest diseases outpatient clinic and diagnosed with COPD according to pulmonary function test results and GOLD stages 2-4 according to the 2017 GOLD criteria and with blood eosinophil counts of ≥ 300 cells/ µL were included in the study. RESULT: 85 patients were included in the study, of which 76.5% (n= 65) were males. There were no significant differences between the 38 patients receiving ICS and the 47 patients not receiving ICS regarding baseline FEV1, FVC, FEF25- 75 absolute values and percentages, and FEV1, FVC values controlled at month six and month 12, and FEF25-75 absolute values and percentages at month six (p> 0.05). However, the difference between the baseline and month 12 absolute values and percentages of FEF25-75 was statistically significant, and the decrease from baseline was greater in the group receiving ICS (p< 0.05). The difference in CAT and mMRC scores were statistically significant at month six and month nine in favor of the group receiving ICS (p< 0.05). The median number of moderate and severe exacerbations were both one (min: 0, max:3) in the group receiving ICS (n= 38) and in the one not receiving ICS (n= 47). The difference of exacerbation rates in both groups were not statistically significant (p> 0.05). CONCLUSIONS: In this study, it was determined that exacerbation rates of eosinophilic COPD patients did not differ depending on the use of ICS in a one-year period. Nevertheless, the 12-month FEF25-75 values of patients not using ICS were lower to a lesser extent, while the CAT and mMRC scores improved in favor of ICS users at different months in the one-year follow-up.

[Long-term macrolide therapy in asthma]. / Astimda uzun süreli makrolid tedavisi.

Macrolides are antibiotics with antiviral, anti-inflammatory and immunomodulatory effects in together with their bacteriostatic effects. In addition to its beneficial effects on chronic respiratory diseases such as COPD, cystic fibrosis, diffuse panbronchiolitis, and bronchiectasis, its effects on uncontrolled severe asthma and asthma exacerbations have been the subject of research in recent years. In randomized controlled trials, azithromycin, a macrolide, has been shown to reduce asthma exacerbations and significantly improve asthma-related quality of life in both eosinophilic and non-eosinophilic asthma phenotypes. However, there are also differences such as doses, durations and some studies not showing its effectiveness in severe eosinophilic asthma. In the GINA report, azithromycin can be recommended as an add-on therapy in patients with uncontrolled non-T2 severe asthma despite high-dose inhaled corticosteroid/ long-acting beta2-agonist/long-acting antimuscariniric treatments, or in T2 severe asthma patients whose asthma is not under control despite biologic therapy. In this review, the use of macrolides, especially azithromycin, in the treatment of asthma, immunomodulatory activities and safety profiles are discussed on the basis of current studies and guidelines.