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.

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.

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.

[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.

Frequency of peripheral blood eosinophilia and obstructive airway disease in sarcoidosis

Background/aim: There is limited information about peripheral blood eosinophilia (PBE) and airway obstruction in sarcoidosis. Since pulmonary sarcoidosis affects the airways, it is often confused with asthma. The aims of the study are to investigate airway obstruction and PBE in sarcoidosis patients and to examine the similarity of clinical presentation with asthma. Materials and methods: The patients matching the ATS/ERS/WASOG diagnosis criteria and were between 18 and 80 years of age were included consecutively between 2018 and 2020. Other diseases causing granulomas were excluded. Results: A total of 84 patients were included of which 26 (31%) had a PBE level of ≥300 µL with no significant difference seen between sarcoidosis stage and PBE (p > 0.05). A significant (p < 0.05) decrease was only seen in FEV1 as the stage of sarcoidosis progressed. Respectively 31 (36.9%), 12 (14.3%) and 4 (4.8%) patients had an obstructive, restrictive and mixed respiratory function disorder. Twenty-four (28.6%) subjects with sarcoidosis had history of asthma. Spring fever, eczema, and skin/nose allergy were noticed in 17 (20.2%) of the patients. Conclusion: Mild PBE may be seen in sarcoidosis. Patients applying with PBE, airway obstruction, bronchial hyperreactivity along with spring fever, eczema, skin/nose allergy, wheezing, chest tightness, shortness of breath and cough may be also evaluated in terms of sarcoidosis.

Blood hyperreosinophilia: A diagnostic challenge.

A very detailed differential diagnosis is necessary to investigate the causes of blood hypereosinophilia. In the differential diagnosis of hypereosinophilia with pulmonary involvement, primary and secondary eosinophilic lung diseases should be kept in mind, and more specific diagnoses should be considered in those with a history of nasal polyposis and asthma. Here, it was aimed to present a case of organ-limited hypereosinophilia with asthma and nasal polyposis.

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

BACKGROUND AND AIM: The differences in molecular mechanisms during 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 pre-defined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. MATERIALS AND 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 more lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p=0.022]. CONCLUSION: 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.

Frequency of peripheral blood eosinophilia and obstructive airway disease in sarcoidosis.

BACKGROUND: There is limited information about peripheral blood eosinophilia (PBE) and airway obstruction in sarcoidosis. Since pulmonary sarcoidosis affects the airways, it is often confused with asthma. The aims of the study are to investigate airway obstruction and PBE in sarcoidosis patients and to examine the similarity of clinical presentation with asthma. METHODS: The patients matching the ATS/ERS/WASOG diagnosis criteria and were between 18 and 80 years of age were included consecutively between 2018 and 2020. Other diseases causing granulomas were excluded. RESULTS: A total of 84 patients were included of which 26 (31%) had a PBE level of ≥300 µL with no significant difference seen between sarcoidosis stage and PBE (p > 0.05). A significant (p < 0.05) decrease was only seen in FEV1 as the stage of sarcoidosis progressed. Respectively 31 (36.9%), 12 (14.3%) and 4 (4.8%) patients had an obstructive, restrictive and mixed respiratory function disorder. Twenty-four (28.6%) subjects with sarcoidosis had history of asthma. Spring fever, eczema, and skin/nose allergy were noticed in 17 (20.2%) of the patients. DISCUSSION: Mild PBE may be seen in sarcoidosis. Patients applying with PBE, airway obstruction, bronchial hyperreactivity along with spring fever, eczema, skin/nose allergy, wheezing, chest tightness, shortness of breath and cough may be also evaluated in terms of sarcoidosis.

Biologics for oral corticosteroid-dependent asthma.

Background: Oral corticosteroid (OCS) dependent asthma is one of the severe asthma phenotypes that requires personalized treatment. Objective: To review the role of biologic treatments in OCS-dependent asthma. Methods: A nonsystematic review was performed of emerging multiple novel biologics for potential treatment of OCS-dependent asthma. Results: The serious adverse effects of OCS can be seen as a result of their regular long-term administration. Anti-interleukin (IL) 5 (mepolizumab), anti-IL-5R (benralizumab), and anti-IL-4Rα (dupilumab) are the therapies of choice for OCS-dependent severe asthma. Results of studies showed the efficacy of mepolizumab, benralizumab, and dupilumab, especially in patients with the OCS-dependent severe eosinophilic asthma phenotype and with nasal polyps. Dupilumab may be the therapy of choice of monoclonal antibodies in cases of moderate-severe atopic dermatitis accompanied by OCS-dependent severe asthma. For reslizumab and omalizumab, placebo controlled double-blind studies conducted with OCS-dependent patient populations are needed. Conclusion: Biologics are effective in the "OCS-dependent asthma" phenotype as add-on therapy. It seems that chronic OCS use in OCS-dependent asthma will be replaced by biologic agents that specifically target type 2 inflammation, along with a much better safety profile. However, real-life studies that compare these biologics in OCS-dependent severe asthma are urgently needed.

Efficacy of mepolizumab treatment in oral corticosteroid-dependent severe eosinophilic asthma patients with chronic rhinosinusitis with nasal polyps: single center, real life study

Background/aim: Oral corticosteroid (OCS)-dependent severe eosinophilic asthma with chronic rhinosinusitis with nasal polyps (SEA-CRSwNP) would be a suitable phenotype for mepolizumab treatment. This study evaluated the short-term efficacy of mepolizumab treatment in OCS-dependent SEA-CRSwNP. Materials and methods: Baseline and 24th week results [daily OCS doses, asthma exacerbation frequency, asthma control test (ACT) scores, blood eosinophil levels, FEV1 values, and numerical analog scale (NAS) of CRSwNP symptoms] of patients who were treated for at least 24 weeks with mepolizumab were retrospectively evaluated and compared. Results: A total of 16 patients were enrolled in the study. Mepolizumab was discontinued in one patient due to side effects. The daily OCS dosage was reduced from baseline in all patients, and at week 24 OCS was discontinued in 40% of the patients (baseline mean steroid dose: 9.2 ± 5.2 mg, 24th week: 1.3 ± 1.4 mg; P < 0.001). The number of asthma exacerbations within 24 weeks significantly decreased after beginning mepolizumab treatment (2.1 ± 2.7 vs. 0.07 ± 0.26; P = 0.012), and a significant increase in ACT scores (baseline mean ACT: 18 ± 5.7; 24th week mean ACT: 23.3 ± 3; P = 0.006) was observed despite the decrease in daily OCS dosages. There was no significant difference in FEV1 values between baseline and week 24. Evaluation of the general symptoms of CRSwNP, as per NAS, revealed that the baseline mean NAS was 5.6 ± 4.4, and the 24th week mean NAS was 3.2 ± 3.2 (P = 0.021). Conclusion: This is the first real-life study evaluating the short-term efficacy of mepolizumab treatment on OCS-dependent SEA-CRSwNP. This study demonstrates that mepolizumab is an effective and safe biologic for the treatment of this severe asthma subphenotype.

The protective effects of thymoquinone on lung damage caused by cigarette smoke.

Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation that usually is caused by exposure to noxious particles or gases. Thymoquinone (TQ) prevents the production of inflammatory mediators, such as thromboxane B2 and leukotriene, by altering arachidonic acid metabolism. We investigated the preventive and curative effects of TQ on lung damage in rats caused by cigarette smoke (CS). We used 50 adult male rats, 30 of which were exposed to CS every day for 3 months. TQ in dimethylsulfoxide (DMSO) was administered intraperitoneally (i.p.) every day to ten animals to investigate the protective effects of TQ, and to ten other animals during the last 21 days to investigate the curative effect. Ten rats received saline for the last 21 days. Ten subjects were untreated controls. Ten controls that were not exposed to CS received TQ for the last ten days. Serum IL-8, IL-6, IL-1ß and MMP-9 levels were measured using ELISA. IL-1ß and IL-8 levels were elevated in the group exposed to CS compared to controls. IL-8 levels were decreased in the group that received only TQ compared to controls, which indicated the anti-inflammatory effect of TQ. The apoptotic index (AI) was increased in all groups that were exposed to CS compared to controls. The AI index was decreased in the group that received TQ for the last 21 days compared to the other CS groups. AI was increased in the group that received TQ daily compared to the other CS groups. Our findings indicate that TQ exerts curative effects for the inflammation caused by CS and may prevent apoptosis if administered in appropriate doses; however, long term TQ or DMSO exposure may produce cumulative toxic effects.

Last station in the eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis march: Eosinophilic asthma with radiological findings associated with blood eosinophilia.

OBJECTIVE: Eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis (EA-CRS/NP) is a subphenotype of adult-onset eosinophilic asthma. Blood eosinophil levels are shown to be highly elevated in patients with EA-CRS/NP and have potential for tissue infiltration. We aimed to demonstrate the clinical features of the patients who have a blood eosinophil level above 10% and have thorax computed tomography findings due to blood eosinophilia. METHODS: Patients who were followed up in our clinic between 2012 and 2017 were retrospectively evaluated. Inclusion criteria were as follows: 1) Eosinophilic severe asthma, 2) eosinophilia >10%, 3) chronic sinusitis and/or nasal polyps, 4) patients with pathologic findings on thorax computed tomography, 5) regular follow-up for at least 1 year. RESULTS: We identified 36 patients who met the above criteria. We defined this group as "Eosinophilic Asthma with chronic Rhinosinusitis and/or nasal polyposis with Radiological findings related to blood eosinophilia" (EARR). The mean age was 44.9 ± 11 years and 64% were females. Nasal polyps, aspirin exacerbated respiratory disease, and atopy, were present in 81%, 47%, and 25% of the patients, respectively. The mean blood eosinophil count was 1828.6 cells/mm3 (19%). The majority of EARR patients had upper lobe dominant ground-glass opacities. The mean follow-up period was 3.2 ± 2.5 years. EARR patients did not evolve into eosinophilic granulomatous polyangiitis in the follow-up. CONCLUSIONS: This phenotype is the first eosinophilic asthma sub-phenotype reported in the literature. EARR is the final stage of the allergic march of EA-CRS/NP.

Eosinophilic asthma with chronic rhinosinusitis/nasal polyps and biologic agents.

The current understanding in severe asthma management is the targeted therapy approach with the evaluation of phenotypes and biomarkers. Therefore, personalized treatments are recently more prominent. Eosinophilic asthma with chronic rhinosinusitis/nasal polyps (CRSwNP) is one of the severe asthma phenotypes which needs a personalized treatment approach. Biological agents which specifically target type 2 (T2) high inflammation have been used in this severe asthma phenotype with a preferable safety profile. In the present review, biological agents in eosinophilic asthma with CRSwNP will be discussed.