Global warming and implications for epithelial barrier disruption and respiratory and dermatologic allergic diseases.

Global warming has direct and indirect effects, as well as short- and long-term impacts on the respiratory and skin barriers. Extreme temperature directly affects the airway epithelial barrier by disrupting the structural proteins and by triggering airway inflammation and hyperreactivity. It enhances tidal volume and respiratory rate by affecting the thermoregulatory system, causing specific airway resistance and reflex bronchoconstriction via activation of bronchopulmonary vagal C fibers and upregulation of transient receptor potential vanilloid (TRPV) 1 and TRPV4. Heat shock proteins are activated under heat stress and contribute to both epithelial barrier dysfunction and airway inflammation. Accordingly, the frequency and severity of allergic rhinitis and asthma have been increasing. Heat activates TRPV3 in keratinocytes, causing the secretion of inflammatory mediators and eventually pruritus. Exposure to air pollutants alters the expression of genes that control skin barrier integrity and triggers an immune response, increasing the incidence and prevalence of atopic dermatitis. There is evidence that extreme temperature, heavy rains and floods, air pollution, and wildfires increase atopic dermatitis flares. In this narrative review, focused on the last 3 years of literature, we explore the effects of global warming on respiratory and skin barrier and their clinical consequences.

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.

Effectiveness of Low-Dose Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA): A Real-Life Experience.

INTRODUCTION: Data showing effectiveness of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) are limited. METHODS: This is a single-center retrospective chart review of patients with EGPA treated with mepolizumab. Clinical, laboratory, functional parameters and asthma, rhinitis control, and quality of life scores (Asthma Control Test [ACT], Asthma Quality of Life Questionnaire [AQLQ], Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ], and SinoNasal Outcome Test [SNOT]-22) were evaluated at the baseline, 6th month, and 12th month. Complete response was defined as the absence of asthma and/or ear, nasal symptoms and exacerbations with a prednisone of ≤7.5 mg/day, partial response if it was achieved with a prednisone of >7.5 mg/day. RESULTS: Overall, 25 patients (18 F/7 M) with a median age of 47 years (23-76) were enrolled. Mepolizumab 100 mg/month was administered (dose increased to 300 mg/month in 3 patients). Mepolizumab significantly decreased daily dose of oral corticosteroid (OCS) from 11.04 mg to 3.65 mg together with a significant improvement in ACT, AQLQ, RQLQ, and SNOT-22 scores and a significant reduction in asthma exacerbations and blood eosinophil count at the 6th and 12th month (all p values <0.05). The mean forced expiratory volume in 1 s increased (at baseline: 1.88 L to 2.46 L at the 12th month [p = 0.037]). Seventy-six percent of patients responded completely at the 6th month and 81.25% at the 12th month. The complete responders at the 6th and 12th month were older than partial responders and nonresponders (p = 0.030 and p = 0.057, respectively). Patients with complete response at the 6th month were on lower doses of OCS than partial responders and nonresponders (p = 0.029). CONCLUSIONS: Low-dose mepolizumab was effective in EGPA patients by improving sinonasal and asthma outcomes, while reducing the need for OCS.

Mepolizumab Is an Effective Option in Severe Eosinophilic Asthma Regardless of Baseline Features: Single-Center Real-Life Data.

BACKGROUND: Mepolizumab has been approved as a treatment option for severe eosinophilic asthma (SEA) patients in our country. We aimed to evaluate the clinical and functional efficacy of mepolizumab in this group of patients in real life as well as the response rates to mepolizumab and the possible factors affecting the response. METHODS: The study was a retrospective chart review of patients with SEA treated with mepolizumab. The data were collected at baseline, and at the 6th and 12th month. RESULTS: A total of 62 patients (41F/21M) with a mean age of 44.41 ± 13.24 years were included in the study. They had poor symptom control with a mean asthma control test (ACT) score of 16.61 ± 5.59, frequent exacerbations with a mean of 3.4 ± 3.7 in the previous 12 months, and 80.6% required daily oral corticosteroid (OCS) with a median dosage of 8 mg/day as methylprednisolone. The ACT score increased to 22.47 ± 3.18 and 22.03 ± 4.31, respectively, and blood eosinophil count decreased from 1,146/µL to 89/µL and 85/µL at the 6th and 12th month, respectively. The mean FEV1 at baseline was 2.102 L there was an increase of 0.373 L at 6th month and 0.596 L at 12th month. The percentage of regular users of OCS decreased to 66.0% at 6th month with a median dosage of 4 mg and 52.6% at 12th month with a median dosage of 2 mg. Mepolizumab reduced the rate of exacerbations compared with the previous year from a mean of 3.40 to 0.15 at 6th month and 0.36 at 12th month. There was a significant improvement in Asthma Quality of Life Questionnaire (AQLQ), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Sino-nasal Outcome Test (SNOT-22) scores at both of time points. The rate of responders and super-responders at 6th month was 60% and 28%, respectively, and consequently, the overall response rate was 88%. At the 12th month, the super-responder rate increased to 44.7% as well as the overall response to 89.4%. The only difference between the nonresponders, responders, and super-responders at the 6th and 12th month was whether regular daily OCS was used pre-mepolizumab. All nonresponders at both 6th and 12th month were using OCS regularly, whereas most of super-responder used the OCS only during exacerbations. CONCLUSION: Mepolizumab effectively reduced asthma exacerbations, steroid requirement, blood eosinophil counts and improved asthma control, pulmonary function, sinonasal symptoms and quality of life. Our data suggest that mepolizumab would be effective in selected patients in real-life settings.

Characteristics of the patients with asthmarhinitis multimorbidity.

Introduction: Asthma and allergic rhinitis frequently coexist and have been regarded as a single airway disease. Clinical features of patients with asthmarhinitis multimorbidity may change depending on the allergic sensitization pattern. The aim of our study is to determine the frequency, type, and characteristics of the patients with asthma-rhinitis multimorbidity. Materials and Methods: Patients who were followed up with a diagnosis of asthma between 2015 and 2020 in our clinic were included in our crosssectional study. Sociodemographic and clinical characteristics of the patients, rhinitis symptoms, and atopy status according to the results of the skin prick test, and sp IgE were recorded from the patient files. Result: Asthma-rhinitis multimorbidity was seen in 138 (113 F/25 M) out of 405 asthmatics and the mean age was 45.51 ± 13.56 years. They were younger and the age of onset of asthma was earlier than asthma patients without rhinitis. The rate of concomitant allergic rhinitis (AR) was 25.9%, and the rate of non-allergic rhinitis (NAR) was 8.1% in the entire group. There was no difference between patients with AR and NAR in terms of comorbidities such as NSAID sensitivity, nasal polyps, chronic rhinosinusitis, and bronchiectasis but, gastroesophageal reflux disease was more common in those with NAR than in those with AR (39.4%, 18.1%, respectively, p= 0.01). Of 105 asthmatic patients accompanied by allergic rhinitis, 41 (39.09%) were monosensitized, and 64 (60.95%) were polysensitized. House dust mites were found to be the most common responsible allergen in monosensitized patients. Sensitization to two allergens was the most common pattern among polysensitized patients, and mites and mold association was the most frequent. Patients with monosensitized allergic rhinitis had more severe asthma and a higher rate of NSAID sensitivity than polysensitized patients (p= 0.03, p= 0.04, respectively). There was no difference in the control level, frequency of eosinophilia, and other comorbidities. Conclusions: Our patients with asthma-rhinitis multimorbidity were mostly polysensitized. The most responsible allergen for the sensitization was house dust mites, regardless of whether the patient was monosensitized or polysensitized.

[Anti-IL-5 treatments in severe eosinophilic asthma: real life datas]. / Agir eozinofilik astimda anti-IL-5 tedaviler: gerçek yasam verileri.

Randomized controlled studies have shown that anti-IL-5 treatments reduce the need for oral corticosteroids, annual asthma exacerbation and hospitalization rates, blood eosinophil count and increase FEV1 values, asthma control, and quality of life in patients with eosinophilic severe asthma. Although the number of real-life studies with anti-IL-5 is limited, there are 10 real life studies with mepolizumab, one real life study with benralizumab and one real life study with reslizumab in the current literature. Similar to randomized controlled trials, real-life studies reported that a reduction in the need for oral corticosteroids, annual asthma exacerbation and hospitalization rates, and blood eosinophil counts and increase FEV1 values, asthma control test and quality of life scores, Response criteria were defined in some of the real-life studies and although different response rates were given according to these criteria, most of the patients with severe eosinophilic asthma showed high response rates to anti-IL-5 treatments. In real-life studies evaluating the safety of anti-IL-5 treatments, the most common adverse effect is mild local injection site reaction that does not require treatment, in conclusion, real-life studies suggest that all three anti-IL-5 treatments in clinical practice are effective and well tolerated.

[The profile of severe asthmatics: Results from a specialized asthma clinic]. / Özellesmis bir astim polikliniginin agir astim verileri.

Introduction: In patients with severe asthma, individualized treatment, and appropriate phenotyping are required to achieve control. In our study, our aim was to examine the characteristics of a specific patient group in a specialized tertiary asthma outpatient clinic, which is the primary setting for evaluating severe asthma patients, with the intention of obtaining national data. Materials and Methods: In this cross-sectional observational study, sociodemographic, clinical presentations, laboratory results, and spirometry measurements of patients with severe asthma who were followed up in our specialized asthma outpatient clinic for at least one year were recorded. Patients were defined as eosinophilic if they had a blood eosinophil count of 300/µL or higher at least twice during the oral corticosteroid free-period or 150/µL or higher under oral corticosteroids as allergic if they had sensitization to at least one inhalant allergen consistent with their history. Result: Overall, 201 severe asthma patients (74.1% female) with a median disease duration of 15 (min-max= 1-49) years and a median follow-up duration of 7 (min-max= 1-40) years were analyzed. Most of the patients (56.7%) had adult-onset asthma [median age of onset was 32 (min-max= 10-62) years]. Overweight and obese patients were in the majority (31.8%, and 41.8%, respectively) and the median body mass index was 29 (min-max= 17.5-49.5). More than half of the patients (55.2%) had controlled asthma and the median Asthma Control Test score at the last visit was 23. Biologic therapies were applied to 73.1% (n= 147) of the patients [60.5% (n= 89) omalizumab, 39.5% (n= 58) mepolizumab]. Half of the group was allergic (49.3%) and three-quarters of them were eosinophilic (72.1%). Allergic patients had earlier asthma onset and had more controlled disease than nonallergic ones. Eosinophilic patients were younger and less obese than noneosinophilic patients. Obese and late-onset asthmatics had more uncontrolled disease than normal weight subjects and early onset patients. Conclusions: The high rate of disease control in the patients with severe asthma in the current study demonstrated the importance of targeted individualized therapy with accurate phenotyping in specialized asthma outpatient clinics.

Rapid drug desensitization with platin-based chemotherapy: Analysis of risk factors for breakthrough reactions.

BACKGROUND: All platin-based chemotherapeutics can cause hypersensitivity reactions (HSRs). With rapid drug desensitization (RDD), few patients experience breakthrough reactions (BTR) during desensitization. However, data about risk factors for BTRs during RDD in patients with HSRs to platins are limited. We first aimed to describe characteristics of our platin-reactive population and to validate the Brigham and Women's Hospital's (BWH's) RDD protocol in our population along with their outcomes with RDD. Our second aim was to identify the risk factors for BTRs. METHOD: This was a retrospective chart review (2013-2020) of patients with symptoms of immediate HSRs to platins. Initial HSRs were classified as grade 1, 2, or 3 based on their severity. Skin prick tests (SPT)/intradermal tests (IDT) were performed with implicated platins. A 12-step protocol was used during RDD. RESULTS: The study comprised 65 women and seven men (mean age 57.78 ± 8.73 years). Initial HSRs to carboplatin, cisplatin, and oxaliplatin occurred in 38, 13, and 21 patients, respectively. All patients reacted at the fifth (median) recurrent infusions (min:1, max:20). The median values for carboplatin, cisplatin, and oxaliplatin were 6 (1-20), 3 (1-15), and 3 (1-11), respectively. Most initial HSRs were grade 2 (n = 40, 55.6%) and 3 (n = 27, 37.5%); only 6.9% (n = 5) were grade 1. Patients with grade 1, 2, and 3 initial HSRs had positive platin skin test results at rates of 80%, 74%, and 88%, respectively.A total of 232 RDDs were performed in 72 patients and 98.7% of these desensitizations were completed. BTRs occurred in 56 (24.1%) (grade 1 n = 14, 25%; grade 2 n = 32, 57%; grade 3 n = 10, 18%) of these desensitizations. Breakthrough reactions were more severe in patients with positive SPTs or 1:100 or 1:10 dilutions of IDT (p = 0.014). BTR was not observed during RDD in any of the patients with positive 1:1 dilutions of IDT. Positivity on prick or 1:100 or 1:10 IDT increased the risk of BTR 5.058 times. There was no significant association between the risk of BTRs and age, drug cycle, sex, comorbidities, or atopy. CONCLUSION: In our experience, 98.7% of 232 RDDs to platins were completed successfully, showing that RDD was safe and effective. Drug skin test positivity is a potential marker for identifying high-risk patients who will have BTRs during RDDs to platins.

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.