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BACKGROUND: Severe asthma is a major burden on health-economic resources; hence, knowing the epidemiology of these patients is important in planning and provision of asthma care. In addition, identifying and managing the comorbidities helps improve symptoms and reduce associated morbidity and mortality. OBJECTIVES: Epidemiology of difficult asthma has not been well studied in the Middle East, so in this study, we present the demographic and clinical characteristics of severe asthma in the United Arab Emirates (UAE). METHODS: We retrospectively reviewed the notes of severe asthma patients attending three tertiary care hospitals between May 2015 and December 2019. Data on baseline demographics, asthma characteristics, treatment, and comorbidities were collected. RESULTS: We reviewed the notes of 458 patients (271 females and 187 males) that fulfilled the 2019 Global Initiative for Asthma guidelines for the diagnosis of severe asthma. The mean age was 47.7 (standard deviation 17.2) years. Males had significantly higher asthma control test scores (17.9 vs. 16, P = 0.01) and mean blood eosinophils (0.401 vs. 0.294, P

Introduction: Several biologic agents have been approved for the treatment of asthma, chronic urticaria and atopic dermatitis. These therapeutic agents are especially useful for patients with severe or refractory symptoms. We present the real-life experience of four of the commonly used biologic agents in the United Arab Emirates. Methods: In this retrospective observational study, we reviewed the demographic, clinical, laboratory and treatment parameters for all patients treated with biologic agents. Results: 270 patients received biologics at our centre between May 2015 and December 2019 with a median age of 36.5 years. Omalizumab was the most prescribed agent (n=183, 67.8%) followed by dupilumab (n=54, 20%), benralizumab (n=22, 8.1%) and mepolizumab (n=11, 4.1%). Urticaria was the commonest treatment indication (n=148, 55%) followed by asthma (n=105, 39%) and atopic dermatitis (n=13, 5%). All chronic urticaria patients were treated with omalizumab and showed improvement in the mean urticaria control test score from 6.7±4.47 to 12.02±4.17, with a p-value of 0.001. Dupilumab was found to be the most commonly prescribed drug for asthma (37%), followed by omalizumab (32%), benralizumab (21%) and mepolizumab (10%). The mean Asthma control test score for all asthmatics combined increased from 17.06 ± 5.4 to 19.44 ± 5.6, with p-value 0.0012 with treatment; FeNO reduced from 60.02 ± 45.74 to 29.11 ± 27.92, with p-value 0.001 and mean FEV1 improved from 2.38L ± 0.8 to 2.67L ± 0.78, with p-value 0.045. Only 4 patients in the entire cohort reported adverse events. Conclusion: Our study demonstrated that biological agents are a safe and effective treatment for atopic asthma, chronic urticaria and atopic dermatitis.

Background: patients with chronic urticaria (CU) are increasingly using information and communication technologies (ICTs) to manage their health. What CU patients expect from ICTs and which ICTs they prefer remains unknown. We assessed why CU patients use ICTs, which ones they prefer, and what drives their expectations and choices. Methods: in this cross-sectional study, 1841 patients across 17 countries were recruited at UCAREs (Urticaria Centers of Reference and Excellence). Patients with CU who were >12 years old completed a 23-item questionnaire. Results: most patients were interested in receiving disease information (87.3%), asking physicians about CU (84.1%), and communicating with other patients through ICTs (65.6%). For receiving disease information, patients preferred one-to-one and one-to-many ICTs, especially web browsers. One-to-one ICTs were also the ICTs of choice for asking physicians about urticaria and for communicating with other patients, and e-mail and WhatsApp were the preferred ICTs, respectively. Many-to-many ICTs such as Facebook, Instagram, LinkedIn, and Twitter were least preferred for all 3 purposes. Living in rural areas and higher education were linked to higher odds of being interested in receiving disease information, asking physicians, and communicating with patients through ICTs. Conclusions: most patients and especially patients with higher education who live in rural areas are interested in using ICTs for their healthcare, but prefer different ICTs for different purposes, ie, web browsers for obtaining information, e-mail for asking physicians, and WhatsApp for communicating with other patients. Our findings may help to improve ICTs for CU., GA2LEN Network of Urticaria Centers of Reference and Excellence (UCARE); World Allergy Organization (WAO)

To the Editor: Asthma is a chronic inflammatory disease characterized by an increase of reactive oxygen and nitrogen species production in the airways (1–3). Oxidative stress has been proportionately linked to the severity of the disease (2, 3). The lung has effective, well-integrated antioxidant systems to combat oxidative and nitrative injury, including superoxide dismutase (SOD), a primary antioxidant enzyme. SOD activity is lower in patients with asthma than in control subjects and decreases further during acute asthma attacks (1, 2, 4–6). Loss of SOD activity is a result of changes in the reducing–oxidizing environment in asthma, which increases the susceptibility of SOD enzymes to oxidative inactivation (2). It has been suggested that corticosteroids have a beneficial effect on antioxidants (7). A previous report has shown that treatment with inhaled or oral corticosteroids does not affect serum SOD activity measures in patients with asthma (1). Oxidative stress causes damage to a variety of biomolecules, including lipid membranes, proteins, and DNA, all of which mechanistically contribute to injury of the asthmatic airways. Increased oxidant production in asthma has been attributed to the activation of leukocytes (7, 8), but accumulating evidence from murine models of asthma and human studies points to a mitochondrial source of oxidant production by airway epithelium and smooth muscle (9). Coenzyme Q10 (CoQ), an integral part of the mitochondrial electron transport chain, also serves as an important mitochondrial antioxidant by scavenging free radicals and inhibiting lipid and protein peroxidation (10). There is evidence that CoQ has beneficial properties as an antioxidant molecule with antiinflammatory properties (10). For example, CoQ increases antioxidant enzyme activities in the liver of diabetic rats (11) and in patients with coronary artery disease (12). CoQ supplementation prevents mitochondrial-mediated oxidative damage in rodent models of sepsis and reperfusion injury of the heart (13). CoQ decreases oxidative and nitrative inflammatory biomarkers in a rodent model of metabolic syndrome and improves endothelial dysfunction (9). A possible beneficial role of CoQ in asthma was found in a study in which CoQ supplementation was associated with corticosteroid dose reduction (14). Here, we hypothesized that CoQ supplementation will restore the reducing–oxidizing balance and antioxidant capacity of patients with asthma to normal levels. To test this, 10 control subjects and 10 patients with asthma were supplemented with oral CoQ (H2Q Advanced Bioavailability CoQ10, H2Q; Health Thru Nutrition, Westbury, NY) for 4 weeks. Informed consent was obtained, and subjects had baseline characterization (visit 1, baseline) (Table 1). Subsequently, CoQ (100 mg) was taken orally with a meal daily for 4 weeks and then evaluated at a second visit (visit 2, end of CoQ). Six weeks after the end of CoQ, subjects were evaluated at a third visit (visit 3, follow-up). At each visit, serum SOD activity, urine oxidation products of DNA damage, and the redox ratio of dihydrobiopterin (BH2) to biopterin were tested. During the study, all patients with asthma were maintained on their standard antiasthma therapy. Spirometry and fractional exhaled nitric oxide were measured according to published guidelines (6). SOD activity and CoQ levels were measured as described previously (6, 15). The urinary pterin metabolites (biopterin, 7,8-BH2, and neopterin) and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined by HPLC Online Tandem Mass Spectrometry (see the online supplement). Table 1. Clinical Baseline Characteristics of Study Population Control subjects and patients with asthma had similar amounts of endogenous CoQ at baseline. CoQ supplementation increased plasma CoQ levels in control subjects and patients with asthma (Figure 1A). The average increase in plasma CoQ was significantly higher in control subjects than in patients with asthma (Figure 1A). As previously reported (1, 2, 5), patients with asthma had lower SOD activity than control subjects at baseline (P = 0.02; Figure 1B). CoQ corrected SOD activity in asthma, leading to SOD activities similar to those of control subjects (P = 0.2). SOD activity increased significantly in patients with asthma with CoQ (Figure 1B). Urinary 8-OHdG was not significantly different between the groups and was not affected by CoQ supplementation (urinary 8-OHdG [ng/mg Cr], mean ± SE: patients with asthma: visit 1, 1.41 ± 0.18; visit 2, 1.69 ± 0.22; visit 3, 1.77 ± 0.19; control subjects: visit 1, 2.11 ± 0.42; visit 2, 1.71 ± 0.21; visit 3: 2.10 ± 0.31). However, patients with asthma had a lower ratio of the reduced to oxidized forms of biopterin (BH2/[biopterin + BH2]) than control subjects at baseline (P = 0.04), which increased significantly with CoQ (paired t test, P = 0.03) (Figure 1C). The effect of CoQ on reduced/oxidized biopterin ratio was sustained even after stopping CoQ. A potential beneficial effect of CoQ on airflow was made evident by a significant increase in FEV1/FVC ratio, which continued to increase even 6 weeks after stopping CoQ (Figure 1D) (P = 0.008). Figure 1. Coenzyme Q10 (CoQ) supplementation in asthma and healthy control subjects. (A) Supplementation of CoQ at 100 mg/d for 4 weeks increases plasma CoQ in patients with asthma and in control subjects. Levels are higher in control subjects than in patients ... Oxidative mechanisms participate in the pathogenesis of asthma, either by direct oxidative damage to basic cellular components or through the activation of redox-sensitive signaling pathways that control apoptosis and inflammation. Here, we show that CoQ supplementation (100 mg daily for 4 wk) in asthma is associated with recovery of normal levels of SOD activity and redox state, as well as improvement in airflow. The study has limitations. First, the numbers of subjects were small. Second, the study was designed using 100 mg CoQ/day, without a placebo control group, for 4 weeks. Larger and longer intervention studies that are randomized and placebo-controlled are needed to investigate the clinical benefits of CoQ or other strategies targeting mitochondrial redox mechanisms in asthma.

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI), which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity. Our objective was to characterize the levels of HA and HC-HA in asthmatic subjects and to correlate these levels with asthma severity. We determined the levels and distribution of HA and HC-HA (i) from asthmatic and control lung tissue, (ii) in bronchoalveolar lavage fluid obtained from non-severe and severe asthmatics and controls, and (iii) in serum and urine from atopic asthmatics after an experimental asthma exacerbation. HC-HA distribution was observed (i) in the thickened basement membrane of asthmatic lower airways, (ii) around smooth muscle cells of the asthmatic submucosa, and (iii) around reserve cells of the asthmatic epithelium. Patients with severe asthma had increased HA levels in bronchoalveolar lavage fluid that correlated with pulmonary function and nitric oxide levels, whereas HC-HA was only observed in a patient with non-severe asthma. After an experimental asthma exacerbation, serum HA was increased within 4 h after challenge and remained elevated through 5 days after challenge. Urine HA and HC-HA were not significantly different. These data implicate HA and HC-HA in the pathogenesis of asthma severity that may occur in part due to repetitive asthma exacerbations over the course of the disease.

Angiogenesis is closely linked to and precedes eosinophilic infiltration in asthma. Eosinophils are recruited into the airway by chemoattractant eotaxins, which are expressed by endothelial cells, smooth muscles cells, epithelial cells, and hematopoietic cells. We hypothesized that bone marrow–derived proangiogenic progenitor cells that contain eotaxins contribute to the initiation of angiogenesis and inflammation in asthma. Whole-lung allergen challenge of atopic asthma patients revealed vascular activation occurs within hours of challenge and before airway inflammation. The eotaxin receptor CCR3 was expressed at high levels on submucosal endothelial cells in patients and a murine model of asthma. Ex vivo exposure of murine endothelial cells to eotaxins induced migration and angiogenesis. In mechanistic studies, wild-type mice transplanted with eotaxin-1/2–deficient bone marrow had markedly less angiogenesis and inflammation in an atopic asthma model, whereas adoptive transfer of proangiogenic progenitor cells from wild-type mice in an atopic asthma model into the eotaxin-1/2–deficient mice led to angiogenesis and airway inflammation. The findings indicate that Th2-promoting hematopoietic progenitor cells are rapidly recruited to the lung upon allergen exposure and release eotaxins that coordinately activate endothelial cells, angiogenesis, and airway inflammation.

To the Editor: Glutathione (l-γ-glutamyl-l-cysteinylglycine) is found at exceptionally high levels in the human lung (1–3), where it serves as the primary redox couple in the reduced GSH and oxidized GSSG forms. We have identified that the airway epithelium of patients with asthma is shifted to greater reducing potential, recognized by a higher ratio of reduced to oxidized glutathione (4), which occurs in response to the episodic oxidative inflammation of asthma (1, 5–9). On this basis, we hypothesized that regional airway inflammation in asthma may be quantitatively evaluated by a nuclear imaging strategy based on uptake of a radiopharmaceutical (99mTc-exametazime [HMPAO]) selectively retained in tissues depending on GSH levels (10–13) (see Figure E1 in the online supplement). To test this concept, airway redox, inflammation, and 99mTc-HMPAO uptake determined by single-photon emission computed tomography (SPECT) were evaluated in individuals with asthma and in control subjects (Table E1). Some of the results of these studies have been previously reported in the form of abstracts (14–16). 99mTc-HMPAO (Ceretec; GE Healthcare, Arlington Heights, IL) readily diffuses into cells, where it is reduced to a hydrophilic form in the presence of GSH and retained in tissues (Figure E1) (10–13). 99mTc-HMPAO accumulation in the lung was confirmed to be glutathione dependent as indicated by markedly less uptake in mice depleted of glutathione with diethyl maleate (17) as compared with naive mice (Figure E1). Many studies report an increase in total glutathione in asthmatic lungs that occurs in an adaptive response to the episodic asthmatic exacerbations that are characterized by profound oxidative bursts of inflammatory cells in the airways (1, 5–9). Here, in anticipation of imaging, intracellular glutathione was determined in airway epithelial cells obtained at bronchoscopy from patients with asthma and control subjects to assess the magnitude of difference in redox potential between asthma and control lungs. Airway epithelium was obtained by gently brushing the airway, and the freshly obtained cells were immediately processed in the bronchoscopy suite for determination of reduced and oxidized glutathione and reducing potential in human airway epithelium of control subjects and patients with asthma in vivo. Similar to a prior report (4), GSH tended to be higher but GSSG lower in asthma (GSH, μM: patients with asthma, 17 ± 3 [n = 3]; control subjects, 8.9 ± 0.5 [n = 3]; P = 0.14; GSSG, μM: patients with asthma, 0.38 ± 0.04; control subjects, 0.48 ± 0.08; P = 0.2), so that the ratio of GSH to GSSG in the airway epithelium of patients with asthma was double that of control subjects (GSH/GSSG: patients with asthma, 43 ± 6; control subjects, 20 ± 4; P = 0.05) (Figure 1A). The reduction potential (Eh) of the GSH:GSSG couple calculated by Nernst equation (18, 19) revealed a significantly greater intracellular reducing state in the airway epithelium of patients with asthma as compared with control subjects (Eh, mV: patients with asthma, –323 ± 4; control subjects, –306 ± 3; P = 0.04) (Figure 1A). On this basis, we tested whether redox-based imaging might differentiate asthmatic from control lungs, and used SPECT and coregistered computed tomography (CT) imaging to quantitate 99mTc-HMPAO concentration and to determine anatomic sites of 99mTc-HMPAO retention (detailed imaging methods are presented in the online supplement). 99mTc-HMPAO SPECT/CT imaging revealed visibly greater HMPAO uptake in asthmatic lungs as compared with control lungs (Figures 1C and 1D; Movie E1). Normalized uptake values (NUVs) were significantly higher in patients with asthma than control subjects within central and middle transverse areas of lower lung regions (Figure 1E). Interestingly, there was significant variance in the 99mTc-HMPAO NUV of upper and lower lung regions of patients with asthma. Control lung uptake was similar among upper and lower lungs, and across the central, middle, and peripheral transverse regions of the lung. In contrast, patients with asthma had significantly greater 99mTc-HMPAO uptake in lower lung as compared with upper lung regions, and the greatest uptake within central lung regions as compared with middle and peripheral transverse regions (Figure 1E and Table 1). The finding of greater uptake in central lung regions is consistent with a greater distribution of conducting airways in central regions, and the notion of greater reducing potential in asthmatic airways. Overall, the 99mTc-HMPAO uptake findings indicate a greater than normal reducing potential in asthmatic airways as compared with normal airways, as well as significant heterogeneity of lung redox, with the most striking changes in the lower and central regions of the asthmatic lung. In this context, the lower and central regions tend to be the most prominent regions of air trapping (20, 21), which also supports the idea of more severe inflammation/airway disease in those regions. Figure 1. Redox imaging of asthmatic lungs. (A) Glutathione, GSH/GSSG, and glutathione (GSH:GSSG) redox potential (Eh) are greater in the airway epithelium of patients with asthma (n = 3) as compared with control subjects (n = 3). (B–D) Quantitation of ... Table 1: Regional Distribution of Inflammation and 99mTc-HMPAO Uptake in Asthmatic Lung The greater 99mTc-HMPAO uptake in lower regions of asthmatic lungs also suggested that inflammation might be greater in lower lung regions. To investigate this, bronchoalveolar lavage (BAL) was performed in the upper and lower lobes of patients with asthma to compare inflammatory cells and cytokines. BAL volume return, protein concentration, and total cell counts were similar among upper and lower lobes (Table 1). Eosinophils and cytokines that typify helper T-cell type 2 (Th2) inflammation, IL-4 and IL-13, were present in greater concentrations in lower lobes as compared with upper lobes (Table 1). In contrast, IFN-γ, a prototypic Th1-type cytokine, tended to be greater in upper lobes (Table 1). The IL-13 levels in BAL were inversely related to IFN-γ levels (R = –0.483, P = 0.02). This letter reveals that there is a greater reducing potential in the asthmatic airway as compared with control lungs but that there is also substantial heterogeneity of reducing potential across the lung in asthma. This supports the general concept that functional imaging based on redox potential may be used to identify intensity and regionality of airway inflammatory disease. It is important to note that the greater uptake of HMPAO may not necessarily be due to the airway epithelium in asthma. In fact, the endothelium is also inflamed in asthma and might also account for the uptake of the HMPAO (22–26). However, vascular endothelial growth factor was similar among upper and lower lung regions in asthma (Table 1). Further, to assess whether the variation of HMPAO uptake in asthma was related to variation in vascular perfusion, the blood flow in the pulmonary circulation was measured in the supine position, using 99mTc-macroaggregated albumin SPECT/CT (patients with asthma, n = 3; control subjects, n = 3). Pulmonary blood flows were not different in upper and lower regions of the lungs (all P > 0.5). Because all subjects underwent 99mTc-HMPAO SPECT/CT in the supine position (during injection, uptake, and scan), this validated that blood flow to upper and lower parts of the lungs was equally distributed and unlikely to be the cause of variance in upper and lower lobe HMPAO uptake in asthma. Likewise, there may be potential effects and/or dependence of 99mTc-HMPAO uptake on participant age or sex. Although numbers are small, there was no apparent association among 99mTc-HMPAO uptake by age or sex (all P > 0.3). Other studies have identified heterogeneity of remodeling and airflow obstruction in the lungs of patients with asthma as identified by anatomical and functional imaging modalities, for example, high-resolution CT imaging and hyperpolarized helium magnetic resonance imaging (21, 27). The participants in this study were patients with stable asthma, and further investigation is necessary to determine whether 99mTc-HMPAO uptake changes with asthma exacerbations and/or with greater asthma severity. Resolution limitation of SPECT imaging precludes the assignment of uptake to specific airways, limiting the generalized application of 99mTc-HMPAO SPECT/CT imaging in asthma. However, future development of redox-imaging compounds detectable by superior resolution modalities, for example, positron emission tomography, would be a valuable approach to visualize sites of remodeling by coregistered CT images and amounts of inflammation by redox imaging. Current studies rely on invasive bronchoscopic approaches to investigate regional asthma inflammation. The invasive nature and risk of these approaches can preclude enrollment of those patients with severe airflow limitation. A noninvasive functional nuclear imaging approach might offer an alternative quantitative solution to advance research in asthma and assess new biologic-based therapies.