Azithromycin targets the CD27 pathway to modulate CD27hi T-lymphocyte expansion and type-1 effector phenotype.

Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors' peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.

Real-World Effectiveness of Mepolizumab in Severe Asthma: Results from the Multi-country, Self-controlled Nucala Effectiveness Study (NEST).

INTRODUCTION: The Nucala Effectiveness Study (NEST) assessed the effectiveness of mepolizumab in patients with severe asthma (SA) in countries previously underrepresented in real-world studies. METHODS: A multi-country, bi-directional, self-controlled, observational cohort study conducted in Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Historical and/or prospective data from patients with SA were assessed 12 months pre- and post-mepolizumab initiation. PRIMARY ENDPOINT: incident rate ratio (IRR) of clinically significant exacerbations (CSEs). Key secondary endpoints: healthcare resource utilisation (HCRU), oral corticosteroid (OCS) use, lung function and symptom control (Asthma Control Test [ACT] scores). RESULTS: Overall, 525 patients with SA burden pre-initiation (geometric mean blood eosinophil count [BEC] 490.7 cells/µl; 31.4% prior biologic use; 37.3% obese) received at least one dose of mepolizumab 100 mg subcutaneously. Post-initiation, a significant reduction in CSEs was observed (76% [p < 0.001]; IRR [95% confidence interval] 0.24 [0.19-0.30]); 72.0% of patients had no CSEs. Mepolizumab treatment led to a reduction in OCS use (52.8% pre-initiation vs. 16.6% post-initiation) and a mean (standard deviation [SD]) change in OCS dose of - 18.1 (20.7) mg post-initiation; 36.1% of patients became OCS-free. Fewer patients were hospitalised post-initiation (22.5% pre-initiation vs. 6.9% post-initiation). Improvements in mean (SD) forced expiratory volume in 1 s (62.8 [20.2]% pre-initiation vs. 73.0 [22.7]% post-initiation) and ACT scores (15.0% pre-initiation vs. 64.5% of patients post-initiation with well-controlled asthma) were observed. Proportion of patients with BEC ≥ 500 cells/µl decreased from 84.4% pre-initiation to 18.1% post-initiation. CONCLUSION: Mepolizumab was effective in reducing the burden of SA by significantly reducing CSEs, reducing OCS use and HCRU, and improving lung function and asthma control, which could translate to improvements in health-related quality of life in patients with SA and high OCS dependency in the countries studied. A graphical abstract is available with this article.

Severe asthma occurs when asthma symptoms remain uncontrolled despite optimised treatment. In many low-middle income countries, and in some countries in the Middle East, Asia, Latin America and the Arab Gulf, the management and treatment of patients with severe asthma remain poor, with many patients having unscheduled hospital visits or admission, and use of steroids for a prolonged period. Mepolizumab is an injectable monoclonal antibody approved as an add-on treatment for severe asthma in patients ≥ 6 years of age. In clinical trials, mepolizumab has demonstrated reductions in the risk of clinically significant exacerbations (CSE; an asthma exacerbation that requires systemic corticosteroids and/or an emergency room visit and/or hospitalisation) and the need for oral corticosteroid (OCS) treatment in patients with severe asthma by reducing inflammation caused by eosinophil (a type of white blood cell) production. The Nucala Effectiveness Study (NEST) was performed to observe the effectiveness of mepolizumab in people with severe asthma in Colombia, Chile, India, Turkey, Saudi Arabia, United Arab Emirates, Kuwait, Oman and Qatar. The frequency of CSEs and other outcomes was compared 12 months pre- and post-mepolizumab initiation. Post-initiation, the risk of CSEs was significantly reduced by 76% (p < 0.001), and 72% of patients had no CSEs. Fewer patients were dependent on OCS, with 36.1% of patients not using OCS at all, and fewer patients were hospitalised. Lung function and asthma control also improved. NEST shows that mepolizumab could benefit people with severe asthma living in countries where disease-related burden and OCS use remain high.

Assessing the impact of storage conditions on RNA from human saliva and its application to the identification of mRNA biomarkers for asthma.

Introduction: Human saliva was used to develop non-invasive liquid biopsy biomarkers to establish saliva as an alternate to blood and plasma in translational research. The present study focused on understanding the impact of sample storage conditions on the extraction of RNA from saliva and the RNA yield, to be applied in clinical diagnosis. In this study, genes related to asthma were used to test the method developed. Methods: Salivary RNA was extracted from three subjects using the Qiazol® based method and quantified by both spectrophotometric (NanoDrop) and fluorometric (Qubit®) methods. RNA integrity was measured using a bioanalyzer. Quantitative PCR was used to monitor the impact of storage conditions on the expression of housekeeping genes: GAPDH and ß-actin, and the asthma related genes: POSTN and FBN2. In addition, an independent cohort of 38 asthmatics and 10 healthy controls were used to validate the expression of POSTN and FBN2 as mRNA salivary biomarkers. Results: Approximately 2 µg of total RNA was obtained from the saliva stored at 40°C without any preservative for 2 weeks showing consistent gene expression with RNA stored at room temperature (RT) for 48 h with RNAlater. Although saliva stored with RNAlater showed a substantial increase in the yield (110 to 234 ng/µL), a similar Cq (15.6 ± 1.4) for the 18s rRNA gene from saliva without preservative showed that the RNA was stable enough. Gene expression analysis from the degraded RNA can be performed by designing the assay using a smaller fragment size spanning a single exon as described below in the case of the POSTN and FBN2 genes in the asthma cohort. Conclusion: This study showed that samples stored at room temperature up to a temperature of 40°C without any preservative for 2 weeks yielded relatively stable RNA. The methodology developed can be employed to transport samples from the point of collection to the laboratory, under non-stringent storage conditions enabling the execution of gene expression studies in a cost effective and efficient manner.

LINCATRA: Two-cycle method to amplify RNA for transcriptome analysis from formalin-fixed paraffin-embedded tissue.

Whole transcriptome analysis (WTA) using RNA extracted from Formalin Fixed Paraffin Embedded (FFPE) tissue is an invaluable tool to understand the molecular pathology of disease. RNA extracted from FFPE tissue is either degraded and/or in very low quantities hampering gene expression analysis. Earlier studies described protocols applied for cellular RNA using poly-A primer-based linear amplification. The current study describes a method, LINCATRA (LINear amplifiCAtion of RNA for whole TRAnscriptome analysis). It employs random nonamer primer based method which can amplify short, fragmented RNA with high fidelity from as low as 5 ng to obtain enough material for WTA. The two-cycle method significantly amplified RNA at ∼1000 folds (p < 0.0001) improving the mean read lengths (p < 0.05) in WTA. Overall, increased mean read length positively correlated with on-target reads (Pearson's r = 0.71, p < 0.0001) in both amplified and unamplified RNA-seq analysis. Gene expression analysis compared between unamplified and amplified group displayed substantial overlap of the differentially expressed genes (DEGs) (log2 fold change cut-off < -2 and >2, p < 0.05) identified between lung cancer and asthma cohorts validating the method developed. This method is applicable in clinical molecular pathology field for both diagnostics and elucidation of disease mechanisms.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Exploring Definitions and Predictors of Response to Biologics for Severe Asthma.

BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.

Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

COVID-19 Hierarchical Classification Using a Deep Learning Multi-Modal.

Coronavirus disease 2019 (COVID-19), originating in China, has rapidly spread worldwide. Physicians must examine infected patients and make timely decisions to isolate them. However, completing these processes is difficult due to limited time and availability of expert radiologists, as well as limitations of the reverse-transcription polymerase chain reaction (RT-PCR) method. Deep learning, a sophisticated machine learning technique, leverages radiological imaging modalities for disease diagnosis and image classification tasks. Previous research on COVID-19 classification has encountered several limitations, including binary classification methods, single-feature modalities, small public datasets, and reliance on CT diagnostic processes. Additionally, studies have often utilized a flat structure, disregarding the hierarchical structure of pneumonia classification. This study aims to overcome these limitations by identifying pneumonia caused by COVID-19, distinguishing it from other types of pneumonia and healthy lungs using chest X-ray (CXR) images and related tabular medical data, and demonstrate the value of incorporating tabular medical data in achieving more accurate diagnoses. Resnet-based and VGG-based pre-trained convolutional neural network (CNN) models were employed to extract features, which were then combined using early fusion for the classification of eight distinct classes. We leveraged the hierarchal structure of pneumonia classification within our approach to achieve improved classification outcomes. Since an imbalanced dataset is common in this field, a variety of versions of generative adversarial networks (GANs) were used to generate synthetic data. The proposed approach tested in our private datasets of 4523 patients achieved a macro-avg F1-score of 95.9% and an F1-score of 87.5% for COVID-19 identification using a Resnet-based structure. In conclusion, in this study, we were able to create an accurate deep learning multi-modal to diagnose COVID-19 and differentiate it from other kinds of pneumonia and normal lungs, which will enhance the radiological diagnostic process.

Recommended approaches for screening and early detection of lung cancer in the Middle East and Africa (MEA) region: a consensus statement.

Background: The prevalence of lung cancer in the Middle East and Africa (MEA) region has steadily increased in recent years and is generally associated with a poor prognosis due to the late detection of most of the cases. We explored the factors leading to delayed diagnoses, as well as the challenges and gaps in the early screening, detection, and referral framework for lung cancer in the MEA. Methods: A steering committee meeting was convened in October 2022, attended by a panel of ten key external experts in the field of oncology from the Kingdom of Saudi Arabia, United Arab Emirates, South Africa, Egypt, Lebanon, Jordan, and Turkey, who critically and extensively analyzed the current unmet needs and challenges in the screening and early diagnosis of lung cancer in the region. Results: As per the experts' opinion, lack of awareness about disease symptoms, misdiagnosis, limited screening initiatives, and late referral to specialists were the primary reasons for delayed diagnoses emphasizing the need for national-level lung cancer screening programs in the MEA region. Screening guidelines recommend low-dose computerized tomography (LDCT) for lung cancer screening in patients with a high risk of malignancy. However, high cost and lack of awareness among the public as well as healthcare providers prevented the judicious use of LDCT in the MEA region. Well-established screening and referral guidelines were available in only a few of the MEA countries and needed to be implemented in others to identify suspected cases early and provide timely intervention thus improving patient outcomes. Conclusions: There is a great need for large-scale screening programs, preferably integrated with tobacco-control programs and awareness programs for physicians and patients, which may facilitate higher adherence to lung cancer screening and improve survival outcomes.

An International Validation of the "DECAF Score" to Predict Disease Severity and Hospital Mortality in Acute Exacerbation of COPD in the UAE.

The DECAF score (the Dyspnea, Eosinopenia, Consolidation, Academia, and Atrial fibrillation score) has been adopted in some hospitals to predict the severity of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD). However, DECAF score has not been widely evaluated or used in Middle Eastern countries. The present study aimed to validate the DECAF score for predicting in-hospital mortality in patients with AECOPD in the United Arab Emirates (UAE). This was a retrospective, observational study conducted in 19 hospitals in the UAE. Data were retrieved from the electronic records of patients admitted for AECOPD in 17 hospitals across the country. Patients aged more than 35 years who were diagnosed with AECOPD were included in the study. The validation of the DECAF Score for inpatient death, 30-days death, and 90-day readmission was conducted using the Area Under the Receiver Operator curve (AUROC). The AUROCDECAF curves for inpatient death, 30-days death, and 90-day readmission were 0.8 (95% CI: 0.8-0.9), 0.8 (95% CI: 0.7-0.8), and 0.8 (95% CI: 0.8-0.8), respectively. The model was a satisfactory fit to the data (Hosmer-Lemeshow statistic = 0.195, Nagelkerke R2 = 31.7%). There were significant differences in means of length of stay across patients with different DECAF score (P = .008). Patients with a DECAF score of 6 had the highest mean length of stay, which was 29.8 ± 31.4 days. Patients with a DECAF score of 0 had the lowest mean length of stay, which was 3.6 ± 2.0 days. The DECAF score is a strong predictive tool for inpatient death, 30 days mortality and 90-day readmission in UAE hospital settings. The DECAF score is an effective tool for predicating mortality and other disease outcomes in patients with AECOPD in the UAE; hence, clinicians would be more empowered to make appropriate clinical decisions by using the DECAF score.

Epidemiological and Clinical Characteristics Associated with COVID-19 Severity Among Hospitalized Patients in the United Arab Emirates: A Retrospective Multicentre Study.

OBJECTIVES: To investigate the clinical and epidemiological factors associated with severe COVID-19 cases in hospitalized patients across two emirates within the United Arab Emirates (UAE). METHODS: A retrospective observational analytical study analysed data from 738 medical records and conducted 573 in-depth interviews with patients hospitalized across multiple healthcare centers in the UAE, between 29 January 2020 and 14 October 2021. Regression analysis predicted risk factors for COVID-19 severity. RESULTS: Main risk factors identified were crowding (aOR 1.919; 95%CI 1.144, 3.221), obesity (aOR 2.383; 95%CI 1.332, 4.263), diabetes (aOR 11.14; 95%CI 2.653-46.797), severe dehydration (aOR 3.219; 95%CI 2.161, 4.795), cough or sore throat (aOR 1.607; 95%CI 1.032, 2.502), shortness of breath (aOR 1.921; 95%CI 1.294, 2.853), increased days from symptom onset to admission (aOR 1.055; 95%CI 1.006, 1.105), elevated ANC (aOR 1.263, 95%CI 1.121, 1.424), and AST/SGOT (aOR 1.055, 95% CI 1.016, 1.095). Protective factors included smoking (aOR 0.367; 95%CI 0.182, 0.740), first dose of COVID-19 vaccination (aOR 0.595; 95%CI 0.377, 0.93), higher oxygen saturation (aOR 0.853; 95%CI: 0.801, 0.907) and elevated ALC (aOR 0.540; 95%CI 0.323, 0.905). CONCLUSION: Identifying risk factors is crucial for high-risk individuals who may require closer monitoring to improve their outcomes. This can provide guidance for surveillance systems and early detection strategies to mitigate the impact of future outbreaks.

International Variation in Severe Exacerbation Rates in Patients With Severe Asthma.

BACKGROUND: Exacerbation frequency strongly influences treatment choices in patients with severe asthma. RESEARCH QUESTION: What is the extent of the variability of exacerbation rate across countries and its implications in disease management? STUDY DESIGN AND METHODS: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables. RESULTS: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39). INTERPRETATION: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Development of Asthma-Like Symptoms After COVID-19: A Cross-Sectional Study in Dubai, United Arab Emirates.

Background Coronaviruses are viral agents that commonly infect animals, but have the ability to cause respiratory illness in humans, exemplified by the ongoing novel coronavirus outbreak (COVID-19). Due to the sparse literature on the effects of COVID-19 on the respiratory system, and the possible development of persistent asthma-like symptoms after infection, this cross-sectional analysis was performed in order to compare the clinical and investigative parameters between post-COVID patients and asthmatic patients. Methods A retrospective cross-sectional study was conducted on patients with prior history of COVID-19 infection that presented to the pulmonology or respiratory outpatient clinics with asthma-like symptoms and were subsequently compared to known asthmatic patients with absent history of prior COVID-19 infection, in order to evaluate the degree of similarity between both cohorts. In this study, asthma-like symptoms were defined as: (i) cough, (ii) wheezing, (iii) chest tightness, and (iv) shortness of breath. Moreover, comparisons of investigative parameters were also performed, including (i) fractional exhaled nitric oxide (FeNO), (ii) serum immunoglobulin E (IgE), (iii) absolute eosinophil counts, and (iv) qualitative spirometry results. All statistical analyses were conducted via chi-squared testing for categorical variables, and independent t-test for continuous variables. Results In this study, there were a total of 76 patients included that conformed to the eligibility criteria, including 39 patients with post-COVID symptoms with absent history of asthma or other respiratory illnesses, and 37 patients with known asthma with absent history of prior COVID-19 infection or other respiratory illnesses. Overall, this study revealed the similarities between both cohorts with respect to the incidence of cough, chest tightness, and shortness of breath. Moreover, there were similarities between the serum IgE and spirometry results. However, there were differences within the complaint of wheeze, FeNO values, and eosinophil counts between both cohorts. The placement of post-COVID patients on bronchodilator therapy involving inhaled corticosteroids and long-acting beta-agonists revealed improvement in all follow-up patients. Conclusion In conclusion, there was considerable similarity in the complaint of asthma-like symptoms after COVID-19 infection, associated with an improvement after the use of bronchodilator therapy, indicating the potential role of anti-asthma therapy (e.g., bronchodilator therapy) in managing post-COVID asthma-like symptoms. In order to validate our conclusion, further comprehensive studies with robust methodologies and larger sample populations are encouraged.

Adult Severe Asthma Registries: A Global and Growing Inventory.

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests. Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised. Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases. Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.

Cell free ACE2 RNA: A potential biomarker of COVID-19 severity.

Despite the downward trend of COVID-19 pandemic and increased immunity of the general population, COVID-19 is still an elusive disease with risks due to emerging variants. Fast and reliable diagnosis of COVID-19 disease would allow better therapeutic interventions for patients at risk to develop more severe outcomes. Cell-free RNAs (cfRNAs) have been proven to be an effective biomarker in cancer and infectious diseases. It has been reported that cfRNAs are amplified in the bloodstream of these patients and at earlier stages of the disease, reflecting tissue damage. Hence, we hypothesize that cfRNAs may serve as a potential indicator of COVID-19 disease severity. To our knowledge, this is the first report to display a significant link between COVID-19 severity and cfRNA of angiotensin converting enzyme-2 (ACE2), the receptor for SARS-CoV-2 virus. qRT-PCR analysis of liquid biopsies from COVID-19 patients (n = 82) displayed a significant increase in ACE2-cfRNA levels in patients with severe manifestations. This finding correlated with blood biomarkers (ANC, WBC, and Creatinine) that were also significantly increased in these patients. We previously showed that bronchial cells from obese subjects express higher ACE2 levels, hence, we further analysed the involvement of obesity as a main contributor to severe outcomes. We confirm a significant increase of ACE2-cfRNA in the plasma of obese/overweight (Ob/Ov) COVID-19 patients compared to lean subjects, with no observed significant change in blood biomarkers. These findings suggest that monitoring ACE2-cfRNAs, as a biomarker, during COVID-19 infection may allow for better disease management, specifically for severe-COVID-19 patients.

HLA class I associations with the severity of COVID-19 disease in the United Arab Emirates.

SARS-CoV-2 appears to induce diverse innate and adaptive immune responses, resulting in different clinical manifestations of COVID-19. Due to their function in presenting viral peptides and initiating the adaptive immune response, certain Human Leucocyte Antigen (HLA) alleles may influence the susceptibility to severe SARS-CoV-2 infection. In this study, 92 COVID-19 patients from 15 different nationalities, with mild (n = 30), moderate (n = 35), and severe (n = 27) SARS-CoV-2 infection, living in the United Arab Emirates (UAE) were genotyped for the Class I HLA -A, -C, and -B alleles using next-generation sequencing (NGS) between the period of May 2020 to June 2020. Alleles and inferred haplotype frequencies in the hospitalized patient group (those with moderate to severe disease, n = 62) were compared to non-hospitalized patients (mild or asymptomatic, n = 30). An interesting trend was noted between the severity of COVID-19 and the HLA-C*04 (P = 0.0077) as well as HLA-B*35 (P = 0.0051) alleles. The class I haplotype HLA-C*04-B*35 was also significantly associated (P = 0.0049). The involvement of inflammation, HLA-C*04, and HLA-B*35 in COVID-19 severity highlights the potential roles of both the adaptive and innate immune responses against SARS-CoV-2. Both alleles have been linked to several respiratory diseases, including pulmonary arterial hypertension along with infections caused by the coronavirus and influenza. This study, therefore, supports the potential use of HLA testing in prioritizing public healthcare interventions for patients at risk of COVID-19 infection and disease progression, in addition to providing personalized immunotherapeutic targets.

Macrolides for better resolution of community-acquired pneumonia: A global meta-analysis of clinical outcomes with focus on microbial aetiology.

OBJECTIVES: This meta-analysis examined the effect of macrolides on resolution of community-acquired pneumonia (CAP) and interpretation of clinical benefit according to microbiology; emphasis is given to data under-reported countries (URCs). METHODS: This meta-analysis included 47 publications published between 1994 and 2022. Publications were analysed for 30-d mortality (58 759 patients) and resolution of CAP (6465 patients). A separate meta-analysis was done for the prevalence of respiratory pathogens in URCs. RESULTS: Mortality after 30 d was reduced by the addition of macrolides (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.82). The OR for CAP resolution when macrolides were added to the treatment regimen was 1.23 (95% CI 1.00-1.52). In the CAP resolution analysis, the most prevalent pathogen was Streptococcus pneumoniae (12.68%; 95% CI 9.36-16.95%). Analysis of the pathogen epidemiology from the URCs included 12 publications. The most prevalent pathogens were S. pneumoniae (24.91%) and Klebsiella pneumoniae (12.90%). CONCLUSION: The addition of macrolides to the treatment regimen led to 35% relative decrease of 30-d mortality and to 23% relative increase in resolution of CAP.

The Role of Vitamin D Supplementation on Airway Remodeling in Asthma: A Systematic Review.

Asthma is a common chronic respiratory disease that affects millions of people worldwide, and its prevalence continues to increase. Vitamin D has been proposed as a potential environmental factor in asthma pathogenesis, due to its immunomodulatory effects. This systematic review aimed to evaluate the effect of vitamin D supplementation in order to prevent airway remodeling in asthmatic patients. Four electronic databases, namely PubMed, Embase, Clinical trails.gov, and CINAHL, were thoroughly searched to conduct a comprehensive literature review. The International Prospective Register of Systematic Reviews (CRD42023413798) contains a record of the registered protocol. We identified 9447 studies during the initial search; 9 studies (0.1%) met the inclusion criteria and were included in the systematic review. All included studies were experimental studies that investigated the impact of vitamin D supplementation on airway remodeling in asthma. The studies included in this review suggest that vitamin D inhibits airway smooth muscle cell contraction and remodeling, reduces inflammation, regulates collagen synthesis in the airways, and modulates the action of bronchial fibroblasts. However, one study suggests that TGF-ß1 can impair vitamin D-induced and constitutive airway epithelial host defense mechanisms. Overall, vitamin D appears to have a potential role in the prevention and management of asthma.