The Role of Airway Epithelial Cell Alarmins in Asthma.

The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Pharmacotherapeutic management of asthma in pregnancy and the effect of sex hormones.

INTRODUCTION: Asthma is a common medical condition that can frequently affect pregnancy, and thus optimal management of asthma in pregnancy is important for both mother and baby. This article reviews recent developments of asthma pharmacotherapy and provides emerging data on the safety of asthma controller medications and biological therapies in pregnancy. The authors highlight the clinical outcomes of asthma during pregnancy, and summarize emerging new data related to the influence of sex hormones and fetal sex on asthma severity. AREAS COVERED: This review of asthma pharmacotherapy during pregnancy examines the recent guidelines and reports the most pertinent publications on safety data and asthma management. EXPERT OPINION: Asthma management during pregnancy follows the same principles as that of non-pregnant asthma. The available data for most asthma medications are reassuring, however there is a lack of adequate safety data available because pregnant women are generally excluded from clinical trials. More clarity is needed in guidelines regarding the management of asthma in pregnancy, and high-quality randomized control trials are required to strengthen the evidence base and inform future guidelines. In particular, safety studies examining biological therapies in pregnant women with severe asthma are needed.

Under- and over-diagnosis of COPD: a global perspective.

Globally, chronic obstructive pulmonary disease (COPD) is the fourth major cause of mortality and morbidity and projected to rise to third within a decade as our efforts to prevent, identify, diagnose and treat patients at a global population level have been insufficient. The European Respiratory Society and American Thoracic Society, along with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document, have highlighted key pathological risk factors and suggested clinical treatment strategies in order to reduce the mortality and morbidity associated with COPD. This review focuses solely on issues related to the under- and over-diagnosis of COPD across the main geographical regions of the world and highlights some of the associated risk factors. Prevalence of COPD obtained mainly from epidemiological studies varies greatly depending on the clinical and spirometric criteria used to diagnose COPD, i.e. forced expiratory volume in 1 s to forced vital capacity ratio <0.7 or 5% below the lower limit of normal, and this subsequently affects the rates of under- and over-diagnosis. Although under-utilisation of spirometry is the major reason, additional factors such as exposure to airborne pollutants, educational level, age of patients and language barriers have been widely identified as other potential risk factors. Co-existent diseases, such as asthma, bronchiectasis, heart failure and previously treated tuberculosis, are reported to be the other determinants of under- and over-diagnosis of COPD. KEY POINTS: Globally, there is large variation in the prevalence of COPD, with 10-95% under-diagnosis and 5-60% over-diagnosis (table 1) due to differences in the definition of diagnosis used, and the unavailability of spirometry in rural areas of low- and middle-income countries where the prevalence of COPD is likely to be high.In order to be diagnosed with COPD, patients must have a combination of symptoms with irreversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of <0.7 or below the fifth centile of the lower limit of normal (LLN), and with a history of significant exposure to a risk factor. Repeat spirometry is recommended if the ratio is between 0.6 and 0.8.Not performing spirometry is the strongest predictor for an incorrect diagnosis of COPD; however, additional factors, such as age, gender, ethnicity, self-perception of symptoms, co-existent asthma, and educational awareness of risk factor by patients and their physician, are also important.COPD can be associated with inhalation of noxious particles other than smoking tobacco. EDUCATIONAL AIMS: To summarise the global prevalence of over- and under-diagnosis of COPD.To highlight the risk factors associated with the under- and over-diagnosis of COPD.To update readers on the key changes in the recent progress made regarding the correct diagnosis of COPD.