Update on asthma biology.

This is an exciting time to be conducting asthma research. The recent development of targeted asthma biologics has validated the power of basic research to discover new molecules amenable to therapeutic intervention. Advances in high-throughput sequencing are providing a wealth of "omics" data about genetic and epigenetic underpinnings of asthma, as well as about new cellular interacting networks and potential endotypes in asthma. Airway epithelial cells have emerged not only as key sensors of the outside environment but also as central drivers of dysregulated mucosal immune responses in asthma. Emerging data suggest that the airway epithelium in asthma remembers prior encounters with environmental exposures, resulting in potentially long-lasting changes in structure and metabolism that render asthmatic individuals susceptible to subsequent exposures. Here we summarize recent insights into asthma biology, focusing on studies using human cells or tissue that were published in the past 2 years. The studies are organized thematically into 6 content areas to draw connections and spur future research (on genetics and epigenetics, prenatal and early-life origins, microbiome, immune and inflammatory pathways, asthma endotypes and biomarkers, and lung structural alterations). We highlight recent studies of airway epithelial dysfunction and response to viral infections and conclude with a framework for considering how bidirectional interactions between alterations in airway structure and mucosal immunity can lead to sustained lung dysfunction in asthma.

Heterogeneity of Treatment Response to Asthma.

The definition of asthma has evolved over the years with significant heterogeneity of the disease increasingly recognized. Complex gene and environment interactions result in different pheno-endotypes of asthma that respond differently to the same treatment. Multiple studies have revealed pharmacogenomic and endophenotypic factors that predict treatment response to standard therapies for asthma. Recent advances in biologic medications have enabled a more tailored approach to the care of patients with moderate to severe asthma, taking into consideration clinical traits and measurable biomarkers. This chapter will review heterogeneity in treatment response to different medication classes for asthma: inhaled and systemic corticosteroids, beta-2 agonists, leukotriene modifiers, muscarinic antagonists, macrolides, and biologics.

Absence of Depressive and Anxious Behavior with Genetic Dysregulation in Adult C57Bl/6J Mice after Prenatal Exposure to Ionizing Radiation.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (<1000 mGy) during the last period of gestation leads to no observable changes in behaviour when assessed as adults, although some changes in gene expression were observed for specific brain regions. These results indicate that the level of oxidative stress occurring during late gestation for this mouse strain is not sufficient for a change in the assessed behavioral phenotype, but results in some modest dysregulation of the genetic profile of the brain.

Use of biologics for the treatment of moderate-to-severe asthma: the age of personalized medicine.

PURPOSE OF REVIEW: There are multiple FDA-approved biologics to treat poorly controlled moderate-to-severe asthma. Given the heterogeneity of asthma and the lack of head-to-head data between biologics, selecting the best biologic for a patient can be difficult. This review summarizes the key literature to date, in hopes of facilitating an evidence-based approach to selecting the most appropriate biologic for patients with asthma. RECENT FINDINGS: In addition to unique mechanisms of action, there is increasing literature on predictors of response to each biologic, such as sensitizations to aeroallergens, peripheral eosinophil count, total serum IgE, and exhaled nitric oxide. Biologics available for asthma are also being increasingly studied in comorbid conditions with asthma, and this may facilitate selecting the most appropriate biologic for a patient. In the absence of head-to-head studies, there is literature of switching between biologics whenever necessary. SUMMARY: The authors outline an approach to selecting a biologic based on various considerations, and hope this suggested approach facilitates selecting the biologic most suitable for each individual with poorly controlled moderate-to-severe asthma.

Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

Asthma biologics: Real-world effectiveness, impact of switching biologics, and predictors of response.

BACKGROUND: Confirmation of effectiveness of asthma biologics in the real world is desirable because patient characteristics and experiences may differ from those included in randomized controlled trials. OBJECTIVE: To evaluate real-world effectiveness of asthma biologics and identify predictors of response. METHODS: We performed a retrospective study in patients with severe asthma receiving biologics. The primary outcome was change in clinically significant exacerbations at 12 months after starting biologic therapy, compared with 12 months before. Secondary outcomes were change in severe exacerbations, maintenance oral corticosteroid (OCS) dose, prebronchodilator forced expiratory volume in 1 second (FEV1), and asthma control test scores. Subgroup analyses were performed for subjects who were biologic naive or not. A stepwise logistic regression model was performed to compare responders to nonresponders. RESULTS: A total of 112 patients were included. Biologic therapy was associated with a 59% reduction in clinically significant exacerbations (P < .001), 65% reduction in severe exacerbations (P < .001), and 54% reduction in maintenance OCS dose (P = .001) in the 12 months after starting therapy. Biologics also resulted in improvement in prebronchodilator FEV1 (P = .002) and Asthma Control Test score (P < .001). Subjects who were previously on another biologic also experienced significant improvements in exacerbation frequency, maintenance OCS dose, and asthma control. Responders were more likely to be nonsmokers and have higher baseline FEV1, gastroesophageal reflux disease, and eosinophil counts greater than 500 cells/µL. CONCLUSION: In a real-world setting, biologic therapy in asthma is effective in improving exacerbations, asthma control, and lung function. Patients who have a suboptimal response to 1 biologic can still benefit from treatment with a different biologic.

A multistakeholder Delphi consensus core outcome set for clinical trials in moderate-to-severe asthma (coreASTHMA).

BACKGROUND: Treatments for long-term control of asthma have improved and include a promising but expensive class of biologic therapies. However, the clinical trials evaluating these and other novel treatments have used a variety of different outcomes to evaluate efficacy. The evolution of asthma care calls for a re-examination of outcomes that are most important to patients and other stakeholders. OBJECTIVE: To develop a core set of outcomes to be measured in phase 3 and phase 4 clinical drug trials in patients with moderate-to-severe asthma. METHODS: We used a robust and in-depth multistakeholder consensus process bringing together patients, clinicians, regulators, payers, health technology assessors, researchers, and product developers to reach consensus on outcomes. We used a modified Delphi method to reach consensus, an approach adapted from the Core Outcome Measures in Effectiveness Trials Initiative aligned with contemporary methodological standards for core outcome set development. RESULTS: The following outcomes were included in the final core set: severe asthma exacerbation, change in asthma control, asthma-specific or severe asthma-specific quality of life, asthma-specific hospital stay (ie, >24-hour stays at any level of care) or admission, and asthma-specific emergency department visit. CONCLUSION: These 5 outcomes represent a minimum set of core outcomes for use in phase 3 and phase 4 clinical drug trials in moderate-to-severe asthma. Consistent collection of these outcomes as minimum, independent of whether additional heterogeneous primary or secondary outcomes are included, will allow for meaningful comparisons of the effect of asthma therapies across clinical trials.

Distinct asthma phenotypes with low maximal attainment of lung function on cluster analysis.

OBJECTIVE: Asthma is a heterogeneous disease with varying clinical presentations, severity and ability to achieve asthma control. The present study aimed to characterize clinical phenotypes of asthma in an Indian cohort of subjects using a cluster analysis approach. METHODS: Patients with confirmed asthma (N = 100) and at least 6-months of follow-up data, identified by retrospective chart review, were included in this study. Demographics, age at disease onset, disease duration, body mass index, serial spirometry and allergen sensitization were assessed. Asthma control was assessed prospectively using Global Initiative for Asthma and Asthma Control Test. R version 3.4.3 was used for statistical analysis. Ward's minimum-variance hierarchical clustering method was performed using an agglomerative (bottom-up) approach. To compare differences between clusters, analysis of variance using Kruskal-Wallis test (continuous variables) and chi-square test (categorical variables) was used. RESULTS: Cluster analysis of 100 treatment-naive patients with asthma identified four clusters. Cluster 1, (N = 40), childhood onset of disease, normal body weight, equal gender distribution and achieved normal lung function. Cluster 2 (N = 16) included adolescent disease-onset, obese, majority males and had poor attainment of maximum lung functions. Cluster 3 (N = 20) were older, late-onset of disease, obese, majority male and had poor attainment of maximum lung function. Cluster 4 (N = 24) had adult-onset of disease, obese, predominantly female and achieved normal lung function. CONCLUSIONS: In an Indian cohort of well-characterized patients with asthma, cluster analysis identified four distinct clinical phenotypes of asthma, two of which had poor attainment of maximum lung functions.

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 µL-1 to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 µL-1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4-5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.

Association of depressive symptoms with health status and markers of uncontrolled severe asthma.

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001). Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001). Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, www.clinicaltrials.gov.

Anesthetic Considerations for Patients Undergoing Bronchial Thermoplasty.

Bronchial thermoplasty (BT) is a novel, Food and Drug Administration-approved nondrug treatment for patients whose asthma remains uncontrolled despite traditional pharmacotherapy. BT involves application of controlled radiofrequency energy to reduce airway smooth muscle in large- and medium-sized airways. Although BT is often performed under general anesthesia, anesthetic management strategies for BT are poorly described. We describe the anesthetic management of 7 patients who underwent 19 BT treatments in a tertiary academic medical center.

Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat.

Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL-1ß, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension.

Oxidative stress and cardiovascular health: therapeutic potential of polyphenols.

Reactive oxygen species (ROS) are important in normal cellular function and physiology. However, oxidative stress resulting from an accumulation of ROS has a detrimental impact on cellular function, and ROS has been implicated in the pathogenesis of a number of diseases, including cardiovascular diseases. This review provides a summary of the impact of ROS on cardiovascular health and diseases, highlighting the therapeutic use of antioxidants. In addition, this review summarizes the health benefits of polyphenols, and the recent progress on understanding the cellular and physiological actions by which polyphenols may impart their beneficial properties on cardiovascular health.

Oxidative stress in aging--matters of the heart and mind.

Oxidative damage is considered to be the primary cause of several aging associated disease pathologies. Cumulative oxidative damage tends to be pervasive among cellular macromolecules, impacting proteins, lipids, RNA and DNA of cells. At a systemic level, events subsequent to oxidative damage induce an inflammatory response to sites of oxidative damage, often contributing to additional oxidative stress. At a cellular level, oxidative damage to mitochondria results in acidification of the cytoplasm and release of cytochrome c, causing apoptosis. This review summarizes findings in the literature on oxidative stress and consequent damage on cells and tissues of the cardiovascular system and the central nervous system, with a focus on aging-related diseases that have well-documented evidence of oxidative damage in initiation and/or progression of the disease. The current understanding of the cellular mechanisms with a focus on macromolecular damage, impacted cellular pathways and gross morphological changes associated with oxidative damage is also reviewed. Additionally, the impact of calorific restriction with its profound impact on cardiovascular and neuronal aging is addressed.

Pulmonary Embolism Diagnosed During Endobronchial Ultrasound in a Patient With Major Trauma.

Pulmonary embolism (PE) is a serious condition that often poses a diagnostic challenge. We report a case of a 57-year-old man with tobacco dependence who presented with multiple trauma, with chest imaging findings concerning for malignancy. While performing bronchoscopy with endobronchial ultrasound (EBUS), an echogenic material was incidentally found in the left pulmonary artery. Computed tomography pulmonary angiography (CTPA) was immediately obtained and confirmed the diagnosis of PE. This case illustrates the utility of routine pulmonary artery examination during EBUS procedures in patients at risk of PE and the importance of prompt management including confirmation with CTPA.

Effect of Prenatal Glucocorticoid Exposure on Circadian Rhythm Gene Expression in the Brains of Adult Rat Offspring.

Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a 'master clock', located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor (GR) signaling has the ability to reset the phase of peripheral clocks. It has been shown that maternal exposure to glucocorticoids (GCs) can lead to modification of hypothalamic-pituitary-adrenal (HPA) function, impact stress-related behaviors, and result in a hypertensive state via GR activation. We previously demonstrated altered circadian rhythm signaling in the adrenal glands of offspring exposed to the synthetic GC, dexamethasone (Dex). Results from the current study show that prenatal exposure to Dex affects circadian rhythm gene expression in a brain region-specific and a sex-specific manner within molecular oscillators of the amygdala, hippocampus, paraventricular nucleus, and prefrontal cortex, as well as the main oscillator in the SCN. Results also show that spontaneously hypertensive rats (SHR) exhibited dysregulated circadian rhythm gene expression in these same brain regions compared with normotensive Wistar-Kyoto rats (WKY), although the pattern of dysregulation was markedly different from that seen in adult offspring prenatally exposed to GCs.

Oral corticosteroid-sparing effects of mepolizumab in severe eosinophilic asthma: evidence from randomized controlled trials and real-world studies.

Oral corticosteroids (OCS) have long been a mainstay of treatment for asthma exacerbations and chronic severe asthma. However, it is increasingly recognized that both long-term and short-term OCS use are directly associated with a wide range of serious adverse effects, and as such OCS-sparing treatment alternatives are now widely recommended for patients with severe asthma. While several international guidelines recommend these treatments, guidance on OCS tapering, and which patients are most likely to tolerate OCS reduction and/or discontinuation, is still lacking. Several biologics have demonstrated efficacy in patients with OCS-dependent asthma. One OCS-sparing treatment is the anti-interleukin-5 monoclonal antibody mepolizumab, which is approved for the treatment of severe eosinophilic asthma. In addition to improved exacerbation rates, asthma control, quality of life, and lung function among patients with severe eosinophilic asthma, mepolizumab also has an OCS-sparing effect, which has been demonstrated in randomized controlled trials and real-world studies. Both physicians and patients express concerns about the adverse effects of OCS, and additional data from the randomized, controlled SIRIUS trial (NCT01691508) highlight the high level of concern among patients regarding OCS-related burden. In this article, we discuss current guidance on OCS-sparing strategies for patients with severe asthma, provide a summary of the available evidence of the OCS-sparing effect of mepolizumab, and highlight patient and physician perspectives on the use of OCS and OCS-sparing treatments in severe asthma.

Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1.

Specific spatial arrangements of proteins and lipids are central to the coordination of many biological processes. Tetraspanins have been proposed to laterally organize cellular membranes via specific associations with each other and with distinct integrins. Here, we reveal the presence of tetraspanin-enriched microdomains (TEMs) containing the tetraspanins CD9, CD63, CD81, and CD82 at the plasma membrane. Fluorescence and immunoelectron microscopic analyses document that the surface of HeLa cells is covered by several hundred TEMs, each extending over a few hundred nanometers and containing predominantly two or more tetraspanins. Further, we reveal that the human immunodeficiency virus type 1 (HIV-1) Gag protein, which directs viral assembly and release, accumulates at surface TEMs together with the HIV-1 envelope glycoprotein. TSG101 and VPS28, components of the mammalian ESCRT1 (endosomal sorting complex required for transport), which is part of the cellular extravesiculation machinery critical for HIV-1 budding, are also recruited to cell surface TEMs upon virus expression, suggesting that HIV-1 egress can be gated through these newly mapped microdomains.

Mediastinal pancreatic pseudocyst masquerading as diffuse alveolar haemorrhage.

Pancreatic pseudocyst formation with extension into the mediastinum is an uncommon complication of pancreatitis that can result in numerous pulmonary and cardiac complications. We present a case of a 56-year-old man with a history of recurrent pancreatitis who presented with haemoptysis. His initial workup was consistent with diffuse alveolar haemorrhage for which he was treated with glucocorticoids. After failure to improve, further imaging demonstrated a complex fluid collection in the mediastinum consistent with extension of his pre-existing pancreatic pseudocyst, leading to erosion into the right lower lobe of the lung. This case highlights a rare pulmonary complication of pancreatitis and underscores the importance of proper identification of this condition to guide successful management.