Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Although asthma has been considered as a single disease for years, recent studies have increasingly focused on its heterogeneity. The characterization of this heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link biology to phenotype, often through a statistically based process. Ongoing studies of large-scale, molecularly and genetically focused and extensively clinically characterized cohorts of asthma should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to asthma therapy.

/pdf/asthma-phenotypes-the-evolution-from-clinical-to-molecular-1a6ydbpfb2.pdf

Asthma phenotypes: the evolution from clinical to molecular approaches

The mechanisms underlying the association between obesity and the development of asthma remain incompletely understood. Dale T. Umetsu and his colleagues report that the number of IL-17A+ type 3 innate lymphoid cells (ILCs) is increased in the lungs of mice fed a high-fat diet. Activation of the NLRP3 inflammasome in lung macrophages promotes IL-1β production and ILC development, and blockade of IL-1 signaling inhibits airway hyperreactivity in obese mice. As these ILCs are also found in the lungs of individuals with asthma, these results suggest that this pathway may be targeted in asthma.

/pdf/interleukin-17-producing-innate-lymphoid-cells-and-the-nlrp3-qijfg9blxk.pdf

Interleukin-17–producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity

Obesity is a vast public health problem and both a major risk factor and disease modifier for asthma in children and adults. Obese subjects have increased asthma risk, and obese asthmatic patients have more symptoms, more frequent and severe exacerbations, reduced response to several asthma medications, and decreased quality of life. Obese asthma is a complex syndrome, including different phenotypes of disease that are just beginning to be understood. We examine the epidemiology and characteristics of this syndrome in children and adults, as well as the changes in lung function seen in each age group. We then discuss the better recognized factors and mechanisms involved in disease pathogenesis, focusing particularly on diet and nutrients, the microbiome, inflammatory and metabolic dysregulation, and the genetics/genomics of obese asthma. Finally, we describe current evidence on the effect of weight loss and mention some important future directions for research in the field.

https://www.atsjournals.org/doi/pdf/10.1164/rccm.201203-0573OC

Obesity and asthma

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

/pdf/clinical-and-inflammatory-characteristics-of-the-european-u-k4nfnzq5cb.pdf

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

Background Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. Objectives We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. Methods We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. Results We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV 1 and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P P 20 , 3.9 to 7.28, P  = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness ( P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4 + T cells increased significantly. Conclusions Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.

/pdf/effects-of-obesity-and-bariatric-surgery-on-airway-4srwn26llv.pdf

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

Pharmacokinetics of omega-3 fatty acids in patients with severe sepsis compared with healthy volunteers: A prospective cohort study.

Toxoplasma gondii is an obligate intracellular pathogen, and belongs to the phylum Apicomplexa. The pathogenesis of the parasite is thought to be due to, in part, repeated cycles of invasion of host cells, replication and lysis of host cells. T.gondii is a haploid organism and forward genetic methods to study invasion are hard to employ, because if genes essential to invasion are disrupted, they will be lethal to the parasite. Although conditional mutants have been generated, it is hard to generate a large library of conditional mutants. As an alternate approach, a library of small molecules can be screened in an assay for a particular phenotype. Then the target of the small molecule responsible for the phenotype can be identified. Two different small molecules screens can be performed: a non-presumptive approach using small molecules with no known targets or a hypothesis based approach using small molecules with known or hypothesized targets. Approximately 12,000 structurally diverse small molecules with no known target were tested in a high throughput screen in our lab to identify inhibitors of T.gondii invasion. In this thesis I have described two different projects using small molecule inhibitors identified from this screen. My first project was hypothesis driven. One of the inhibitors identified, 118793, is structurally similar to a known inhibitor of mammalian cGMP Phosphodiesterase. The goal of the project was to test the hypothesis that cGMP Phosphodiesterase is the target of the compound 118793 during invasion. This hypothesis is also supported by the fact, that cGMP dependent protein kinase is important for invasion and motility of T.gondii. An in-vitro phosphodiesterase assay using tritiated cGMP as substrate and anion exchange chromatography was adopted to test the hypothesis. The effect of compound 118793 on the cGMP hydrolytic activity of phosphodiesterase in T.gondii extracts and purified bovine phosphodiesterase was tested. From our assay, compound 118793 does not appear to inhibit cGMP phosphodiesterase in T.gondii or purified cGMP Phosphodiesterase. In addition, I also generated a FRET based cGMP indicator called CYGNET 2.1 to test the hypothesis in vivo. The second project was to test the effect of the invasion inhibitors identified in our screen on T.gondii egress. The dogma in the field is that the process of invasion and egress are mechanistically similar. I thought it would of interest to determine if any of the small molecules inhibited invasion but not egress. I adopted an ionophore induced egress assay to address this question. Ionophore-induced egress is thought to involve active motility. I tested invasion inhibitors that inhibit motility and some that do not inhibit motility. From my assay, it appears that one of the motility inhibitors does not inhibit egress. In addition, two of the non-motility inhibitors inhibit egress. These results prompt us to revisit current theories about invasion and egress. Given the limitations we have to study T.gondii, small molecule approach has proven to be very useful and advantageous in identifying proteins and pathways involved in invasion.

https://scholarworks.uvm.edu/cgi/viewcontent.cgi?article=1087&context=graddis

Jayanthi Garudathri

Papers

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

Pharmacokinetics of omega-3 fatty acids in patients with severe sepsis compared with healthy volunteers: A prospective cohort study.

Use of Small Molecules to Study Invasion and Egress in Toxoplasma gondii.

Effects Of Weight Loss On Asthma Control, Airway Inflammation And Airway Hyperresponsiveness

Airway Disease Is Significantly Related To Visceral Adipose Tissue Inflammation In Obese Asthmatics