Personalized Medicine in Respiratory Diseases PDF

Personalized Medicine in Respiratory Diseases Samiksha Prasad, Ph.D. Assistant Professor – Microbiology and Immunology Course Director, Hematology and Step-1 Study Blocks Dr. Kiran C. Patel College of Allopathic Medicine [email protected] 1 Respiratory Diseases and Personalized Medicine Respiratory d...

Personalized Medicine in Respiratory Diseases Samiksha Prasad, Ph.D. Assistant Professor – Microbiology and Immunology Course Director, Hematology and Step-1 Study Blocks Dr. Kiran C. Patel College of Allopathic Medicine [email protected] 1 Respiratory Diseases and Personalized Medicine Respiratory diseases are affecting people globally Chronic lung diseases (e.g., asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, etc.) and lung cancer causing extensive morbidity and mortality These conditions are highly heterogeneous & require an early diagnosis Initial symptoms are nonspecific, and the clinical diagnosis is made until later stages Personalized medicine has emerged as a medical care approach that uses novel technology aiming to personalize treatments according to the particular patient's medical needs 2 Respiratory Diseases and Personalized Medicine Asthma and chronic obstructive pulmonary disease (COPD) are the two most prevalent human airway diseases Still diagnosed following traditional approaches à fundamentally based on clinical presentation and associated lung function abnormalities à both of which are nonspecific Thus, asthma and COPD are often treated similarly and, potentially, sub optimally. The Acute Respiratory Distress Syndrome (ARDS) represents a major cause of death in the critical care units worldwide, with mortality rates around 40% 3 Personalized Medicine (PM) Also referred to as Precision Medicine PM is treatment targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations Goal of PM à improve clinical outcomes for individual patients and minimizing unnecessary side effects for those less likely to have a response to a particular treatment 4 Need for Personalized Medicine The concept of PM relates to the likelihood of responding (or not) to a given therapeutic intervention and/or suffering (or not) undesired side-effects Chakma Justin (Journal of Young Investigators, 2009, Vol 16) The heterogeneity of any human disease and the potential impact of stratifying the population appropriately 5 Potential Pulmonary, Extrapulmonary and Behavioral/ lifestyle treatable traits to consider in patients with chronic airway diseases 6 Personalized Medicine and Respiratory Disorders In the context of chronic airways diseases, precision medicine can be a promising strategy to improve their management Feb 2017- present: European Respiratory Society convened a research seminar in Barcelona aimed at discussing how to best apply precision medicine to airway diseases and specifically to asthma and COPD 7 Chronic Obstructive Pulmonary Disease (COPD) Heterogeneity a) Each node represents one patient, and each color represents different clinical characteristics b) The approach to COPD complexity based on similar clinical presentations (colors), socalled phenotypes c) Given that phenotypes can coexist in the same patient, an approach based on treatable traits has been proposed more recently 8 Personalized Medicine and Respiratory Disorders University of California, SF: https://youtu.be/HQKFgfMO5Sw 9 The Key Players in PM: Exposome, Genes, Phenotypes, Biomarkers, Endotypes and Treatable Traits Relationships between Exposome & Genome: - Via complex biological networks - Emergence of endotypes and phenotypes, & the possibility of identifying them through validated biomarkers of treatable traits 10 Development of Biomarkers Biomarkers in allergic diseases and asthma are gaining importance There is no single biomarker sufficient to be used as a gold standard (as yet) à Necessitates using a combination of biomarkers for improvement of disease management Novel biomarkers need to be identified from studies investigating the particular disorder and related disorders Discovery of biomarkers valuable in many aspects such as: Identifying patients, who will benefit from the treatment Monitoring during and after the treatment Adapting immunization schemes and dosing Inaugurating biological mechanisms of action of efficacious immunotherapy Supporting the authorization process for a treatment or a drug Prediction of side effects Prediction of long-lasting protection Improve acceptance of a specific therapy Improve patient compliance Eg.: Several biomarkers have been projected for monitorization of allergic inflammation (e.g., eosinophil numbers or levels of eosinophilic cationic protein in sputum, nasal fluid tryptase levels) 11 Characteristics of a Good Biomarker Easy determination including point-of-care Should be detected in easily accessible whole blood, serum, body fluids Should not include difficult to perform cellular assays Should respond to all questions above related to better patient care No requirement for cell cultures Should be cost efficient 12 Limitations on the Way to Define Biomarkers The extremely low rate of allergen-specific T- and B-cells responsible for allergen-specific immune responses is the major limiting factor for the biomarker discovery Very low frequency of T-cells specific for a certain allergen Very low frequency of allergen-specific B-cells Difficulties in feasibility, material transport, time, costs Difficulties in handling expertise of cellular assays with T-cells, B-cells, basophils Low number of samples and individuals so far tested No changes in specific IgE due to long living established IgE memory in bone marrow Success in individual patients does not always depend on immunological parameters (i.e., mastocytosis, multiple allergies, combined nonallergic inflammation) No human method to analyze mast cells Boonpiyathad et al. (2017); Zaleska et al. (2014) 13 Major Clinical trials for allergic diseases and PM Kucuksezer UC et al. Archivum Immunologiae et Therapiae Experimentalis (2018) 14 Personalized Medicine and Acute Respiratory Distress Syndrome (ARDS) ARDS is defined according to the presence of all the following clinical criteria: a. Recent onset of symptoms after a known risk factor b. Severe hypoxemia defined by a PaO2/FiO2 ratio less than 200 mmHg c. Bilateral infiltrates on chest radiograph d. Absence of cardiogenic pulmonary edema Based on the severity of the ARDS presentation, it may be divided into (mild, moderate, severe) categories ARDS is associated with high mortality Risk factors commonly associated with ARDS 15 Pathophysiology of ARDS Pathologically and clinically, ARDS can be divided into early and late phases of lung injury, corresponding to exudative and fibroproliferative phases 16 Pathophysiology of ARDS For ARDS biomarkers have promise in diagnosis and stratification, assessment of prognosis and to evaluate response to therapy 17 Biomarkers for ARDS Type of Marker Name Outcome Surfactant proteins (SP) Epithelial Generally increased, and SP-B can cross damaged alveolocapillary membranes Blood SP levels been shown to correlate with ARDS mortality Krebs von den Lungen-6 (KL-6) protein Levels have been correlated with ARDS mortality Vascular endothelial growth factor (VEGF) Shown to correlate with severity of illness and reflect patient outcome Use as a marker has been questionable but some studies have shown higher levels of RAGE were associated with impaired alveolar fluid clearance in patients with ARDS hence the severity of lung epithelial injury Soluble receptor for advanced glycation endproducts (sRAGE) 18 A Combined Approach with Exposome Patient involvement and understanding compliance often entail patient education and increased focus on patient-reported outcome measures (PROMs) as a tool 19 Personalized Medicine and Treatment of Lung Cancer Joshua R. Sonett, MD Columbia University Department of Surgery https://youtu.be/1c9sKHtNuKQ 20 Questions? 21