Asthma updates

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  • 1.Asthma UpdatesGamal Rabie Agmy, MD, FCCP Professor of chest Diseases, Assiut university

2. Definition of Asthma A chronic inflammatory disorder of the airwaysMany cells and cellular elements play a roleChronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughingWidespread, variable, and often reversible airflow limitation 3. Asthma Inflammation: Cells and MediatorsSource: Peter J. Barnes, MD 4. Mechanisms: Asthma InflammationSource: Peter J. Barnes, MD 5. Asthma Inflammation: Cells and MediatorsSource: Peter J. Barnes, MD 6. Asthma Pathobiology Smooth Muscle Dysfunction Bronchoconstriction Bronchial Hyperreactivity Hypertrophy/Hyperplasia Inflammatory Mediator ReleaseAirway Inflammation Inflammatory Cell Infiltration/Activation Mucosal Edema Cellular Proliferation Epithelial Damage Basement Membrane ThickeningSymptoms/Exacerbations 7. Pathology of Asthma 8. Factors that Exacerbate Asthma Allergens Respiratory infections Exercise and hyperventilation Weather changes Sulfur dioxide Food, additives, drugs 9. Factors that Influence Asthma Development and Expression Host Factors Genetic - Atopy - Airway hyperresponsiveness Gender ObesityEnvironmental Factors Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections Diet 10. Is it Asthma? Recurrent episodes of wheezingTroublesome cough at nightCough or wheeze after exerciseCough, wheeze or chest tightness after exposure to airborne allergens or pollutantsColds go to the chest or take more than 10 days to clear 11. 90% of the asthma problem is not seen: The inflammation!!!Bronchospasm= 10% 12. SymptomsWhen this disappearsHave we eliminated this? Underlying disease 13. Levels of Asthma Control CharacteristicControlledPartly controlled(All of the following)(Any present in any week)Daytime symptomsNone (2 or less / week)More than twice / weekLimitations of activitiesNoneAnyNocturnal symptoms / awakeningNoneAnyNeed for rescue / reliever treatmentNone (2 or less / week)More than twice / weekLung function (PEF or FEV1)Normal< 80% predicted or personal best (if known) on any dayExacerbationNoneOne or more / yearUncontrolled3 or more features of partly controlled asthma present in any week1 in any week 14. Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids by Age DrugLow Daily Dose (g) > 5 y Age < 5 yMedium Daily Dose (g) > 5 y Age < 5 yBeclomethasone200-500100-200>500-1000>200-400Budesonide200-600100-200600-1000>200-400Budesonide-Neb Inhalation Suspension Ciclesonide250-500 80 160High Daily Dose (g) > 5 y Age < 5 y >1000 >1000>500-100080-160>160-320>160-320>400 >400>1000 >320-1280>320Flunisolide500-1000500-750>1000-2000>750-1250>2000>1250Fluticasone100-250100-200>250-500>200-500>500>500Mometasone furoate200-400100-200> 400-800>200-400400-1000400-800>1000-2000>800-1200Triamcinolone acetonide>800-1200 >2000>400 >1200 15. Asthma is a complex disease or a syndrome that includes several disease variants.The term asthma, like arthritis, equates to a definition ofgrouped clinical and physiological characteristics. These characteristics could identify syndromes, phenotypes or even multiple diseases rather than a single disease. 16. For revealing the complexity and the heterogeneity of this disease, asthma patients were grouped into subtypes called phenotypes.Term phenotype describes subtypes of asthma focused on clinically observable characteristics of a disease. 17. Therefore, there are many definitions for asthma phenotypes, many of which are related to differences in symptoms and severity rather than to differences in underlying mechanisms. but this kind of subtyping does little to help understand prognosis and target therapy.When a link can be made between clinical characteristics and molecular pathways, the term endotype can be introduced to describe distinct subtypes with a defining etiology and consistent pathobiologic mechanisms. 18. The definition of a true phenotype (or endotype) requires an underlying pathobiology with identifiable biomarkers and genetics .Gene-expression profiling allows definition of expression signatures to characterize patient subgroups, predict response to treatment, and offer novel therapies. 19. By The study of wenzel ,et al 2013 Combining clinical, statistical and molecular approaches two broad emerging endotypes have been defined.Traditionally asthma has been thought to be a Th2-associated disease. There is strong evidence supporting a TH2-high phenotype in up to 50% of people with asthma of any severity, yet 50% show no evidence for this immune process. 20. These patients are characterized by atopy, eosinophilic inflammation and favorable response to corticosteroids. Early-onset allergic asthmaLate-onset persistent eosinophilic asthmaExercise induced asthma 21. Clinical characteristics: This group of asthmatic patients developed their disease in childhood, and maintained their symptoms into adulthood. . The majority of early-onset allergic asthma is mild but that anincreasing complexity of immune processes leads to greater severity. Most people with asthma are likely to have this phenotype.Positive skin prick tests, specific IgE antibodies in serum, eosinophilia in the peripheral blood . 22. Genetics: Early-onset allergic patients commonly have a family history of asthma, suggesting a genetic component. Several Th2 cytokine SNPshigher numbers of mutations in TH2-related genes (IL4, IL13,IL4R ) associated with greater severity of disease. 23. Biomarkers: Positive SPT, elevated IgE/elevated FeNOTh2 cytokines IL-4 ,IL-5 , IL-9, IL-13, and periostin measured in sputum, BAL, serum and bronchial biopsies.Treatment responses: Corticosteroid-responsive. Th2 Targeted therapy: Anti IgE (omalizumab)in Severe allergic asthma.AntiIL-13( lebrikizumab) in Allergic asthma with dominant IL-13activation Surrogate marker predicting better response is high circulating levels of periostin. . 24. Inhaled IL-4R antagonist . Surrogate marker predicting better response is IL-4 receptor a polymorphism. 25. Clinical characteristics: The majority of this group develops disease in adult life, often in the late 20s to 40s. Severe from onset, Severe exacerbations with persistentsputum eosinophilia (>2%), despite corticosteroid therapy. less clinical allergic responses( non atopic) than earlyonset asthma.It is often associated with sinus disease. 26. Genetics: Few patients in this group have a family history of asthma. little is known regarding the genetics of adult onset persistentasthma. 27. Biomarkers: Lung eosinophilia. Persistent sputum eosinophilia (2%) The lack of clinical allergy in this phenotype suggests that the TH2 process differs from and is probably more complex than the one associated with the early-onset allergic phenotype but the presence of IL-13 and IL-5 in the lower airways confirm Th2 pathway.Some individuals show sputum neutrophilia intermixed with their eosinophilic process. This mixed inflammatory process implies thatthere are interactions of additional immune pathways with TH2 immunity, including activation of pathways related to IL-33 and IL17 . Elevations in FeNO 28. Treatment responses: persistent eosinophilia in late-onset disease inspite of ICS implies that theTH2 process in this type of asthma is refractory to corticosteroids but high systemic doses of corticosteroids are generally able to overcome this refractoriness in late-onset asthma. IL-5 targeted therapy may show much better efficacy in this endotype, compared in early-onset allergic asthma patients, as IL-5 dependent eosinophilia may be more important in this potential endotype.(decreasing exacerbations and systemic corticosteroid requirements) L-4 and IL-13 targeted therapy pathway. 29. AERD is probably a subendotype or a similar endotype. It is anacquired condition on top of an intrinsic or less frequently allergic asthma and thus, despite its peculiar sensitivity to NSAIDs, still has major overlap with these conditions.Clinical characteristics : AERD is frequently progressive severe asthma starts late in life and is associated with eosinophilia and sinus disease Polyposis.Response to aspirin challenge 30. Genetics : LT-related gene polymorphisms.Gene-expression study identified upregulation of periostin a potent regulator of fibrosis and collagen deposition has also been identified in polyps of and in airway epithelial cells of patients with AIA. Overexpression of periostin has been associated withaccelerated cell growth and angiogenesis(subtype).Biomarkers: high cysteinyl leukotriene level. 31. Treatment responses : Many patients require systemic corticosteroids to control their sinusitis and asthma.Leukotriene modifiers especially 5-LO inhibitors can have a robust impact on the AERD subset.Downregulation of periostin after treatment of asthmatic patients with corticosteroids suggests that normalization of periostin expression is a part of the therapeutic effects of corticosteroids. This opens a possibility of specifically targeting periostin in future therapies for nasal polyps andasthma 32. Clinical characteristics: Exercise induced asthma refers to asthma whose symptoms are experienced primarily after exercise. EIA is a milder form ofTH2 asthma. Consistent with a relationship to TH2 processes, EIA common in atopic athletes and high percentages of eosinophils and mast cells and their mediators . 33. Biomarkers: Th2 cytokines and cysteinyl leukotrieneGenetics: No distinct genetic factors .Treatment responses: Leukotriene modifiers high LTE4/FENO ratio is Surrogate marker predicting better response.IL-9 targeted therapy has been shown effective on patients of this group, which implies that Th2 immunity is involved in the pathophysiology of EIA. 34. The lack of eff