Asthma phenotypes and endotypes


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Asthma phenotypes and endotypes

  1. 1. Asthma Phenotypes and Endotypes Gamal Rabie Agmy, MD, FCCP Professor of chest Diseases, Assiut university
  2. 2. Definition of Asthma  A chronic inflammatory disorder of the airways  Many cells and cellular elements play a role  Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing  Widespread, variable, and often reversible airflow limitation
  3. 3. Asthma Inflammation: Cells and Mediators Source: Peter J. Barnes, MD
  4. 4.  Asthma is a complex disease or a syndrome that includes several disease variants. The term asthma, like ‘arthritis’, equates to a definition of grouped clinical and physiological characteristics. These characteristics could identify syndromes, phenotypes or even multiple diseases rather than a single disease.
  5. 5. ◙ 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.
  6. 6. 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.
  7. 7. 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.
  8. 8. Th2-associated asthma These patients are characterized by atopy, eosinophilic inflammation and favorable response to corticosteroids. Early-onset allergic asthma Late-onset persistent eosinophilic asthma Exercise induced asthma
  9. 9. Early-onset allergic asthma 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 an increasing 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 .
  10. 10. Genetics: Early-onset allergic patients commonly have a family history of asthma, suggesting a genetic component. ►Several Th2 cytokine SNPs ►higher numbers of mutations in TH2-related genes (IL4, IL13, IL4Rα ) associated with greater severity of disease.
  11. 11. Biomarkers: Positive SPT, elevated IgE/elevated FeNO Th2 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. Anti–IL-13( lebrikizumab) in Allergic asthma with dominant IL13 activation . Surrogate marker predicting better response is high circulating levels of periostin. .
  12. 12. Inhaled IL-4Rα antagonist . Surrogate marker predicting better response is IL-4 receptor a polymorphism.
  13. 13. Late-onset persistent eosinophilic asthma 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 persistent sputum eosinophilia (>2%), despite corticosteroid therapy. less clinical allergic responses( non atopic) than earlyonset asthma. It is often associated with sinus disease.
  14. 14. Genetics: Few patients in this group have a family history of asthma. little is known regarding the genetics of adult onset persistent asthma.
  15. 15. 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 that there are interactions of additional immune pathways with TH2 immunity, including activation of pathways related to IL-33 and IL-17 . Elevations in FeNO
  16. 16. Treatment responses: • persistent eosinophilia in late-onset disease inspite of ICS implies that the TH2 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) • IL-4 and IL-13 targeted therapy pathway.
  17. 17. Aspirin exacerbated airway disease (AERD) AERD is probably a subendotype or a similar endotype. It is an acquired 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
  18. 18. 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 with accelerated cell growth and angiogenesis(subtype). Biomarkers: high cysteinyl leukotriene level.
  19. 19. 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 and asthma
  20. 20. Exercise induced asthma Clinical characteristics: • Exercise induced asthma refers to asthma whose symptoms are experienced primarily after exercise. EIA is a milder form of TH2 asthma. • Consistent with a relationship to TH2 processes, EIA common in atopic athletes and high percentages of eosinophils and mast cells and their mediators .
  21. 21. Biomarkers: • Th2 cytokines and cysteinyl leukotriene Genetics: • 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.
  22. 22. Non Th2-associated asthma The lack of efficacy of Th2 targeted therapy suggests that a subgroup of asthma develops in the absence of Th2 immunity. Little is understood about the non Th2 asthma and its related molecular elements. • Obesity-related asthma • Neutrophilic asthma • Smoking asthma
  23. 23. Whether obesity is a driving component in asthma development or a mere confounder or comorbidity of its presence remains controversial. It is likely that obesity differentially impacts asthma that develops early in life, as compared to later in life, being a more prominent independent contributor in later onset disease. So a distinct obesity-related asthma phenotype seems to occur only in non-TH2 asthma.  ,  ..
  24. 24. Clinical characteristics : Patients in this group are commonly women, obese, late onset (mid-40s), less allergic (obesity is neither a risk factor for atopy nor a risk factor for allergic asthma).with a high burden of symptoms.
  25. 25. Biomarkers: High expression of non Th2 mediators such as tumor  necrosis factor (TNF)-a, IL-6 . Hormones of obesity, such as adiponectin, leptin, and resistin  either alone or in association with increased oxidative stress.  Elevations in an endogenous inhibitor of iNOS, asymmetric dimethyl arginine (ADMA).  lower amounts of FeNO, fewer eosinophils.
  26. 26. Treatment responses:  Patients of this subgroup usually respond poorly to corticosteroids.  Bariatric surgery induced weight loss was associated with profound improvements in lung function and symptoms in obese asthma.  However, the effect of weight loss on bronchial hyper responsiveness was only shown in late-onset, nonallergic (non-Th2) asthma patient, consistent with late onset obese asthma being a separate endotype. This is further supported by the increase in ADMA in association with worsening severity and control in late onset obese asthma only.
  27. 27. Clinical characteristics and biomarkers:  It remains controversial whether neutrophilia is an independent driving component, a synergistic factor with eosinophilia or just a consequence of corticosteroid therapy.  Still unclear whether this represents a unique form of asthma or just a different stage of severity or persistent bacterial colonization or infection of the airways on the background of a previously eosinophilic asthma.  Airway pathophysiology in neutrophilic asthma is characterized by (fixed) airflow limitation measured by CT) . more trapping of air, thicker airway walls (as
  28. 28.  Novel mechanisms implicated in the pathogenesis of noneosinophilic asthma involve the activation of innate immune responses with a possible role of bacteria, viruses.  Neutrophilia can also co-exist with eosinophilia, and this identifies the people with the most severe asthma and emphasizes the complexity of the immunobiology of severe asthma in which multiple different innate and adaptive immune pathways and cells may have roles.   Impaired nuclear recruitment of histone deacetylase (HDAC). The role of TH17 immunity
  29. 29. Biomarkers:  IL-8, IL-17A, LTB4, and possibly IL-32.  IL-1 and TNF-α pathways are upregulated and associated with neutrophilic inflammation in a sputum gene-expression study.  low levels of FeNO.
  30. 30. Treatment responses:   Corticosteroids are less effective in patients of this subgroup. Macrolide antibiotics may have some efficacy on neutrophilic asthma, By modulating the innate immune response in the lung, by reducing the expression of neutrophilic markers .  Restoration of HDAC 2 nuclear recruitment with theophylline.  Anti-TNF-α responsive( infliximab )  The efficacy of IL-17 targeted therapy in this subtype of asthma awaits evidence from ongoing clinical trials.
  31. 31.  Smoking has a complex relationship with asthma. It is associated with deteriorating lung function and resistance to corticosteroids.  Smoking asthma has been associated with neutrophilia in lung tissue. It is unknown if smoking asthma is a subtype of neutrophilic asthma or an independent endotype . Since not all smoking asthma is accompanied by neutrophilia, it is more likely that there is only a partial overlap between neutrophilic asthma and smoking asthma. 
  32. 32.  Some reports have suggested that smoking is associated with elevated total IgE and that active smoking may increase the risk of sensitization to workplace allergens.  However, little is understood regarding the role of genetics, biomarkers or pathobiology.  FeNO levels are decreased by smoking and could help to differentiate asthmatic subjects from non-asthmatic subjects. Treatment responses   Quitting smoking Restoration of HDAC 2 nuclear recruitment with theophylline.
  33. 33. The intensity of the colors represents the range of severity; the relative sizes of the subcircles suggest relative proportions of affected individuals
  34. 34. Lötvall et al.2011 proposed endotyping asthma into six classes depending on several parameters used to define an endotype.  Aspirin sensitive asthma  Allergic asthma (adults)  Severe late-onset hypereosinophilic  ABPM  API-positive preschool wheezer  Asthma in cross country skiers
  35. 35. The principle of personalized or individualized medicine is to 'bring the right drug to the right patient at the right dose', such that therapeutic efficacy is maximized and the side effects are kept to a minimum.
  36. 36.  The consideration of disease endotypes in treatment design should be able to bridge the present era of treating asthma based on family history, patient characteristics and laboratory test, to the future era of personalized medicine where treatment scheme will be based on individual biological data such as genomic, proteomic and metabolic profiles.