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Practice of Asthma
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Practice of Asthma

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Practice of Asthma lecture presented by Dr Samir Khedr at Allergy Alex 2014, the leading Allergy, Asthma and COPD Management event in Egypt. www.allergalex.com

Practice of Asthma lecture presented by Dr Samir Khedr at Allergy Alex 2014, the leading Allergy, Asthma and COPD Management event in Egypt. www.allergalex.com

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  • 1. 1 The Practice of Asthma Prof. Samir Khedr
  • 2. 2 Asthma Definition  Chronic inflammatory disorder of the airways  Many cells & cellular elements play a role  Chronic inflammation is associated with airway hyper- responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness & cough  Widespread, variable & often reversible airflow limitation  Asthma is a variable disease which, when not fully controlled, may leave the patient with a sense of fear, anger & a loss of many normal activities of daily living  The reasons for these fears range from the concern of having an asthma attack to concerns about taking medications especially steroids  Complex treatment regimens & a lack of understanding by the patient of their asthma may lead to denial & a reduction in adherence to medication resulting in poor treatment outcomes
  • 3. 3  Data demonstrate that asthma not controlled with maintenance medications can be a variable & unpredictable disease, with severity that changes from week to week  Physicians should recognize that asthma may initially be thought to be mild frequently becomes more severe if these patients are followed over time  No one parameter reliably predicted overall severity for individual patients at any given point in time  Failure to take this into consideration could possibly result in either an under-estimation or over-estimation of asthma severity  When asthma patients are classified as having mild, moderate or severe persistent asthma, they shouldn’t assume that the severity of their asthma will remain stable overtime
  • 4. 4 Is Asthma Controlled in The Real Life?  Based on surveys in USA, Canada, Central & western Europe, Asia & Japan (RABE 2004) which have been carried out in around 12000 subjects with clinical diagnosis of asthma & who had symptoms or treatment for asthma during the past year  The studies have shown that the disease is not well controlled as defined by the NAEPP 2007, Canadian Bault 2004 or GINA 2009  Physicians & patients often under estimate severity & over estimate control.  Patients are under- treated (ICS !!)  Patients have insufficient education & monitoring as it is important to assess the control of asthma
  • 5. 5 ICS Inflammation LABA Salmeterol •Mast Cells •Endothelial cells •Monocytes ICS Fluticasone •Neutrophils •Macrophages •Fibroblasts •Basophils •Dendeiritic cells •Epithelial cells •T-Lymphocytes •Eosinophils Anti-Inflammatory actions of Corticosteroids & LABA
  • 6. 6 Inflammatory Pathways in Infective vs. Non- infective Exacerbations in Asthma  Virus Allergen Eotaxin, RANTES, Prostaglandin D2 Eotaxin, RANTES Neutrophil elastase IL-8 Myeloperoxidase Eosinphilic cationic protein Neutrophil Eosinphil Epithelial cell Mast cell Molecular Mechanisms in Infective Asthma Exacerbations  Virus ICAM-1 NFkB Inflammatory genes mRNA Epithelial cells Adhesion molecules: e.g., ICAM-1 and E-selection Chemokines: e.g., IL-8 and RANTES Cytokines: e.g., TNF-α and IL-1β + + ???
  • 7. 7 GARD  Asthma is the only preventable one of the major chronic respiratory diseases which include: respiratory allergies, COPD, occupational lug diseases, sleep apnea & pulmonary hypertension  This lead to the formation of WHO Global Alliance Against Chronic Respiratory Diseases (GARD) which considers all CRDs together taking into accounts co-morbidities & risk factors GARD Objectives 1. Develop a standard procedures to obtain relevant data in CRDs & risk factors 2. Encourage countries to implement CRD prevention policies 3. Propose recommendations of simples strategies for CRDs management Although asthma guidelines may not be perfect, they appear to be the best vehicle to assist 1ry care physicians & patients to receive the best possible care of asthma (Bousquet et al 2007)
  • 8. 8 Asthma: A Global Healthcare Problem  Prevalence is increasing worldwide  It causes significant morbidity & mortality  Patients need continuous medical care  Major healthcare cost burden So what are the reasons for the continuing asthma burden? reason could be!! the inherent variability of the disease Is Asthma an Inflammatory Disease
  • 9. 9 Many cells, Inflammatory Mediators & Inflammatory Effects are involved in Asthma Cells Mast Cells Macrophages Eosinophils T-lymphocytes Epithelial cells Fibroblasts Neurons Neutrophils Platelets? Basophils? Mediators Histamine Leukotrienes Prostaglandins Thromboxane Platelet activating factor Bradykinin Tachykinins Reactive oxygen species Adenosine Anaphylato9xins Nitric oxide Cytokines Growth factors Effects Bronchoconstriction Plasma exudation Mucous hypersecretion Airway hyperresponsiveness Structural changes ( fibrosis, smooth muscle hyperplasia, angiogenesis, mucous hyperplasia) Inflammatory mediators Allergic rhinitis Asthma Atopic eczema, urticaria Food allergy Adapted from Roitt J. Essential Immunology 1994 Allergen IgE synthesis Mast cell degranul- ation Clinical symptoms Xolair® (anti-IgE) stops IgE binding to effector cells Allergen avoidance Hypo- sensitization Mast-cell stabilization: cromones, isoprenaline Late-phase inhibitors: steroids Mediator antagonists: antihistamines, antileukotrienes Mechanism Treatment Rationale for anti-IgE therapy
  • 10. 10 Inflammation in the Airways of Asthmatic Patients leads to Airway hyperresponsiveness & Symptoms Inflammation Chronic eosinophilic bronchitis Symptoms Cough, wheeze, chest tightness, Dyspnoea Triggers Allergens Exercise Cold air SO2 Particulates Allergens Chemical sensitizers Virus infections Air pollution? Airway hyperresponsiveness Asthma is Characterized by a preponderance of Th2- helper T- cells over Th1 cells IL-1 MHCII TCR IL-2 IFN-γ TNF-β IL-4 IL-5 IL-6 IL-10 IL-13 Th2 Antigen Y Y Th1 IL-4 IL-12 Th0 CD4+ lymphocytes Antigen-presenting cell Dendritic cell (Macrophages, airway epithelial?) IL-3 GM-CSF IL-10- IFN-γ -
  • 11. 11 In allergic diseases there appears to be an imbalance between Th1 & Th2 cells, with the balance tipped in favor of Th2 cells. Environmental factors, especially those in early life, may determine this imbalance Early infection (eg. TB, measles) Allergen Certain viruses (RVS?) Cigarette smoking? Th1 cells IL-2 IFN-γ Th1 cells IL-4 IL-5 IL-13 IL-12 IL-4 Mediators & asthma  There are multiple mediators involved in asthma & almost every cell in the airway may contribute to the complex mediator “soup”. This mixture of mediators then produces the pathophysiology of asthma Mediator Soup Histamine Lipid mediators Cytokines Growth factors Airway hyperresponsiveness Mucous hypersecretion Microvascular Leak Bronchoconstriction Mast cells Macrophages Eosinphils T-lymphocytes Epithelial cells Platelets Neutrophils Myofibroblasts Basophils
  • 12. 12 The Cytokine Network in Asthma Mast cell B- lymphocyte Eosinophil Monocyte Macrophage Dendritic cell Th0- lymphocyte Th2- lymphocyte IL-8 GM-CSF Antigen presentation IL-2 IL-3, IL-5, GM-CSFIL-4 IgE IL-3,SCF GM, CSF TNF IL-4 IL-5 IL-1 TNFα Epithelial cells Antigen Remodelling in Asthma Source: PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 6 2009
  • 13. 13  Airway remodeling refers to the structural changes that occur in both the large and the small airways of miscellaneous diseases, including asthma.  In asthma, airway structural changes include sub epithelial fibrosis, increased smooth muscle mass, enlargement of glands, neovascularization, and epithelial alterations.  Although controversial, airway remodeling is commonly attributed to the underlying chronic inflammatory process.  These remodeling changes contribute to thickening of airway walls and consequently lead to airway narrowing, bronchial hyperresponsiveness, airway edema, and mucous hypersecretion.  Airway remodeling is associated with poorer clinical outcome among patients with asthma.  Early diagnosis and prevention of airway remodeling has the potential to decrease disease severity, to improve control, and to prevent disease expression.
  • 14. 14 Principle of add on therapy Main Characteristics of Airway Remodeling Airway Remodelling Subepithelial Fibrosis Increased smooth Muscle Mass Goblet & Mucous Gland Hyperplasia Angiogenesis Loss of Cartilage Integrity Inflammation Epethilial Alteration
  • 15. 15 Inflammation  Inflammation is another component of airway remodeling.  There is good evidence that asthma is a heterogeneous disease.  Airways of individuals with mild and moderate asthma are characterized by a Th2 profile inflammation, in which there is an overabundance of eosinophils, mast cells, and Th2 lymphocytes.  These inflammatory cells release mediators which then trigger bronchoconstriction, mucus secretion, and, possibly, remodeling.  The number of infiltrating leukocytes such as mast cells, eosinophils, and CD8+ and CD45+ T cells correlates with airway hyperresponsiveness in patients treated ICS.  The inflammatory mediators that drive this process include Th2 cytokines (IL-4, IL-5, IL-9, and IL-13), transforming growth factor (TGF)-β, granulocyte/ macrophagecolony stimulating factor (GM-CSF), lipid mediators, and histamine.
  • 16. 16  Some of these mediators have potent remodeling properties, such as TGF-β, IL-11, and IL-17.  Recently, a new subtype of T cells has been implicated in the pathogenesis of asthma, particularly in severe asthma, where the importance of noneosinophilic or neutrophilic inflammation is well described.  This subtype of T cells are called Th-17, which secrete IL- 17 A and F and might be involved in airway remodeling. Remodeling in Allergic Diseases is Not Restricted to The Airways  Allergen exposure triggers in sensitized subjects an inflammatory response that will be expressed in the targeted organ, such as the nasal mucosa, the skin, and the airway mucosa.  Allergic rhinitis, atopic dermatitis, and asthma share many pathologic features.  In fact, the same profile of inflammation, mediators, and adhesion molecules are observed in upper and lower allergic airway diseases as well as skin allergic disease.  There is a common cellular inflammation pattern characterized by eosinophil, mast cell, and CD4+ T cell influx.
  • 17. 17  Mediators, including histamine, cysteinyl-leukotrienes, interleukin (IL)-4, IL-5, IL-13, RANTES, and eotaxin are expressed in both upper and lower airways.  Although initial inflammation induced by allergens is similar in upper and lower airways, long-term structural consequences differ.  In allergic rhinitis, minimal epithelial shedding is observed with less subsequent degree of basement membrane thickening.  Atopic dermatitis is also characterized by remodeling with increased expression of profibrotic cytokines (including TGF-b, IL-11, and IL-17) and increased subepithelial deposition of collagen.  Remodeling is observed in all atopic diseases, which reinforces the hypothesis that remodeling is an inflammatory driven process.
  • 18. 18 Conclusions  The features of airway remodeling include subepithelial fibrosis, elevated numbers and volume of mucous cells in the epithelium, increased amounts of airway smooth muscle, and increased vascularization of the airway wall.  It is important to understand the etiology of airway remodeling in asthma to develop therapies that inhibit or reverse it.  The concern that asthma is associated with airway remodeling and loss of pulmonary function prompts clinicians to consider early recognition and early intervention.  Currently, antiinflammatory drugs, including steroids, form the basis of asthma therapy.  However, their effects on remodeling and chronic structural changes in the airways remains to be elucidated.  It is for this reason that new treatments should be directed not only against inflammation itself but also against these chronic changes in the asthmatic lungs.
  • 19. 19 Monitoring inflammation in asthma  Induced sputum  Eosinophoil cationic protein (ECP)  Urinary LTE4  Exhaled mediators The Differential Diagnosis of Asthma  Upper airways disease  Vocal cord dysfunction  Congenital airway anomalies  Aspiration  Foreign body aspiration  Tumors  COPD  Interstitial lung diseases
  • 20. 20  Cardiac disease  Acute viral bronchiolitis  Chronic post-bronchiolitic wheezing  Bronchiolitis obliterans  Bronchopulmonary dysplasia  Primary ciliary dyskinesia  Cystic fibrosis (CF)  Alph-1 anti-trypsin deficiency The Differential Diagnosis of Asthma cont’d Rationale for therapy  Inhaled corticosteroids are the most effective anti- inflammatory drugs available and suppress most aspects of the inflammatory process, with effects on eosinophils, macrophages, T-lymphocytes, dendritic cells, mast cells and structural cell such as epithelial cells, which are a major source of inflammatory mediators in asthma.
  • 21. 21  Asthma is an inflammatory disease that is localized to the airways and this provides an important rationale for therapy with inhaled drugs  Inhaled β2-agonists are by far the most effective bronchodilators available, whereas ICS are the most effective anti-inflammatory drugs  Furthermore, the inhaled route prevents or reduces the systemic side-effects of these drugs.  Better understanding of the mechanisms understand how currently used drugs work at a cellular and molecular level and this has led to more rationale use of these drugs. Research has also identified new targets for drug therapy and several new classes of drug for asthma are now in clinical development
  • 22. 22 Anti-inflammatory drugs  New glucocorticoids (mometasone, cyclesonide, RP 106541 )  Immunomodulators (inhaled oxeclosporin, tacrolimus, rapamycin, mycophenolate mofetil )  PDE4 inhibitors (CDP 840, RP73401, SB 207499)  Adhesion molecule blockers (VLA-4 antibody )  Cytokine inhibitors (anti-IL4, anti-IL5, anti-TNF antibodies )  Anti-inflammatory cytokines (IL-1ra, IFN- γ, IL-10, IL12)  Anti-IgE antibody ( Xolair ) for patients above 6 years  Peptides for immunotherapy Potential Phenotypic Categories of Asthma  Clinical or Physiological phenotypes • Severity: defined Exacerbation: prone • Defined by chronic restriction Treatment: resistant • Defined by age at onset  Phenotypes are related to the following triggers • Aspirin or NSAIDs Environmental allergens • Occupational allergens or irritants Menses • Exercise  Inflammatory phenotypes • Eosinophilic Neutrophilic • Pauci- granulocytic Mixed Source: Lancet 2006,368:804-13
  • 23. 23 Questions to be Answered  Does he have asthma?  Does it explain clinical symptoms?  Does he take the drug properly?  Does he take adequate anti-inflammatory drug?  Patient has no GOR  Patient has no chronic sinusitis  Patient received other drugs as β blockers  Sensitivity to food or food additives  Psychological factors Causes of Bad Response  Inhalation techniques (critical errors)  No adherence to treatment  The use pattern is sporadic  Misdiagnosis  Location of inflammation is distal especially at night  Lack of eosinophilic inflammation
  • 24. 24 Causes of Bad Response cont’d  Genetic: • allergy & atopy • Fibrosis & remodeling • Response to treatment (ARG-ARG & GLY-GLY)  Other factors: • Environmental factors • Continuous allergen exposure • Infection of RSV & Atypicals (Clamydia & mycoplasma) • Smoking- Sinusitis- GOR- Obesity Newer Strategies for Poorly Controlled Asthma  Bronchodilators plus PDI inhibitors  ICS: • High potency • Soft  Leukotriene modifiers  Combined therapy  Biological: • Anti-IgE  thermoplasty
  • 25. 25 What’s recent? The concept of TH1/TH2 imbalance in asthma does not answer all the questions  Therapies directed at inhibiting TH2 processes are generally met with only partial success.  Viral infections ( which are the classic stimulators of TH1 immune responses) cause asthma symptoms in infancy, contribute to initiation of asthma, and commonly precipitate asthma exacerbations.  In atopic dermatitis, both TH1 and TH2 inflammation exist.
  • 26. 26 The concept of TH1/TH2 imbalance in asthma does not answer all the questions  These observations suggest that the crucial factor in asthma is impaired ability to regulate inflammation .  Recently, search for immuno-regulatory mechanisms has focused on a specific subset of T regulatory cells the “CD25+ Treg cells” Treg Cells  CD4+ CD25+ Treg cells arise in the thymus and represent 5-10% of CD4+ T cells in the periphery.  Subsets of T cells involved in the maintenance of peripheral self tolerance by actively suppressing the activation and expansion of auto reactive T cells.  CD4+ CD25+ T reg cells are the most prominently natural and inducible Treg cells.
  • 27. 27 Treg Cells  CD4+ CD25+ Treg cells constitutively express: - IL-2R (Interleukin-2 receptor) α chain - CTLA-4 (cytotoxic T lymphocyte associated antigen 4) - GITR (glucocorticoid-induced TNF receptor family related gene) - Foxp3 (Transcription factor ) – a master switch gene for CD4+CD25+ Treg cells - TGF-ß and IL-10 ASTHMA Five Medication Moves You Must Get Right To reduce the inflammation, regularly take your inhaled corticosteroids or other anti-inflammatory medications, as directed by your physician – whether you feel like you need them or not. Are you using more than one inhaler a month of albuterol ? Then your asthma is out of control. It’s time to make adjustments to your treatment plan. Schedule an appointmentwith your doctor today. Take short-acting bronchodilators to control your bronchospasm as soon as coughing or wheezing begins DON’T WAIT until symptoms “get worse” Learn to use inhalers correctly. The medicine needs to be inhaled deep into the airways for full effect. If you’re not inhaling the right way, you’re not getting your full dose ! Check each prescription you have filled to make sure it matches what your doctor ordered.
  • 28. 28 10 Things that I (an Allergy Specialist) Learned as a Parent of a child with Asthma 1. Does my child really have asthma ? 2. To act is better than to react. 3. Don’t let the environment control your child’s symptoms. 4. Not all coughs indicate asthma or allergies. 5. Early treatment makes a difference. 6. Will my child outgrow his/her asthma? 7. “Yes doctors, I understand everything you say.” 8. Over-cleaning might not be as good you think. 9. Prevention may be possible. 10. Education is always important.
  • 29. 29 Thank You