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Case Study

  1. 1. Case Study Gamal Rabie Agmy, MD, FCCP Professor of chest Diseases, Assiut university
  2. 2. Patient Details  A 20 years old male.  Smoking Status: Ex-smoker  His weight is 100 Kg.  Occupation: Student  His grandfather died with asthma 4 years ago.
  3. 3. Past respiratory history  Age at onset of symptoms – Childhood  Hospitalizations – He was admitted on three occasions.  Life threatening attacks/ICU admissions/ventilated: 1 ICU intervention 4
  4. 4. Patient Details (cont.’):  Cannot socialize with friends.  Patient’s lifestyle was restricted.  Unable to participate in any sport  Gained weight due to lack of physical activity.  He misses up to 50% of college lectures due to asthma  Shortness of breath prevented him from using public transport  The patient is very depressed as a consequence of his asthma.
  5. 5. Patient Details (cont.’):  He has daytime symptoms as breathlessness and coughing 2 to 3 times per week.  He uses his rescue treatment around 5 to 6 times per week.  He wakes up on the early morning 3 to 4 times per week due to coughing and chest tightness.
  6. 6.  He is poorly controlled on maximum doses of inhaled medications  Despite of taking his medications regularly, He is still uncontrolled with poor quality of life. Patient Details (cont.’):
  7. 7. Clinical Findings: Clinical findings: Reversibility test > 12% FEV1 improvement. FEV1= 52% predicted. Serum Eosinophil count 630 /mm3 .
  8. 8. Allergic status  Positive skin prick test to grass, cat, dog.  Total serum IgE 175 IU/ml. 9
  9. 9. Respiratory Medications (include unsuccessful trials):  Maximum dose ICS/LABA fixed combination twice daily.  Tried Leukotriene modifiers and discontinued  Theophylline.  Salbutamol when needed.
  10. 10. Medications’ effects  Mood swings  Tachycardia  Nausea 11
  11. 11. Questions  Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?
  12. 12. Severe Asthma Definitions (cont.’):  Continuing signs of inadequate control in the presence of nearly continuous use of oral steroids or of maximal doses of inhaled corticosteroids. (SARP)1.  One or more acute exacerbations within the past year despite treatment with at least maximum recommended doses of inhaled corticosteroids. (ENFUSOMA)2. Postgrad Med J. 2008 Mar;84(989):115-20 SARP: The Severe Asthma Research Program ENFUSOMA: European Network for Understanding Mechanismsof Severe Asthma
  13. 13. Definition of The American Thoracic Society (ATS) for severe asthma:  Definition requires that at least one major criterion and two minor criteria are met in the same patient. Major characteristics:  Treatment with continuous or near continuous (≥50% of year) oral corticosteroids.  Need for treatment with high-dose inhaled corticosteroids. Lancet. 2006 Aug 26;368(9537):780-93
  14. 14. Definition of The American Thoracic Society for severe asthma (cont.’): Minor Characteristics:  Need for additional daily treatment with a controller medication (e.g. Long-acting β agonist, theophylline, or leukotriene antagonist)  Asthma symptoms needing short-acting β agonist use on a daily or near-daily basis  One or more urgent care visits for asthma per year  Three or more oral steroid bursts per year  Near-fatal asthma event in the past Lancet. 2006 Aug 26;368(9537):780-93
  15. 15. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma December 2013
  16. 16.  When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic CS) to prevent it from becoming “uncontrolled” or which remains “uncontrolled“ despite this therapy.” Definition of Severe Asthma
  17. 17. Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids by Age Drug Low Daily Dose (g) Medium Daily Dose (g) High Daily Dose (g) > 5 y Age < 5 y > 5 y Age < 5 y > 5 y Age < 5 y Beclomethasone 200-500 100-200 >500-1000 >200-400 >1000 >400 Budesonide 200-600 100-200 600-1000 >200-400 >1000 >400 Budesonide-Neb Inhalation Suspension 250-500 >500-1000 >1000 Ciclesonide 80 – 160 80-160 >160-320 >160-320 >320-1280 >320 Flunisolide 500-1000 500-750 >1000-2000 >750-1250 >2000 >1250 Fluticasone 100-250 100-200 >250-500 >200-500 >500 >500 Mometasone furoate 200-400 100-200 > 400-800 >200-400 >800-1200 >400 Triamcinolone acetonide 400-1000 400-800 >1000-2000 >800-1200 >2000 >1200
  18. 18. Asthma Pathophysiology 19
  19. 19. FCƹR1 Cƹ3
  20. 20. Source: Peter J. Barnes, MD Asthma Inflammation: Cells and Mediators
  21. 21. Source: Peter J. Barnes, MD Mechanisms: Asthma Inflammation
  22. 22. Source: Peter J. Barnes, MD Asthma Inflammation: Cells and Mediators
  23. 23. Smooth Muscle Dysfunction Airway Inflammation • Inflammatory Cell Infiltration/Activation • Mucosal Edema • Cellular Proliferation • Epithelial Damage • Basement Membrane Thickening • Bronchoconstriction • Bronchial Hyperreactivity • Hypertrophy/Hyperplasia • Inflammatory Mediator Release Symptoms/Exacerbations Asthma Pathobiology
  24. 24. Questions  Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?  What are the risk factors that associated with this case?
  25. 25. Risk factors associated with this case  Medical History  Family history
  26. 26. Risk Factors & Associated Characteristics of Severe Asthma
  27. 27. Risk Factors:  In most cases, multiple factors are responsible for difficult-to-treat asthma.  Many of the risk factors that contribute to disease chronicity are also triggers of worsening asthma and exacerbations, indicating complex interactions with the environment. Lancet. 2006 Aug 26;368(9537):780-93
  28. 28. Risk Factors (cont.’):  ENFUMOSA is among several studies that have found higher concentrations of neutrophils in induced sputum or bronchoscopic biopsy specimens from patients with severe asthma than in samples from patients with mild- to-moderate asthma.  This neutrophil predominant inflammation is significant because corticosteroids may protect these cells from undergoing apoptosis. Postgrad Med J. 2008 Mar;84(989):115-20 1-Neutrophils
  29. 29. Risk Factors (cont.’):  The genetics of asthma is a growing focus of interest, with a number of mutations having been associated with increased asthma risk.  Several of these mutations, are associated with an increased likelihood that asthma will be severe.  One such example is a mutation in the promoter region of transforming growth factor b1 (TGF-b1)  TGF-b1 is a pro-fibrotic cytokine that induces secretion of extracellular matrix proteins and thus could contribute to airway remodelling. Postgrad Med J. 2008 Mar;84(989):115-20 2-Genetics
  30. 30. Risk Factors (cont.’):  The frequency of this mutation in patients with severe asthma was twice as great as in those with mild asthma and more than five times as great as in control subjects Postgrad Med J. 2008 Mar;84(989):115-20 2-Genetics
  31. 31. Risk Factors (cont.’):  Severe asthma is two to three times more common in women than in men,  At its inception in childhood, asthma is more common in boys, but during the early teenage years severe asthma becomes more common in girls than in boys and this pattern persists into adulthood.  The higher prevalence of adult-onset asthma and severe asthma in women than in men is probably the result of endocrine factors Lancet. 2006 Aug 26;368(9537):780-93 3-Endocrine Factors:
  32. 32. Risk Factors (cont.’):  Strong associations have been reported with the menstrual cycle, whereas in pregnancy asthma commonly improves, especially in the mid and late trimesters.  Thyrotoxicosis is a recognized endocrine factor leading to loss of asthma control.  Obesity is a newly recognized risk factor for both asthma and its severity, especially in women, with weight loss being accompanied by improved asthma control. Lancet. 2006 Aug 26;368(9537):780-93 3-Endocrine Factors:
  33. 33. Risk Factors (cont):  The co-existence of chronic rhinitis, nasal polyposis, and sinusitis contribute to asthma severity.  Gastro-esophageal reflux is also commonly associated with chronic asthma both in adults and children, possibly related to the proximity of the organs and neural connections. Lancet. 2006 Aug 26;368(9537):780-93 4-Comorbid Diseases:
  34. 34. Risk Factors (cont):  Severe asthma has long been associated with psychological and psychiatric disorders, which are particularly strong risk factors for frequent emergency room visits and asthma mortality with depression, anxiety, panic or fear, and behavioral problems that adversely affect disease control. Lancet. 2006 Aug 26;368(9537):780-93 5-Psychopathological Factors:
  35. 35. Risk Factors (cont):  β blockers can lead to severe asthma that is refractory to β2-adrenoceptor agonists. Asthma is, therefore, a contraindication for this drug class.  Inhibitors of angiotensin converting enzyme and adenosine for cardiovascular diseases are also associated with deterioration of asthma.  However, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) present the most common and difficult problems.  Aspirin intolerance has emerged as a prominent risk factor of severe asthma. Lancet. 2006 Aug 26;368(9537):780-93 6-Adverse Drug Effects:
  36. 36. Do oral Beta Blockers Really Exacerbate Asthma? Recent investigations suggest BB therapy may actually improve asthma. A 2002 meta- analysis found no significant adverse effects of beta-blocker therapy in people with mild-to- moderate asthma, and in fact, bronchodilator response increased with chronic beta-blocker treatment. Thorax 2011;66:502-507.
  37. 37.  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.
  38. 38.  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.
  39. 39.  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.
  40. 40.  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.
  41. 41.  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.
  42. 42. 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
  43. 43. 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 .
  44. 44. 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.
  45. 45. 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 IL-13 activation Surrogate marker predicting better response is high circulating levels of periostin. .
  46. 46.  Inhaled IL-4Rα antagonist . Surrogate marker predicting better response is IL-4 receptor a polymorphism.
  47. 47. 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 early- onset asthma.  It is often associated with sinus disease.
  48. 48. Genetics:  Few patients in this group have a family history of asthma.  little is known regarding the genetics of adult onset persistent asthma.
  49. 49. 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
  50. 50. 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)  L-4 and IL-13 targeted therapy pathway.
  51. 51. 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
  52. 52. 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.
  53. 53. 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
  54. 54. 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 .
  55. 55. 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.
  56. 56. 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
  57. 57. 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.  ,  ..
  58. 58. 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.
  59. 59. 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.
  60. 60. 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.
  61. 61. 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 more trapping of air, thicker airway walls (as measured by CT) .
  62. 62.  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
  63. 63. 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.
  64. 64. 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.
  65. 65.  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.
  66. 66.  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.
  67. 67. The intensity of the colors represents the range of severity; the relative sizes of the subcircles suggest relative proportions of affected individuals
  68. 68. 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
  69. 69. The Asthma–Chronic Obstructive Pulmonary Disease Overlap Syndrome (ACOS)
  70. 70. The Spanish COPD guidelines propose four COPD phenotypes that determine differential treatment: nonexacerbator with emphysema or chronic bronchitis, mixed COPD–asthma, exacerbator with emphysema and exacerbator with chronic bronchitis ACOS
  71. 71. ACOS The mixed COPD–asthma phenotype was defined as an airflow obstruction that is not completely reversible accompanied by symptoms or signs of an increased reversibility of the obstruction.[7] In other guidelines, these patients are described as 'patients with COPD and prominent asthmatic component' or as asthma that complicates COPD.
  72. 72. ACOS The following major criteria for ACOS: a physician diagnosis of asthma and COPD in the same patient, history or evidence of atopy, for example, hay fever, elevated total IgE, age 40 years or more, smoking >10 pack-years, postbronchodilator FEV1 <80% predicted and FEV1/FVC <70%. Minor criteria: A ≥15% increase in FEV1 or ≥12% and ≥200 ml increase in FEV1 postbronchodilator treatment with albuterol .
  73. 73. 78 Lessons learnt from studies of asthma deaths Management of acute asthma. Thorax 2012 B Health care professionals must be aware that patients with severe asthma and one or more adverse psychosocial factors are at risk of death  Keep patients who have had near fatal asthma or brittle asthma under specialist supervision indefinitely  Respiratory specialist should follow up patients admitted with severe asthma for at least a year after admission Many deaths from asthma are preventable – 88-92% of attacks requiring hospitalisation develop over 6 hours Factors include: • inadequate objective monitoring • failure to refer earlier for specialist advice • inadequate treatment with steroids
  74. 74. 79 Levels of severity of acute asthma exacerbations Management of acute asthma. Thorax 2012 Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures
  75. 75. 80 Levels of severity of acute asthma exacerbations Management of acute asthma. Thorax 2012 Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patient with severe asthma: • Altered conscious level • Exhaustion • Arrythmias • Hypotension • Cyanosis • Silent chest • Poor respiratory effort • PEF <33% best or predicted • SpO2 <92% • PaO2 <8 kPa • “normal” PaCO2 (4.6–6.0 kPa)
  76. 76. 81 Levels of severity of acute asthma exacerbations Management of acute asthma. Thorax 2012 Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patient with severe asthma: •PEF <33% best or predicted •SpO2 <92% •PaO2 <8 kPa •normal PaCO2 (4.6-6.0 kPa) •silent chest •cyanosis •feeble respiratory effort •bradycardia •dysrhythmia •hypotension •exhaustion •confusion •coma Acute severe asthma Any one of: • PEF 33-50% best or predicted • respiratory rate 25/min • heart rate 110/min • inability to complete sentences in one breath
  77. 77. 82 Levels of severity of acute asthma exacerbations Management of acute asthma. Thorax 2012 Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patient with severe asthma: •PEF <33% best or predicted •SpO2 <92% •PaO2 <8 kPa •normal PaCO2 (4.6-60 kPa) •silent chest •cyanosis •feeble respiratory effort •bradycardia •dysrhythmia •hypotension •exhaustion •confusion •coma Acute severe asthma Any one of: •PEF 33-50% best or predicted •respiratory rate 25/min •heart rate 110/min •inability to complete sentences in one breath Moderate asthma exacerbation • Increasing symptoms • PEF >50-75% best or predicted • No features of acute severe asthma
  78. 78. 83 Levels of severity of acute asthma exacerbations Management of acute asthma. Thorax 2012 Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patient with severe asthma: •PEF <33% best or predicted •SpO2 <92% •PaO2 <8 kPa •normal PaCO2 (4.6-6.0 kPa) •silent chest •cyanosis •feeble respiratory effort •bradycardia •dysrhythmia •hypotension •exhaustion •confusion •coma Acute severe asthma Any one of: •PEF 33-50% best or predicted •respiratory rate 25/min •heart rate 110/min •inability to complete sentences in one breath Moderate asthma exacerbation •Increasing symptoms •PEF >50-75% best or predicted •No features of acute severe asthma Brittle asthma • Type 1: wide PEF variability (>40% diurnal variation for >50% of the time over a period >150 days) despite intense therapy • Type 2: sudden severe attacks on a background of apparently well-controlled asthma
  79. 79. 84 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2012 Clinical features Clinical features can identify some patients with severe asthma, eg severe breathlessness (including too breathless to complete sentences in one breath), tachypnea, tachycardia, silent chest, cyanosis, accessory muscle use, altered consciousness or collapse. None of these singly or together is specific. Their absence does not exclude a severe attack.
  80. 80. 85 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2012 Clinical features Clinical features, symptoms and respiratory and cardiovascular signs helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway caliber improve recognition of the degree of severity, the appropriateness or intensity of therapy, and decisions about management in hospital or at home. PEF or FEV1 are useful and valid measures of airway caliber. PEF is more convenient in the acute situation. PEF expressed as a percentage of the patient‟s previous best value is most useful clinically. PEF as a percentage of predicted gives a rough guide in the absence of a known previous best value. Different peak flow meters give different readings. Where possible the same or similar type of peak flow meter should be used.
  81. 81. 86 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2012 Clinical features Clinical features, symptoms and respiratory and cardiovascular signs helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway calibre improve recognition of severity and guide hospital or at home management decisions. PEF is more convenient and cheaper than FEV1. PEF as % previous best value or % predicted most useful Pulse oximetry Measure oxygen saturation (SpO2) with a pulse oximeter to determine the adequacy of oxygen therapy and the need for arterial blood gas (ABG) measurement. The aim of oxygen therapy is to maintain SpO2 94-98%.
  82. 82. 87 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92 Clinical features Clinical features, symptoms and respiratory and cardiovascular signs helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway calibre improve recognition of severity and guide hospital or at home management decisions. PEF is more convenient and cheaper than FEV1. PEF as % previous best value or % predicted most useful Pulse oximetry Necessary to determine adequacy of oxygen therapy and need for arterial blood gas measurement. Aim of oxygen therapy is to maintain SpO2 92% Blood gases (ABG) Measure oxygen saturation (SpO2) with a pulse oximeter to determine the adequacy of oxygen therapy and the need for arterial blood gas (ABG) measurement. The aim of oxygen therapy is to maintain SpO2 94-98%.
  83. 83. 88 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92 Clinical features Clinical features, symptoms and respiratory and cardiovascular signs helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway calibre improve recognition of severity and guide hospital or at home management decisions. PEF is more convenient and cheaper than FEV1. PEF as % previous best value or % predicted most useful Pulse oximetry Necessary to determine adequacy of oxygen therapy and need for arterial blood gas measurement. Aim of oxygen therapy is to maintain SpO2 92% Blood gases (ABG) Necessary for patients with SpO2 <92% or other features of life threatening asthma Chest X-ray Not routinely recommended in patients in the absence of: • suspected pneumomediastinum or pneumothorax • suspected consolidation • life threatening asthma • failure to respond to treatment satisfactorily • requirement for ventilation
  84. 84. 89 Initial assessment – the role of symptoms, signs and measurements Management of acute asthma. Thorax 2012 Clinical features Clinical features, symptoms and respiratory and cardiovascular signs helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway calibre improve recognition of severity and guide hospital or at home management decisions. PEF is more convenient and cheaper than FEV1. PEF as % previous best value or % predicted most useful Pulse oximetry Necessary to determine adequacy of oxygen therapy and need for arterial blood gas measurement. Aim of oxygen therapy is to maintain SpO2 92% Blood gases (ABG) Necessary for patients with SpO2 <92% or other features of life threatening asthma Chest X-ray Not routinely recommended in patients in the absence of: •suspected pneumomediastinum or pneumothorax •suspected consolidation •life threatening asthma •failure to respond to treatment satisfactorily •requirement for ventilation Systolic paradox Abandoned as an indicator of the severity of an attack
  85. 85. Radiographic Signs of Pneumomediastinum Subcutaneous emphysema Thymic sail sign Pneumoprecardium Ring around the artery sign Tubular artery sign Double bronchial wall sign Continuous diaphragm sign Extrapleural sign Air in the pulmonary ligament
  86. 86. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma
  87. 87.  When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic CS) to prevent it from becoming “uncontrolled” or which remains “uncontrolled“ despite this therapy.” Definition of Severe Asthma
  88. 88. Recommendation  CT chest  Sputum eosinophil count  Exhaled NO  Omalizumab  Methotrexate  Macrolide antibiotics  Antifungal agents  Bronchial thermoplasty
  89. 89. Questions  Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?  What are the risk factors that associated with this case?  Guided by guidelines, what’s our Goal of managing this case?
  90. 90. GINA Goals For Asthma Management:  Achieve and maintain control of symptoms.  Maintain normal activity levels.  Prevent asthma mortality.  Maintain pulmonary function as close to normal.  Prevent asthma exacerbations. Adapted from Global strategy for Asthma management and prevention guidelines 2012.
  91. 91. Goals for this case  Patient Goals - Reduction in symptoms - To improve quality of life. - To complete college course.  HCP Goal • Reduction in healthcare utilization • Improvement in patient’s QoL. • Reducing exacerbation frequency. • Reduce the potential for repeated admissions
  92. 92. Questions  Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?  What are the risk factors that associated with this case?  Guided by guidelines, what’s our Goal of managing this case?  What is the classification for this case?
  93. 93. Level of Control:  Regarding the mentioned case:  He has daytime symptoms. (He misses college).  He has limitation of activities (Unable to participate in sports).  Regarding the nocturnal awakening. (He wakes up at the early morning) (3 to 4 times/week).  He uses his rescue treatment more than twice/week (5 to 6 times/week).  Lung function FEV1< 80% (FEV1 = 52%).
  94. 94. Levels of Asthma Control Characteristics Controlled (All of the following) Partly controlled (Any measure present) Uncontrolled Daytime symptoms None (twice or less/week) More than twice/week Three or more features of partly controlled asthma Limitation of activities None Any Nocturnal symptoms/ Awakening None Any Need for reliever/rescue treatment None (twice or less/ week) More than twice/week Lung function (PEF or FEV1) Normal <80% predicted or personal best (if known) Assessment of current clinical control (preferably over 4 weeks) Adapted from Global strategy for Asthma management and prevention guidelines 2012
  95. 95. Questions  Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?  What are the risk factors that associated with this case?  Guided by guidelines, what’s our Goal of managing this case?  What is the classification for this case?  How can we manage this case?
  96. 96. What are treatment Options for this Patient? | Presentation Title | Presenter Name | Date | Subject | Business Use Only105
  97. 97. Treatment Options Maintain Treatment Step 4 | Presentation Title | Presenter Name | Date | Subject | Business Use Only106
  98. 98. Treatment according To guidelines: Adapted from Global strategy for Asthma management and prevention guidelines 2012. Treatment Steps Step 1 Step 2 Step 3 Step 4 Step 5 Asthma education Environmental control As needed rapid- acting β2-agonist As needed rapid-acting β2-agonist Controller options Select one Select one To step 3 treatment, select one or more To step 4 treatment, add either Low-dose ICS Low-dose ICS plus LABA Medium- or high-dose ICS plus LABA Oral corticosteroid (lowest dose) Leukotriene modifier Medium- or high-dose ICS Leukotriene modifier Anti-IgE treatment Low-dose ICS plus Leukotriene modifier Sustained release Theophylline Low-dose ICS plus sustained release Theophylline Reduce Increase
  99. 99. The Mentioned Case Is Classified As: •Uncontrolled (According to the GINA classification for the level of control). •GINA step 5 (according to the treatment steps). •Allergic(Atopic) (+ve skin test to 2 allergens).  Despite of taking his medications even with high doses regularly he is:
  100. 100. Treatment Options Maintain Treatment Step 4 Oral Corticosteroids | Presentation Title | Presenter Name | Date | Subject | Business Use Only109
  101. 101. Treatment according To guidelines: Adapted from Global strategy for Asthma management and prevention guidelines 2012. Treatment Steps Step 1 Step 2 Step 3 Step 4 Step 5 Asthma education Environmental control As needed rapid- acting β2-agonist As needed rapid-acting β2-agonist Controller options Select one Select one To step 3 treatment, select one or more To step 4 treatment, add either Low-dose ICS Low-dose ICS plus LABA Medium- or high-dose ICS plus LABA Oral corticosteroid (lowest dose) Leukotriene modifier Medium- or high-dose ICS Leukotriene modifier Anti-IgE treatment Low-dose ICS plus Leukotriene modifier Sustained release Theophylline Low-dose ICS plus sustained release Theophylline Reduce Increase
  102. 102. Side effects of Oral Corticosteroids?!  OCS are used sparingly due to a broad array of serious adverse events including: • Bone fractures • Osteoporosis • Susceptibility to infections • Hyperglycemia • Obesity • Psychiatric condition • Hypertension • Skin condition • Adrenal insufficiency • Ocular condition • Non-Hodgkin lymphoma • Deep vein thrombosis • Cardiac condition • Weakness • Abnormal hair growth • Gastric condition • Impaired growth S.C. Manson et al. Respiratory Medicine (2009) 103, 975-994
  103. 103. Not only do the identified adverse events have a strong negative impact on the health of patients, but they also have economic and societal consequences as well. | Presentation Title | Presenter Name | Date | Subject | Business Use Only112 S.C. Manson et al. Respiratory Medicine (2009) 103, 975-994
  104. 104. Steroid avoidance became a key focus  As the multi-faceted negative consequences of OCS therapy are becoming better understood, the drive to find OCS substitutes becomes more urgent  Steroid avoidance has become a key focus in the effective management of patients treated with OCS | Presentation Title | Presenter Name | Date | Subject | Business Use Only113 S.C. Manson et al. Respiratory Medicine (2009) 103, 975-994
  105. 105. Treatment Options Maintain Treatment Step 4 Oral Corticosteroids Anti- IgE | Presentation Title | Presenter Name | Date | Subject | Business Use Only114
  106. 106. Treatment according To guidelines: Adapted from Global strategy for Asthma management and prevention guidelines 2012. Treatment Steps Step 1 Step 2 Step 3 Step 4 Step 5 Asthma education Environmental control As needed rapid- acting β2-agonist As needed rapid-acting β2-agonist Controller options Select one Select one To step 3 treatment, select one or more To step 4 treatment, add either Low-dose ICS Low-dose ICS plus LABA Medium- or high-dose ICS plus LABA Oral corticosteroid (lowest dose) Leukotriene modifier Medium- or high-dose ICS Leukotriene modifier Anti-IgE treatment Low-dose ICS plus Leukotriene modifier Sustained release Theophylline Low-dose ICS plus sustained release Theophylline Reduce Increase
  107. 107. What Is Anti-IgE (Xolair®) Treatment?
  108. 108. Murine MAb Humanized IgG Xolair® Humanizing the anti-IgE monoclonal antibody: Xolair® 5% murine residues
  109. 109. Allergic inflammation: Eosinophils and lymphocytes Asthma exacerbation Omalizumab Mechanism of Action in IgE Mediated Asthma Perennial aeroallergens Allergic mediators Omalizumab 1-Binds to free IgE, reducing cell-bound IgE 2-Reduces high-affinity receptors 4-Reduces asthma exacerbations and symptoms B lymphocyte Release of IgE Mast cells Basophils Plasma cell 3-Reduces mediator release
  110. 110. Omalizumab IgE Xolair (Omalizumab) binds to the region of IgE that interact with IgE receptors C3 region
  111. 111. Xolair interrupts the allergic cascade by inhibiting the crosslinking of IgE by allergen fragments.
  112. 112. Indication
  113. 113. Indication: Xolair Basic Prescribing Information
  114. 114. Dose And Administration
  115. 115. Dosage and Administration:  The appropriate dose and dosing frequency of Xolair® is determined by baseline immunoglobulin E (IgE) (IU/mL), measured before the start of treatment, and body weight (kg).  Prior to initial dosing, patients should have their IgE level determined for their dose assignment. Xolair® Basic Prescribing Information
  116. 116. Dosage and Administration (cont):  For subcutaneous administration (every 2 or 4 weeks) only in the deltoid region of the arm.  Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region of the arm. Xolair® Basic Prescribing Information
  117. 117. Dosage and Administration (cont):  Do not administer by the intravenous or intramuscular route.  There is limited experience in the self administration of Xolair®.  Therefore, treatment is intended to be administered by a healthcare professional. Xolair® Basic Prescribing Information
  118. 118. Dosing: Xolair® Basic Prescribing Information
  119. 119. Dosing: Xolair® Basic Prescribing Information
  120. 120. Treatment duration, monitoring and dose adjustments  In clinical trials there were reductions in asthma exacerbation events and rescue medication use with improvements in symptom scores during the first 16 weeks of treatment.  At 16 week after commencing Xolair® therapy patients should be assessed by their physicians for treatment effectiveness before further injections are administered. Xolair® Basic Prescribing Information
  121. 121. Treatment duration, monitoring and dose adjustments  Discontinuation of treatment generally results in a return to elevated free IgE levels and associated symptoms. Xolair® Basic Prescribing Information
  122. 122.  Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment.  Therefore, re-testing of IgE levels during Xolair® treatment cannot be used as a guide for dose determination. Xolair® Basic Prescribing Information Treatment duration, monitoring and dose adjustments
  123. 123.  Dose determination after treatment interruptions lasting less than one year should be based on serum IgE levels obtained at the initial dose determination.  Total serum IgE levels may be re-tested for dose determination if treatment with Xolair® has been interrupted for one year or more.  Doses should be adjusted for significant body weight Changes. Xolair® Basic Prescribing Information Treatment duration, monitoring and dose adjustments
  124. 124. Clinical Outcomes
  125. 125. INNOVATE INvestigatioN of Omalizumab in seVere Asthma TrEatment Humbert M, et al. Allergy 2005 (60): 309-316
  126. 126. The INNOVATE Study • The primary objective of the INNOVATE study was to evaluate the effect of add-on omalizumab on asthma exacerbations in patients with severe persistent asthma who were inadequately controlled despite GINA step 4 therapy, which comprises high- dose ICS plus LABA and additional controller medication if required Objective Humbert M, et al. Allergy 2005 (60): 309-316
  127. 127. Study design Screening tests (7 days) 28 weeks Omalizumab (n=209) or placebo (n=210) as add-on to GINA step 4 therapy Off study drug Randomization Run-in phase (8 weeks) Follow-up (16 weeks) A 28-week randomized double-blind, placebo-controlled study Humbert M, et al. Allergy 2005 (60): 309-316
  128. 128. Omalizumab (n=209) Placebo (n=210) 1.2 1.0 0.8 0.6 0.4 0.2 0 Clinicallysignificant asthmaexacerbationrate Omalizumab significantly reduces clinically significant exacerbations  26% p=0.042 Humbert M, et al. Allergy 2005 (60): 309-316 0.68 0.91
  129. 129. Xolair® Significantly Reduces Severe Exacerbation Rate Humbert M, et al. Allergy 2005 (60): 309-316
  130. 130. Xolair® Significantly Reduces Emergency Visits Due to Asthma Worsening Humbert M, et al. Allergy 2005 (60): 309-316
  131. 131. Xolair® Significantly Improved Overall QoL & Across All Domains 49% improvement in Overall QoL with Omalizumab Humbert M, et al. Allergy 2005 (60): 309-316 49% 40% 55% 51% 49%
  132. 132. Omalizumab was well tolerated  The percentage of patients who experienced adverse events (AEs) was similar in both treatment groups. - Omalizumab, 72.2%; placebo, 75.5%  Fewer serious AEs in the Omalizumab group. - Omalizumab, 11.8%; placebo, 15.6%  AEs were generally mild or moderate in nature and of short duration. Humbert M, et al. Allergy 2005 (60): 309-316
  133. 133. Italian Real Life Experience M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416
  134. 134. Study Design  A 12-month, prospective observational trial conducted in a real-life setting evaluating the efficacy of omalizumab as an add-on treatment in 142 patients with uncontrolled severe persistent allergic asthma.  Data was collected at baseline, month 4, 8 and 12.  The evaluation performed at the end of the study (month 12). Patients treated with omalizumab for at least 4 months (n =130). M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416
  135. 135. With Xolair®: Effective reduction of emergency visits and hospitalizations | Presentation Title | Presenter Name | Date | Subject | Business Use Only144 p < 0.001 M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416
  136. 136.  Pooled analysis of seven trials (24-52 weeks long) were included on common study efficacy variables.  With objective of testing the association between the effect of OMA on need for rescue bursts of systemic steroids (SB).  4308 patients were in the pooled analysis (2511 OMA, 1797 control) 145 Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract).
  137. 137. Xolair® significantly reduces the need for systemic corticosteroid bursts: Pooled Analysis. 0.4 0.6 Steroidbursts(mean) Omalizumab (n=2,511) Control (n=1,797) 0.8 0.6 0.4 0.2 0 p<0.001 Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract). Relative risk: –43.0%
  138. 138. Conclusion  Xolair® is indicated for adults and children (6 years and above) with moderate to severe persistent allergic asthma whose symptoms are inadequately controlled with ICS.1  Omalizumab significantly reduces clinically significant exacerbations.2  Xolair® Significantly Reduces Severe Exacerbation Rate.2 Xolair® Basic Prescribing Information Allergy 2005;60:309–16
  139. 139. Conclusion  Xolair® Significantly Reduces Emergency Visits Due to Asthma Worsening.2  Xolair® Significantly Improved Overall QoL & Across All Domains.2  Xolair® Effectively reduced emergency visits and hospitalizations.  Xolair® significantly reduced the need for systemic corticosteroid bursts 1-Allergy 2005;60:309–16 2- M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416 3- Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract).
  140. 140. | Presentation Title | Presenter Name | Date | Subject | Business Use Only149

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