Bronchial Asthma Updates

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Bronchial Asthma Updates

  1. 1. Asthma Updates 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. Mechanisms: Asthma Inflammation Source: Peter J. Barnes, MD
  5. 5. Asthma Inflammation: Cells and Mediators Source: Peter J. Barnes, MD
  6. 6. Asthma Pathobiology Smooth Muscle Dysfunction • • • • Bronchoconstriction Bronchial Hyperreactivity Hypertrophy/Hyperplasia Inflammatory Mediator Release Airway Inflammation • Inflammatory Cell Infiltration/Activation • Mucosal Edema • Cellular Proliferation • Epithelial Damage • Basement Membrane Thickening Symptoms/Exacerbations
  7. 7. Pathology of Asthma
  8. 8. Factors that Exacerbate Asthma       Allergens Respiratory infections Exercise and hyperventilation Weather changes Sulfur dioxide Food, additives, drugs
  9. 9. Factors that Influence Asthma Development and Expression Host Factors  Genetic - Atopy - Airway hyperresponsiveness  Gender  Obesity Environmental Factors  Indoor allergens  Outdoor allergens  Occupational sensitizers  Tobacco smoke  Air Pollution  Respiratory Infections  Diet
  10. 10. Is it Asthma?  Recurrent episodes of wheezing  Troublesome cough at night  Cough or wheeze after exercise  Cough, wheeze or chest tightness after exposure to airborne allergens or pollutants  Colds “go to the chest” or take more than 10 days to clear
  11. 11. 90% of the asthma problem is not seen: The inflammation!!! Bronchospasm= 10%
  12. 12. Symptoms When this disappears… Have we eliminated this? Underlying disease
  13. 13. Levels of Asthma Control Characteristic Controlled Partly controlled (All of the following) (Any present in any week) Daytime symptoms None (2 or less / week) More than twice / week Limitations of activities None Any Nocturnal symptoms / awakening None Any Need for rescue / “reliever” treatment None (2 or less / week) More than twice / week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) on any day Exacerbation None One or more / year Uncontrolled 3 or more features of partly controlled asthma present in any week 1 in any week
  14. 14. Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids by Age Drug Low Daily Dose (g) > 5 y Age < 5 y Medium Daily Dose (g) > 5 y Age < 5 y Beclomethasone 200-500 100-200 >500-1000 >200-400 Budesonide 200-600 100-200 600-1000 >200-400 Budesonide-Neb Inhalation Suspension Ciclesonide 250-500 80 – 160 High Daily Dose (g) > 5 y Age < 5 y >1000 >1000 >500-1000 80-160 >160-320 >160-320 >400 >400 >1000 >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 >200-400 400-1000 400-800 >1000-2000 >800-1200 Triamcinolone acetonide >800-1200 >2000 >400 >1200
  15. 15.  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.
  16. 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. 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. 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. 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. 20. 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
  21. 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 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 .
  22. 22. 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.
  23. 23. 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. .
  24. 24.  Inhaled IL-4Rα antagonist . Surrogate marker predicting better response is IL-4 receptor a polymorphism.
  25. 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 persistent sputum eosinophilia (>2%), despite corticosteroid therapy.  less clinical allergic responses( non atopic) than earlyonset asthma.  It is often associated with sinus disease.
  26. 26. Genetics:   Few patients in this group have a family history of asthma. little is known regarding the genetics of adult onset persistent asthma.
  27. 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 that there are interactions of additional immune pathways with TH2 immunity, including activation of pathways related to IL-33 and IL17 .  Elevations in FeNO
  28. 28. 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.
  29. 29. 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
  30. 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 with accelerated cell growth and angiogenesis(subtype). Biomarkers: high cysteinyl leukotriene level.
  31. 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 and asthma
  32. 32. 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 .
  33. 33. 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.
  34. 34. 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
  35. 35. 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.  ,  ..
  36. 36. 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.
  37. 37. 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.
  38. 38. 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.
  39. 39. 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
  40. 40.  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
  41. 41. 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.
  42. 42. 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.
  43. 43.  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. 
  44. 44.  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.
  45. 45. The intensity of the colors represents the range of severity; the relative sizes of the subcircles suggest relative proportions of affected individuals
  46. 46. 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
  47. 47. Lotvall J et al JACI 2011
  48. 48. Agache,etal 2o12
  49. 49. 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.
  50. 50.  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.
  51. 51. Asthmatic Granulomatosis A Novel Disease with Asthmatic and Granulomatous Features This study present video-assisted thoracoscopic biopsy findings from 10 patients, previously diagnosed with severe asthma and meeting criteria for asthma. Pathobiologically, these patients have evidence for asthmatic small airway inflammation and infrequent nonnecrotizing granulomas with interstitial inflammation. This distinct pathobiology in addition to their response to cytotoxic agents suggests that these patients represent a newly described disease, which we term asthmatic granulomatosis. Sally E. Wenzel1, Catherine A. Vitari1, Manisha Shende2, Diane C. Strollo3, Allyson Larkin4, and Samuel A. Yousem5 Am J Respir Crit Care Med Vol 186, Iss. 6, pp 501–507, Sep 15, 2012
  52. 52. The Asthma–Chronic Obstructive Pulmonary Disease Overlap Syndrome (ACOS)
  53. 53. ACOS 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
  54. 54. 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.
  55. 55. ACOS *Two major criteria (FEV1 >15% and >400 ml after bronchodilator or sputum eosinophils or history of asthma) and *Two minor criteria (elevated total IgE or history of atopy or FEV1 >12% and >200 ml after bronchodilator) are recommended.
  56. 56. ACOS *Asthma with partially reversible airflow obstruction – that is, based on change in FEV1 with bronchodilators – with or without emphysema or reduced carbon monoxide diffusing capacity (DLco) to <80% predicted; *COPD with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLco.
  57. 57. 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 .
  58. 58. Do oral Beta Blockers Really Exacerbate Asthma? Recent investigations suggest BB therapy may actually improve asthma. A 2002 metaanalysis found no significant adverse effects of beta-blocker therapy in people with mild-tomoderate asthma, and in fact, bronchodilator response increased with chronic beta-blocker treatment. Thorax 2011;66:502-507.
  59. 59. Lessons learnt from studies of asthma deaths 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 B  Keep patients who have had near fatal asthma or brittle asthma under specialist supervision indefinitely  72 Health care professionals must be aware that patients with severe asthma and one or more adverse psychosocial factors are at risk of death Respiratory specialist should follow up patients admitted with severe asthma for at least a year after admission Management of acute asthma. Thorax 2012
  60. 60. Levels of severity of acute asthma exacerbations Near fatal asthma 73 Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Management of acute asthma. Thorax 2012
  61. 61. Levels of severity of acute asthma exacerbations Near fatal asthma Life threatening asthma 74 Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures 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) Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92
  62. 62. Levels of severity of acute asthma exacerbations 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 • silent chest • dysrhythmia • predicted cyanosis • hypotension • SpO2 <92% • feeble respiratory • exhaustion • PaO2 <8 kPa • effort confusion • normal PaCO2 (4.6-6.0 kPa) • bradycardia • coma • Acute severe asthma 75 Any one of: • PEF 33-50% best or predicted • respiratory rate 25/min • heart rate 110/min • inability to complete sentences in one breath Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92
  63. 63. Levels of severity of acute asthma exacerbations 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 • silent chest • dysrhythmia • predicted cyanosis • hypotension • SpO2 <92% • feeble respiratory • exhaustion • PaO2 <8 kPa • effort confusion • normal PaCO2 (4.6-60 kPa) • bradycardia • coma • Acute severe asthma Any one of: inability to complete sentences • in one breath Moderate asthma exacerbation 76 PEF 33-50% best or predicted respiratory rate 25/min heart rate 110/min • • • • Increasing symptoms • No features of acute severe • PEF >50-75% best or predicted asthma Management of acute asthma. Thorax 2012
  64. 64. Levels of severity of acute asthma exacerbations 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 • silent chest • dysrhythmia • predicted cyanosis • hypotension • SpO2 <92% • feeble respiratory • exhaustion • PaO2 <8 kPa • effort confusion • normal PaCO2 (4.6-6.0 kPa) • bradycardia • coma • Acute severe asthma Any one of: inability to complete sentences • in one breath Moderate asthma exacerbation Brittle asthma PEF 33-50% best or predicted respiratory rate 25/min heart rate 110/min Increasing symptoms PEF >50-75% best or predicted No features of acute severe asthma • • Type 1: wide PEF variability (>40% diurnal variation for >50% of • 77 • • • • • the time over a period >150 days) despite intense therapy Type 2: sudden severe attacks on a background of apparently well-controlled asthma Management of acute asthma. Thorax 2012
  65. 65. Initial assessment – the role of symptoms, signs and measurements Clinical features 78 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. Management of acute asthma. Thorax 2012
  66. 66. Initial assessment – the role of symptoms, signs and measurements Clinical features PEF or FEV1 79 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 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. Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92
  67. 67. Initial assessment – the role of symptoms, signs and measurements 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%. 80 Management of acute asthma. Thorax 2012
  68. 68. Initial assessment – the role of symptoms, signs and measurements 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 SpO 2 92% Blood gases (ABG) 81 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%. Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92
  69. 69. Initial assessment – the role of symptoms, signs and measurements 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 SpO 2 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 • failure to respond to treatment pneumothorax satisfactorily • suspected consolidation • requirement for ventilation • life threatening asthma 82 Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92
  70. 70. Initial assessment – the role of symptoms, signs and measurements Clinical features 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 SpO 2 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 • failure to respond to treatment • pneumothorax satisfactorily suspected consolidation • requirement for ventilation • life threatening asthma • Systolic paradox 83 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 Abandoned as an indicator of the severity of an attack Management of acute asthma. Thorax 2012
  71. 71. 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
  72. 72. Pediatric Asthma Not all wheezing is asthma Wheezing occurrences in children: - single episode in 30% to 50% of children before 5 yr of age - 40% who wheeze before 3 yr of age continue at 6 yr (“persistent wheezers”) - 50% of infants who wheeze once will wheeze again within several months
  73. 73. Wheezing in Children - Phenotypes
  74. 74. Childhood asthma phenotypes
  75. 75. Childhood asthma phenotypes *A 2012 study described 2 "new" phenotypes for young children with wheezing: "boys atopic multiple-trigger" and "girls nonatopic uncontrolled wheeze". JACI, 2012. *Toward a definition of asthma phenotypes in childhood: early viral wheezers, multitrigger wheezers (MTWs), and nonatopic uncontrolled wheezers (NAUWs). Some children have “allergic bronchitis” rather than “asthma”. JACI, 2012.
  76. 76. Diagnosing Asthma in Young Children – Asthma Predictive Index • Major criteria – Parent with asthma • > 4 episodes/yr of – Physician diagnosed wheezing lasting atopic dermatitis more than 1 day affecting sleep in a • Minor criteria child with one MAJOR – Physician diagnosed or two MINOR criteria allergic rhinitis – Eosinophilia (>4%) – Wheezing apart from colds 1Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403
  77. 77. Modified Asthma Predictive Index (API)
  78. 78. Cough-variant asthma Cough-variant asthma presents as dry cough at night. It worsens with exercise (EIA) and nonspecific triggers (cold air). Cough-variant asthma responds to asthma therapy with ICS. Cough-variant asthma is diagnosed with pulmonary function testing (PFTs) with response to bronchodilator. The most common cause of chronic cough in children is cough-variant asthma.
  79. 79. Guidelines National Heart, Lung, and Blood Institute (NHLBI) guidelines for diagnosis and management of asthma Key concepts: - severity dictates therapy - - distinction between intermittent and persistent asthma - - "rule of 2s” - - 4 levels of asthma severity - intermittent; 3 sublevels of persistent - - inhaled corticosteroids (ICS) preferred for all levels of persistent asthma - - use of asthma action plans - - spirometry recommended
  80. 80. Rule of 2s - if symptoms are present for more than 2 days per week or for more than 2 nights per month, asthma categorized as persistent. - Within this category, disease must be classified as mild, moderate, or severe. However, as severity of asthma not constant, must monitor patients for changes; as severity changes, therapy should change too. - The category of “mild intermittent” asthma was eliminated in the 2007 guidelines - now it is just called “intermittent” asthma.
  81. 81. The concepts of “impairment”, “risk”, and “control” were introduced in the 2007 guidelines: - impairment - refers to symptoms - - risk - refers to likelihood that the patient will eventually have exacerbation of asthma and present to emergency department (ED) or hospital, or need course of oral corticosteroids - - control - refers to the level of patient’s asthma control
  82. 82. Classification of asthma severity - impairment domain - daytime and nighttime symptoms (rule of 2's), use of short-acting beta-agonist (SABA), interference with normal activities - - risk domain - number of exacerbations per year (if more than 2, daily controller medication is needed). Increased risk is conferred by parental history of asthma or history of eczema. - Childhood Asthma Control Test (ACT) is validated down to age 4 yr. Adult ACT questionnaire should be used for teenagers (cutoff age is 11 years).
  83. 83. Treatment steps - step 1 - SABA as needed – - step 2 - low-dose ICS monotherapy vs. leukotriene receptor antagonist (LTRA) - - step 3 - low-to-medium dose ICS plus long-acting betaagonist (LABA) - - step 4 - high-dose ICS therapy plus LABA and (if needed) systemic corticosteroids. Omalizumab (Xolair; anti-IgE antibody) is prescribed before placing patient on daily oral corticosteroids.
  84. 84. “Rule of 2s” to determine level of control - daytime symptoms more than 2 days/wk - rescue β2 -agonist use more than 2 times per week - nighttime symptoms more than 2 nights/mo - more than 2 rescue β2-agonist canisters/yr
  85. 85. Step Down or Step Up When to step down therapy? If patient is well-controlled for 3 mo, consider stepping down therapy. When to step up therapy? If the patient is not wellcontrolled, step up therapy and re-evaluate in 2 to 6 wk. If the patient is very poorly controlled, step up therapy 2 steps, consider short course of steroids, and reassess in 2 wk.
  86. 86. When to consider long-term ICS treatment - positive API and more than 3 wheezing episodes in previous 12 mo lasting more than 1 day and affecting sleep - consistent requirement for SABA treatment (more than 2 times/wk, on average, over 1-2 mo); 2 exacerbations in 6 mo requiring oral corticosteroids
  87. 87. Treatmnt
  88. 88. Inhaled corticosteroid Relative binding affinity for glucocorticoid receptor (GR): mometasone = fluticasone > budesonide > triamcinolone. Relative anti-inflammatory potency: mometasone fluticasone > budesonide = beclomethasone triamcinolone. = >
  89. 89. Severe asthma - differential diagnosis and management
  90. 90. Treating to Maintain Asthma Control Stepping up treatment in response to loss of control  Use of a combination rapid and long-acting inhaled β2-agonist (e.g., formoterol) and an inhaled glucocorticosteroid (e.g., budesonide) in a single inhaler both as a controller and reliever is effecting in maintaining a high level of asthma control and reduces exacerbations (Evidence A)  Doubling the dose of inhaled glucocorticosteroids is not effective, and is not recommended (Evidence A)
  91. 91. Difficult Asthma
  92. 92. Other terminology • Severe asthma • Difficult to control asthma • Difficult to treath asthma • Refractory asthma • Steroid resistant asthma • Unstable asthma • Life threatening asthma
  93. 93. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors
  94. 94. Definition - ERS Task Force • ‘failure to achieve asthma control when maximally recommended doses of inhaled therapy are prescribed for at least 6 12 months’ ERS Task Force: ERJ 1999;13:1198-6
  95. 95. Levels of asthma control GINA 2006 Characteristic Controlled (all of the following) Partly controlled (any measure present in any week) Daytime symptoms None (twice or less/week) More than twice/week Limitations of activities None Any Nocturnal None symptoms/awakenin g 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) Uncontrolled Three or more features of partly controlled asthma present in any week
  96. 96. Definition - ATS Major Criteria Use of oral corticosteroids >50% of time Continious use of high dose ICS Minor Criteria Requirement for daily treatment with LABA, theophilline or LTRA Daily asthma symptoms requiring rescue medication Persistent airway obstruction, diurnal PEF variability >20% >1 urgent care visits for asthma in the last year >3 courses oral steroid bursts in the last year Prompt deterioration with >25% reduction in oral or ICS dose Near fatal asthma event in the past ATS- JACI 2000;106:1033-1042
  97. 97. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors
  98. 98. Factors that could be preventing a normal response to asthma medication • Incorrect diagnosis • Continuing exposure to sensitising agents • Unrecognised aggravating comorbidities • Non-compliance with therapy
  99. 99. Incorrect Diagnosis Alternative Diagnoses • COPD • Congestive heart failure • Central airway obstruction – Foreign body, tumour, sarcoidosis, tracheobronchomalacia • • • • • • • Cystic fibrosis Recurrent pulmonary embolism Obstructive bronchiolitis Recurrent aspiration Vocal cord disfunction Allergic bronchopulmonary aspergillosis Churg-Strauss syndrome Bel EH. Breathe 2006; 3:2; 129139
  100. 100. Incorrect diagnosis : pseudotm
  101. 101. Incorrect diagnosis : tracheomalasia
  102. 102. Strategy for the diagnosis-1 • History of asthma development (age of onset, atopy, response to treatment, smoking) • Severity of disease (exacerbations, hospitalisations, ICU admissions) • Exogenous aggravating factors (allergens, occupationnal agents, drugs, foods..) • Endogenous aggrating factors (Rhinosinusitis, GER, OSA, influence of menstruation, psychiatric disease..) • Miscellaneous (adherence, advers effect, psychosocial circumstances) • Physical examination (specific points of attention) (Body mass index, Nasal polypes, cardiac failure, adverse effects of treatment)
  103. 103. Strategy for the diagnosis: Laboratory tests • Peripheral blood (ESR, blood count, tIgE, sIgE, T3, T4, TSH) • Lung function (spirometry, flow-volume, PEF variability, challenge tests, arterial blood gases) • Radiology (chest radiography, thorax CT or HRCT, sinus CT scans) • Additional tests for comorbidities and alternative diagnoses (nasal endoscopy, oesophageal pH or PPI, polysomnography, broncoscopy, D-dimer, ANCA, IgG againts aspergllus fumigatus….) Bel EH. Breathe 2006; 3:2; 129139
  104. 104. Continuing exposure to sensitising agents • Allergen exposure at home • Allergen or occupationnal exposure at work • Drugs • Dietary factors - metabisulphite, salicylate, food allergens • Smoking Bel EH. Breathe 2006; 3:2; 129-139
  105. 105. Allergic Sensitization Patients with Severe Asthma Early-onset asthma Late-onset asthma 18% 30% 9% 56% 73% 14% Multiple allergies Single allergy Non-atopic Grootendorst DC et al., AJRCCM 2000
  106. 106. Allergic Sensitization Patients with Severe Asthma Percentage of atopic patients 100 80 60 40 20 0 Grootendorst DC et al., AJRCCM 2000
  107. 107. Exposure to sensitizing drugs • ß-Blockers • Aspirin and NSAIDS • ACE inhibitors
  108. 108. Smoking and steroid responses in asthm Non-smokers (n=21) Smokers (n=17) 30 ** 25 Placebo 20 Fluticasone (1mg/day) 15 10 5 0 -5 Sputum Eos % change 0 -1.8 * 0 0 Chalmers GW et al: Thorax 2002
  109. 109. Smoking and response to oral steroids Prednisolone 40mg daily x 2 weeks Ex-smokers (10) FEV1 300 p<0.01 200 NS 100 NS 0 Δ Asthma control score Non-smokers (26) Current smokers (14) 0 NS -0.2 -0.4 -0.6 NS -0.8 p<0.001 -1 Asthma control Chaudhuri R et al: AJRCCM 2003
  110. 110. Unrecognised aggravating comorbidities • Chronic rhinosinusitis • Recurrent respiratory tract infections • Gastro-oesophageal reflux • Obstructive sleep apnea • Psychological dysfunctioning • Obesity • Systemic diseases (thyrotoxicosis…) Bel EH. Breathe 2006; 3:2; 129-139
  111. 111. Co-morbid factors in asthmatic patients with frequent exacerbations 100 p=0.10 p=0.03 p=0.03 p=0.04 p=0.01 Prevlanece (%) 75 50 25 0 sleep apnoea psychopathology sinus disease gastric reflux recurrent infections ten Brinke A et al., ERJ 2005;26:812-
  112. 112. Co-morbid factors in asthmatic patients with frequent exacerbations 4 co-morbid 5 co-morbid factors factors 5% 8% 3 co-morbid factors 39% 1 co-morbid factor 13% 2 co-morbid factors 35% ten Brinke A et al., ERJ 2005;26:812-8.
  113. 113. Co-morbid factors in severe asthma 90 * Women Mild 80 70 Severe * 60 50 * 40 * 30 * 20 10 0 Premenstrual Stress Exercise Rhinitis Sinusitis Aspirin ENFUMOSA Study: ERJ 2003, 22:470-477
  114. 114. Reccurent infections in severe asthma Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-8
  115. 115. Reccurent infections in severe asthma Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-
  116. 116. Reccurent infections in severe asthm PCR for Mycoplasma pneumoniae and Chlamydia pneumo PCR + PCR p<0.05 3 NS 2.5 2 B/L Clari Clarithromycin 500mg b.d. B/L Clari Kraft M et al: Chest 2002
  117. 117. Non- compliance with therapy • Psychological problembs • Missed appointments • Complexity of treatement • Lack of insight into illness • Inhalation technique Bel EH. Breathe 2006; 3:2; 129-139
  118. 118. İnhaler cihaza uyumsuzluk • Kullanımında hata % 14 - 74 • Kullanmak istememe % 31 Wilson A. Aerosol delivery system. In: Weiss EB, Stein M.(eds). Bronchial Asthma.1993:749-755
  119. 119. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors
  120. 120. Difficult asthma phenotypes • Unstable asthma (Brittle, Nocturnal, Premenstrual) • Poor response to treatment (Steroiddependent asthma, Steroid-resistant asthma) • “Fixed” asthma
  121. 121. Brittle asthma •Type I: wide variability in PEF despite maximum therapy •Type II: sudden attack from normally well controlled asthma Ayres J, Miles J, Barnes PJ: Thorax 1998
  122. 122. Nocturnal Asthma • Nocturnal hyperreactivity with an increase 8-10 fold • High PEF variability Teraschima T: Chest 2002, Barnes PJ. ERJ 1998
  123. 123. Premenstrual asthma • Worsening of asthma ~7days premenstrually • Recovers with menstruation 0 1 2 3 PEF Beynon H et al: Lancet 1988 4wk
  124. 124. Spectrum of steroid responsiveness Mild Asthma control Moderate Severe Steroid dependent Systemic side effects Resistant 100 400 1600 Inhaled steroids (µg) Oral steroids
  125. 125. Poor response to corticosteroids • Poor adherence • Wrong diagnosis • Dose too low • Increased metabolism (e.g. carbamazepine, rifampicin) • Relative resistance / Complete resistance
  126. 126. Corticosteroid-resistant asthma Prednisolone 30-40 mg om Peak flow CORTICOSTEROID-SENSITIVE 0 1 Peak flow 2 weeks CORTICOSTEROID-RESISTANT 0 1 2 weeks
  127. 127. Fixed asthma moderate asthma n=13 Age (med.range) Sex (m:f) FEV1 (% pred) severe asthma n=15 49 (42-61) 47 (25-61) 7:6 7:8 88.6 (4.8) 72.7 (6.5) Pepe C et al, J Allergy Clin Immunology 2005;116:544-9)
  128. 128. Fixed Asthma Pepe C et al, J Allergy Clin Immunology 2005;116:544-
  129. 129. Fixed Asthma (r = −0.58, P < .05). Pepe C et al, J Allergy Clin Immunology 2005;116:544
  130. 130. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors
  131. 131. ENFUMOSA Study: Risk factors • Female predominance • Reduced influence of atopy on asthma phenotypes • Exposure to aspirin as a risk factor • Association with increased body mass index, especially in women • A proportion of fixed airflow obstruction with increased residual volumes to total lung capacity ratio, suggesting the presence of structural changes Eur Res J 22:470-477 (2003)
  132. 132. Severe Asthma is associated with Increased Health Care Utilization Non-cases (n=77) p-value n % Health care utilization parameters Cases (n=21) n % GP visits:  4 last yr 15 71.4 23 29.9 0.02 Chest physician visits:  4 last yr 17 81.0 60 77.9 0.78 Emergency visits:  2 last yr 15 71.4 24 31.2 0.01 12/13 92.3 29/51 56.9 0.02 Hospital admissions:  2 last yr 4 19.0 4 5.2 0.04 Maintenance oral corticosteoids 8 38.1 26 33.8 0.71 Ever ICU admission 3 14.3 8 10.4 0.62 Ever mechanical ventilation 3 14.3 2 2.6 0.03 Exacerbations:  2 last yr * PARAPLU study, AJRCCM 2001;163:1093-1096
  133. 133. Associated Factors of Airflow Obstruction in Patients with Severe Asthma Adjusted OR* Sputum eosinophils  2% PC20 histamine  1.0 mg/ml Adult-onset of asthma Exhaled NO  10 ppb Reversibility FEV1  9% Total IgE > 100 IE/ml Blood eosinophil count > 450.106/l Sputum neutrophils  64% Ex-smoker Atopic (95% CI) 7.7 3.9 3.3 (2.4 – 25.1) (1.2 – 13.0) (1.2 – 9.0) 1.9 1.7 1.7 1.5 1.4 1.3 0.8 (0.8 (0.8 (0.8 (0.6 (0.5 (0.6 (0.4 – 4.8) – 3.6) – 3.7) – 3.6) – 4.0) – 2.9) – 1.9) *OR adjusted for age, gender, and asthma duration PARAPLU-study, LUMC Leiden: AJRCCM 164:744-748 (200
  134. 134.  150 Estimated loss in FEV (ml/yr) 1 Risk factors: FEV1 decline and Chlam P. 100 50 0 Cp+ Cp- ______ ______ Cp+ Cp______ Cp+ Cp- Cp+ Cp- ______ atopic non-atopic ______________ ______________ atopic non-atopic childhood-onset adult-onset PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454
  135. 135. Risk Profile of Patients with Frequent Asthma Exacerbations Adjusted OR (95% CI) 10.8 1.1 – 108.4 Recurrent respiratory tract infections 6.9 1.9 – 24.7 Gastro-oesophageal reflux 4.9 1.4 – 17.8 Severe chronic sinus disease 3.7 1.2 – 11.9 Obstructive sleep apnoea 3.4 1.2 – 10.4 Hormonal influences 2.8 0.5 – 15.8 1.9 0.7 0.6 0.6 0.5 0.4 0.2 0.2 – 19.6 0.2 – 2.1 0.1 – 2.9 0.1 – 3.5 0.2 – 1.3 0.1 – 1.7 0.1 – 1.9 Psychological dysfunctioning Hyperthyroidism Occupational sensitisers Poor inhaler technique Food allergens Ongoing allergen exposure Relative immune deficiency Drugs PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454
  136. 136. 154

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