2.Asthma hypersensetivity for undergraduates

Asthma

1. Asthma 1

2. Introduction Asthma is a syndrome characterized by airflow obstruction with reversible narrowing of airways. In some patients with chronic asthma there may be an element of irreversible airflow obstruction. 2

3. Prevalence Asthma is one of the most common chronic diseases globally and currently affects ~ 300 million people . In developed, ~ 10–12% of adults and 15% of children affected by the disease. In developing countries where the prevalence of asthma had been much lower, there is a rising incidence that appears to be associated with increased urbanization . 3

4. ----introduction. Asthma can present at any age with a peak age of 3 years. In childhood, 2X M, than females but by adulthood the sex ratio has equalized. The idea that children "grow out of their asthma" is justified to some extent. Adults with asthma, rarely become permanently asymptomatic. 4

5. ----introduction Major risk factors for asthma deaths are : poorly controlled disease with frequent use of bronchodilator inhalers lack of corticosteroid therapy previous admissions to the hospital with near-fatal asthma . 5

6. Risk Factors and Triggers Involved in Asthma Endogenous Factors   Genetic predisposition Atopy Airway hyperresponsiveness Gender Ethnicity? 6

7. ------risk factors Environmental Factors   Indoor allergens Outdoor allergens Occupational sensitizers Passive smoking Respiratory infections   Obesity? Esp women.   Early viral infections ? 7

8. Triggers     Allergens   URTI - viral.   Exercise and hyperventilation   Cold air   Sulfur dioxide   Drugs ( blockers, aspirin)   Stress   Irritants (household sprays, paint fumes)   8

9. Atopy Atopy is due to the genetically determined production of specific IgE antibody . Atopy is the major risk factor for asthma, and nonatopic individuals have a very low risk of developing asthma. Patients with asthma commonly suffer from other atopic diseases; allergic rhinitis ( 80% of asthmatic patients ), and atopic dermatitis (eczema ). Atopy may be found in 40–50% of the population in affluent countries, with only a proportion becoming asthmatic. 9

10. Intrinsic Asthma approximately 10% asthmatics have normal serum concentrations of IgE . These patients, with nonatopic or intrinsic asthma , usually show: later onset of disease (adult-onset asthma) commonly have concomitant nasal polyps may be aspirin-sensitive. usually have more severe, persistent asthma. *There is recent evidence for increased local production of IgE in the airways, suggesting that there may be common IgE mediated mechanisms. 10

11. Hygiene Hypothesis "hygiene hypothesis" proposes that early childhood exposure to infections and endotoxin results in a shift toward a predominant protective T H 1 response: -less likely to develop allergic sensitization. Children brought up on farms who are exposed to a high level of endotoxin are less likely to develop allergic sensitization than children raised on dairy farms. Intestinal parasite infection may also be associated with a reduced risk of asthma. 11

12. Pathogenesis Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways(trachea-terminal bronchioles) The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells. One of the main aims of treatment is to reduce this inflammation. The degree of inflammation is poorly related to disease severity and may be found in atopic patients without asthma symptoms. 12

13. pathology thickening of the basement membrane due to subepithelial collagen deposition; also The airway wall itself may be thickened, edematous & narrowed rarely fibrosis. Hypertrophy and hyperplasia of airway sm ms. There is also vasodilatation and increased numbers of blood vessels (angiogenesis). In fatal asthma, occlusion of the airway lumen by a mucous plug , which is composed of mucus GPs secreted from goblet cells and plasma proteins from leaky bronchial vessels. 13

14. Mast Cells Mast cells are important in initiating the acute bronchoconstrictor responses mast cells are localized to the airway sm ms layer; not found in normal subjects or in patients with eosinophilic cough. Mast cells are activated by allergens through an IgE -dependent mechanism, and binding of specific IgE to mast cells renders them more sensitive to activation. 14

15. ----mast cells Mast cells release several bronchoconstrictor mediators; prostaglandin D2 , histamine, cysteinyl-leukotrienes , cytokines, chemokines , growth factors, and neurotrophins . 15

16. Macrophages and Dendritic Cells release of certain pattern of cytokines, but they also release anti-inflammatory mediators, such as IL-10, and thus their role in asthma is uncertain. Dendritic cells are specialized macrophage-like cells in the airway epithelium, which are the major antigen-presenting cells. 16

17. Eosinophils Allergen inhalation results in a marked increase in activated eosinophils in the airways. Eosinophils are linked to the development of AHR through the release of basic proteins and oxygen-derived free radicals. 17

18. Other cells Increased numbers of activated neutrophils are found in sputum and airways of some patients with severe asthma and during exacerbations; role not clear . T lymphocytes : release specific patterns of cytokines , resulting in the recruitment and survival of eosinophils and in the maintenance of a mast cell population in the airways. 18

19. ----other cells Structural cells of the airways, including epithelial cells, fibroblasts and airway sm ms cells , are also an important source of inflammatory mediators, such as cytokines and lipid mediators, in asthma. 19

20. Inflammatory Mediators Mediators such as histamine, PG, and cysteinyl-leukotrienes ; - contract airway smooth muscle -increase microvascular leakage -increase airway mucus secretion attract other inflammatory cells. Chemokines are involved in attracting inflammatory cells from the bronchial circulation into the airways. 20

21. Nitric Oxide Nitric oxide (NO) is produced by airway epithelial cells and macrophages by NO- synthase . Increased NO may contribute to the bronchial vasodilation observed in asthma. Exhaled NO is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not used routinely in clinical practice. 21

22. Cytokines The T H 2 cytokines ( IL-4, IL-5, and IL-13 ) mediate allergic inflammation. proinflammatory cytokines;( TNF-alpha) and IL-1 , amplify the inflammatory response. Some cytokines(IL-10 and IL-12) are anti-inflammatory and may be deficient in asthma . 22

23. Exercise Exercise-induced asthma (EIA) typically begins after exercise has ended and recovers spontaneously in 30 min. EIA is worse in cold, dry climates than in hot, humid conditions. more common in cross-country running in cold weather & ice hockey than in swimming. It may be prevented by prior administration of β 2 -agonists and antileukotrienes , but is best prevented by regular treatment with inhaled glucocorticoids . 23

24. Pathophysiology Limitation of airflow is due mainly to bronchoconstriction , but airway edema, vascular congestion, and luminal occlusion with exudate may also contribute. This results in a reduction in (FEV 1 ), FEV 1 /forced vital capacity (FVC) ratio, and peak expiratory flow (PEF), as well as an increase in airway resistance. Early closure of peripheral airway results in lung hyperinflation (air trapping), and increased residual volume, particularly during acute exacerbations. 24

25. ---- pathophysiology . Ventilatory failure is very uncommon, even in patients with severe asthma, and arterial Pa CO2 tends to be low due to increased ventilation. AHR = excessive bronchoconstrictor response to multiple inhaled triggers that would have no effect on normal airways. The increase in AHR is linked to the frequency of asthma symptoms; thus, an important aim of therapy is to reduce AHR. 25

26. --- pathophysiology . 26

27. Clinical Features The characteristic symptoms of asthma : - wheezing - dyspnea -Coughing -Chest tightness Signs=use of accessory ms, expiratory ronchi . *Symptoms may be worse at night, and patients typically awake in the hours. early morning *There is increased mucus production in some patients, with typically tenacious mucus that is difficult to expectorate. 27

28. …. Danger signs during acute attacks: - Paradoxical breathing - Profound diaphoresis - Cyanosis - Exhaustion Arrhythmia - Silent chest on auscultation - Drowsiness or confusion - Agitation - SPO2 < 90 % 28

29. Diagnosis History Physical exam. PFT Imaging 29

30. Lung Function Tests Simple spirometry confirms airflow limitation with a reduced FEV 1 , FEV 1 /FVC ratio, and PEF. Reversibility is demonstrated by a >12% and 200-mL increase in FEV 1 15 min after an inhaled short-acting β 2 -agonist or, in some patients, by a 2- to 4-week trial of oral glucocorticoids (prednisone or prednisolone 30–40 mg daily). 30

31. Imaging CxR - is usually normal but may show hyperinflated lungs in more severe patients. In exacerbations, there may be evidence of a pneumothorax . High-resolution CT - may show areas of bronchiectasis in patients with severe asthma, or there may be thickening of the bronchial walls. 31

32. DDx E ndobronchial obstruction with a FB = Persistent wheezing in a specific area of the chest LV failure = basilar crackles are present in contrast to asthma. Eosinophilic pneumonias and systemic vasculitis , including Churg -Strauss syndrome and polyarteritis nodosa , may be associated with wheezing. (COPD) is usually easy to differentiate from asthma as symptoms show less variability, never completely remit , and show much less (or no) reversibility to bronchodilators. * Approximately 10% of COPD patients have features of asthma, respond to oral corticosteroids; these patients probably have both diseases concomitantly. 32

33. Asthma: Treatment Pharmacologic vs non pharmacologic The main drugs 1. bronchodilators :which give rapid relief of symptoms mainly through relaxation of airway smooth muscle. 2. controllers :which inhibit the underlying inflammatory process. 33

34. Non-pharmacologic 1. Hospital admission-Admit patients with any feature of a severe attack persisting after initial treatment in the emergency room to wards. Admit patients with life threatening attacks directly to ICU. 2. Oxygen-give supplementary oxygen via face mask or nasal cannula to all hypoxic patients with acute asthma to maintain a SpO2 level of >90%. Lack of pulse oximetry should not prevent the use of oxygen. 3. Positioning-sitting upright and/or leaning. 4. Hydration-most patients need IV hydration. 34

35. Aims of Asthma Therapy Minimal (ideally no) chronic symptoms No emergency visits Minimal (ideally no) use of β 2 -agonist No limitations on activities Minimal (or no) adverse effects from medicine 35

36. Bronchodilator Therapies Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma. Thus, bronchodilators are not sufficient to control asthma in patients with persistent symptoms. There are three classes : -β 2 -adrenergic agonists - anticholinergics , and - theophylline *of these, β 2 -agonists are by far the most effective. 36

37. B 2 -Agonists Mech : - β 2 -Agonists activate β 2 -receptors β 2 -Receptors are coupled through a stimulatory G protein to adenylyl cyclase , resulting in increased intracellular cyclic AMP , which relaxes smooth-muscle cells and inhibits certain inflammatory cells. additional effects: inhibition of mast cell mediator release . No effect on AHR. 37

38. 38

39. Clinical Use (SABAs ) , such as albuterol and terbutaline , have a duration of action of 3–6 hours. used as needed for symptom relief. also useful in preventing EIA if taken prior to exercise. used in high doses by nebulizer or via a metered dose inhaler with a spacer. 39

40. -----bronchodilators. LABAs include salmeterol and formoterol , both of which have a duration of action over 12 hours and are given twice daily. LABAs should not be given in the absence of ICS therapy as they do not control the underlying inflammation. Better to use fixed combination inhalers that contain a corticosteroid and a LABA , which have proved to be highly effective in the control of asthma. 40

41. Side Effects The most common S/Es are muscle tremor and palpitations , which are seen more commonly in elderly patients. There is a small fall in plasma potassium due to increased uptake by skeletal muscle cells, transient. 41

42. Anti- Cholinergics M-receptor antagonists, such as ipratropium bromide, prevent bronchoconstriction and mucus secretion . They are much less effective than β 2 -agonists in asthma therapy as they inhibit only the cholinergic reflex component of bronchoconstriction , whereas β 2 -agonists prevent all bronchoconstrictor mechanisms. Anticholinergics are therefore only used as an adjuvant in patients with asthma that is not controlled on other inhaled medications. 42

43. ---- anticholinergics slower onset of bronchodilation . Side effects are not usually a problem as there is little or no systemic absorption. The most common side effect - dry mouth; in elderly patients, -urinary retention -glaucoma. 43

44. Theophylline inexpensive. It has now fallen out of favor as side effects are common. The bronchodilator effect is due to inhibition of phosphodiesterases in airway smooth-muscle cells, which increases cyclic AMP . Aminophylline is occasionally used (via slow iv infusion) in patients with severe exacerbations that are refractory to high-dose SABAs. 44

45. Side Effects Oral theophylline is well absorbed and is largely inactivated in the liver. The most common side effects—nausea, vomiting, and headaches —are due to phosphodiesterase inhibition. Diuresis and palpitations may also occur, and at high concentrations cardiac arrhythmias, epileptic seizures, and death may occur due to adenosine receptor antagonism. Theophylline side effects are related to plasma concentration 45

46. Controller Therapies 1.Inhaled Corticosteroids ICSs are by far the most effective controllers for asthma, and their early use has revolutionized asthma therapy. 2.Systemic steroids. 3.cromones. 4. Omalizumab 46

47. Mode of Action ICSs are the most effective anti-inflammatory agents , reducing the number of inflammatory cells and their activation in the airways. ICSs reduce eosinophils in the airways and sputum, and numbers of activated T lymphocytes and surface mast cells in the airway mucosa. 47

48. uses ICSs reduce AHR , but maximal improvement may take several months of therapy. Early treatment with ICSs appears to prevent irreversible changes in airway function that occur with chronic asthma. they suppress inflammation and symptoms but do not cure the underlying condition. 48

49. Side Effects Local side effects include hoarseness ( dysphonia ) and oral candidiasis . have minimal systemic effects . 49

50. Systemic Corticosteroids intravenously ( hydrocortisone or methylprednisolone ) for the treatment of acute severe asthma. A course of oral corticosteroids (usually prednisone or prednisolone 30–45 mg od for 5–10 days) is used to treat acute exacerbations of asthma; no tapering of the dose is needed. Approximately 1% of asthma patients may require maintenance treatment with oral corticosteroids. 50

51. Side effects truncal obesity, bruising, osteoporosis, diabetes, hypertension. gastric ulceration, proximal myopathy , depression, and cataracts * im triamcinolone acetonide is a depot preparation that is occasionally used in noncompliant patients, but proximal myopathy is a major problem with this therapy. 51

52. Cromones Cromolyn sodium and nedocromil sodium: are asthma controller drugs that appear to inhibit mast cell and sensory nerve activation effective in blocking EIA, and allergen- and sulfur dioxide–induced symptoms. little benefit in the long-term control of asthma due to their short duration of action (at least 4 times daily by inhalation). They are very safe. 52

53. Steroid-Sparing Therapies Methotrexate , cyclosporine, azathioprine , gold, and intravenous gamma globulin have all been used as steroid-sparing therapies, but none of these treatments has any long-term benefit and each is associated with a relatively high risk of side effects. 53

54. Anti- IgE Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE ; it thus inhibits IgE -mediated reactions. can reduce the number of exacerbations in patients with severe asthma and may improve asthma control very expensive and only used in those who have a circulating IgE within a specified range. Patients should be given a 3–4 month trial of therapy to show objective benefit. usually given as as SQ injection every 2–4 weeks appears not to have significant side effects. 54

55. Management of Chronic Asthma Triggers that worsen asthma control, such as allergens or occupational agents, should be avoided. 55

56. Step wise therapy 56

57. Stepwise Therapy For patients with mild, intermittent asthma, a SABA is all that is required use of a reliever medication more than 3X a week indicates the need for regular controller therapy, ICS given twice daily. If symptoms are not controlled, an LABA should be added 57

58. In patients with severe asthma: low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting anticholinergic tiotropium bromide may be tried. maintenance treatment with an oral corticosteroid may be needed, and the lowest dose that maintains control should be used. Once asthma is controlled, it is important to slowly decrease therapy in order to find the optimal dose to control symptoms. 58

59. Acute severe asthma increasing chest tightness, wheezing, and dyspnea patients may be so breathless that they are unable to complete sentences, may become cyanotic . Examination usually shows increased ventilation, hyperinflation, and tachycardia. There is a marked fall in spirometric values and PEF. Arterial blood gases on air show hypoxia. A CxR is not usually informative, but may show pneumonia or pneumothorax . 59

60. Acute Severe Asthma: Treatment A high concentration of oxygen should be given by face mask to achieve oxygen saturation of >90%. The mainstay of treatment is high doses of SABA that are given either by nebulizer or via a metered dose inhaler with a spacer. An inhaled anti-cholinergic may be added if there is not a satisfactory response to SABA alone, as there are additive effects . 60

61. ----- acute severe asthma . In patients who are refractory to inhaled therapies, a slow infusion of aminophylline may be effective, monitor blood levels especially if already given oral theophylline . MgSo4 given iv or by nebulizer has also been shown to be effective when added to inhaled SABA, but is not routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure, when the Pa CO2 is normal or rises. 61

62. ------ Acute severe asthma . Sedatives should never be given as they may depress ventilation. Antibiotics should not be used routinely unless there are signs of pneumonia. 62

63. Refractory Asthma (approximately 5% of asthmatics) are difficult to control despite maximal inhaled therapy. Some of these patients will require maintenance treatment with oral corticosteroids. In managing these patients, it is important to investigate and correct any mechanisms that may be aggravating asthma. 63

64. Mechanisms noncompliance with medication, particularly ICS. exposure to high, ambient levels of allergens or unidentified occupational agents. Severe rhinosinusitis may make asthma more difficult to control; upper airway disease GERD common in asthmatics due to bronchodilator treatment, but not significant factor in worsening asthma. Some have chronic infection with M pneumoniae or C pneumoniae and benefit from Rx with a macrolides . . 64

65. ------refractory asthma,mechanisms 6. Drugs such as β blockers, aspirin, and other (COX) inhibitors may worsen asthma. 7. Some women develop severe premenstrual worsening of asthma-treat with progesterone. 8. Hypo/hyperthyroidism Some patients with COPD may be diagnosed as asthmatic and may show poor response to corticosteroids and bronchodilators, but this situation is complicated by the fact that some patients with COPD also have concomitant asthma. 65

66. Refractory Asthma: Treatment check compliance and the correct use of inhalers identify and eliminate any underlying triggers. Low doses of theophylline may be helpful in some patients, and theophylline withdrawal has been found to worsen many patients. Most of these patients will require maintenance treatment with oral corticosteroids . In some with allergic asthma, omalizumab is effective, particularly when there are frequent exacerbations. A few patients may benefit from infusions of β 2 -agonists. 66

67. Brittle Asthma Some patients show chaotic variations in lung function despite taking appropriate therapy. type I brittle asthma = a persistent pattern of variability and may require oral corticosteroids or, at times, continuous infusion of β 2 -agonists . type 2 brittle asthma = normal or near-normal lung function but precipitous, unpredictable falls in lung function that may result in death. -These patients are difficult to manage; do not respond well to corticosteroids, and the worsening of asthma does not reverse well with inhaled bronchodilators. 67

68. NGL…. Pharmacologic First line Salbutamol, 4 to 6 puffs every 20 minutes in the first 1-4 hours. Then the same dose every 1-4 hours depending on the patient need. OR Salbutamol, 2 –5mg every 20 minutes for 3 doses, then 2.5–10mg every 1–4 hours as needed, or 10–15mg/hour continuously ADRs: headache, nervousness, dizziness, palpitation, tachycardia, fine tremor, muscle cramp, paradoxical broncho -spasm. C/Is: cardiac arrythmias 68

69. NGL… PLUS Ipratropium bromide , 4–8 puffs every 20 minutes as needed up to 3 hours, 0.25–0.5mg every 20 minutes for 3 doses, then as needed. ADRs: urinary retention, constipation, tachycardia, palpitations and arrhythmias, hypersensitivity reactions, including uriticaria , angioedema, anaphylaxis. D/Is: anticholinergics. P/Cs: prostatic hypertrophy; pregnancy; acute angle closure glaucoma. 69

70. OR Aminophylline, IV 250mg IV bolus slowly over 20 minutes Maintenance: 0.5mg/kg/hour (maximum: 900mg/day). For patients cardiac decompensation, cor pulmonale , hepatic dysfunction, Multiorgan dysfunction decrease dose by 50%. Old patients (>60 years): 0.38 mg/kg/hour (maximum:400mg/day). 70

71. When there are no other options: Adrenaline , 1:1000, 0.5ml sc. Repeat after 1/2 if patient doesn’t respond. ADRs: Arrythmias , headache, nervousness, dizziness, cardiac Dosage forms: injection, 0.1% in 1ml ampoule PLUS Systemic steroids Hydrocortisone , 200mg IV as a single dose. Further IV doses are needed only if oral dosing is not possible (100mg, IV, 3-4 X per day). 25mg/ampoule, 500mg vial; injection (sodium succinate), 50mg/ml in 2ml ampoule, 125mg/ml Followed by Prednisolone , 40-60mg P.O., should be started immediately, for 5-7 days. Discontinuation does not need tapering. 71

72. Maintenance therapy for chronic asthma in adults Objectives - Prevent chronic and troublesome symptoms - Minimize use of inhaled SABA for quick relief of symptoms - Maintain (near) normal pulmonary function - Maintain normal activity levels. - Prevent recurrent exacerbations - Minimize adverse effects of therapy Non pharmacologic - Avoid identified allergens and smoking 72

73. … Intermittent asthma First line Salbutamol , inhaler 200microgram/puff, 2 puffs to be taken as needed but not more than 3-4 times a day, or tablet, 2-4mg 3-4/D. Alternative Ephedrine + Theophylline, 11mg + 120mg P.O., BID OR TID Persistent mild asthma Salbutamol, inhaler, 200micro gram/puff 1-2 puffs to be taken, as needed but not more than 3-4 times/day, or tablet, 2-4mg 3-4 times a day PLUS (Inhaled corticosteroid) Beclomethasone, oral inhalation 200�g, BID. Decrease the dose to 100�g, BID if symptoms are controlled after three months. 73

74. Persistent moderate asthma Salbutamol, inhalation 200/puff 1-2p�g/puffs as needed PRN not more than 3-4 times a day. PLUS(Inhaled corticosteroid) Beclomethasone , oral inhalation 200�g, BID. Decrease the dose to 100�g, BID if symptoms are controlled after three months. OR (Preferred if symptoms are mor severe or if response is not optimal to Beclomethasone ) Fluticasone/Salmeterol, 250/50�g oral inahalation , BID Dosage forms: 250/50 �g per dose, 500/50 �g per dose PLUS(if required) Ephedrine + Theophylline , 11mg + 120mg P.O., BID OR TID 74

75. Severe persistent asthma Salbutamol,inhalation 200/puff 1-2p�g/puffs as needed PRN not more than 3-4 times a day. PLUS (Inhaled corticosteroid) Beclomethasone, oral inhalation 200�g, BID. Decrease the dose to 100�g, BID if symptoms are controlled after three months. OR(Preferred if symptoms are mor severe or if response is not optimal to Beclomethasone) Fluticasone/Salmeterol, 250/50�g oral inahalation , BID Dosage forms: 250/50�g per dose, 500/50�g per dose PLUS Ephedrine + Theophylline, 11mg + 120mg P.O., BID OR TID PLUS(if required) Prednisolone, 5-10mg P.O., QOD. Doses of 20-40mg daily for seven days may be needed for short-term exacerbations in patients not responding to the above treatment. 75

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