1. KENYA MEDICAL ASSOCIATION CME: SAROVA PANAFRIC HOTEL ASTHMA UPDATE DR. JOSEPH A ALUOCH F.R.C.P., E.B.S., 2nd JUNE 2011

3. ASTHMA Less understanding of Aetiology/Pathogenesis Genetics complex Control of Airway Tone? Reversible AWO: variability BHR Asthma no single aetiology Chronic Inflammation Dynamic Process Healing and Repair (Remodelling)

4. ASTHMA THE DISEASE No clear concept of normality Disease variation Lack of correlation between disease and outcome Patient understanding the severity. Lack of correlation between FEV and other outcome.

5. Defining asthma can be difficult !

6. Defining Asthma Bronchial hyperresponsiveness Airway inflammation Central features, but not defining for individual characteristics of phenotypes

7. DEFINITION Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role The ability to synthesize IgE antibody to environmental allergens (i.e., atopy) remains a major risk factor in asthma pathogenesis.

8. INFLAMMATION IN ASTHMA MECHANISM: CHANGES PROCESS ASSESSMENT HISTOLOGICAL CHANGES INFLAMMATORY CELLS LOCAL FACTOR FACTORS :STILL LARGELY UNCLEAR : PRIMARY OR SECONDARY : INITIATION :PERSISTENCE PROGRESS E.C.P, N.O, PEFR; RELATION TO SEVERITY : NON-ALLERGIC :ATOPY :EXERCISE INDUCED :PRIMARY :SECONDARY :LUNG TRANSPLANT :ATOPY :ENVIRONMENT

9. INDUCERS Allergens,Chemical sensitisers, Air pollutants, Virus infections INFLAMMATION Airway Hyper-responsiveness Airflow Limitation SYMPTOMS Cough Wheeze Chest tightness Dyspnoea TRIGGERS Allergens, Exercise Cold Air, SO2 Particulates

10. ASTHMA UPDATE OTHER FACTORS LIMITING AIRFLOW Airway edema secondary to eosinophilic inflammation Mucus hypersecretion Structural changes i.e. hypertrophy and hyperplasia of smooth muscular tissue; tissue fibrosis as part of remodeling.

11. Inflammatary Cells Mast Cells Eosinophils Th2 Cells Basophils Platelets Structural Cells Epithelial Cells Smooth Muscles Cells Fibroblast Nerves Mediators Histamine Leukotrienes Prostanoids PAF Kinins Adenosine Endothelins Nitric Oxide Cytokines Chemokines Growth Factors Effects Bronchospasm Plasma exudation Mucus secretion AHR Structural Changes

12. IgE PATHOGENESIS IgE antibodies are synthesized to environmental allergens (atopy) Synthesized IgE binds to mast cells and basophils via high-affinity IgE receptors These cells are signaled to release preformed and newly generated mediators, including histamine & cysteinyl leukotrienes to rapidly contract airway smooth muscle Mast cells also produce a variety of cytokines (pro-inflammatory proteins) including interleukin (IL 1,2,3,4 &5), granulocyte-macrophage colony-stimulating factor, interferon and tumor necrosis factor-α

13. ATOPY Atopy is the genetic susceptibility to produce IgE ABs directed toward common environmental allergens, including house-dust mites, animal proteins, and fungi. With the production of IgE ABs, mast cells and possibly other airway cells (e.g., lymphocytes) are sensitized and become activated when they encounter specific antigens. Atopy has been found in 30 to 50% of the general population, therefore frequently found in the absence of asthma. Atopy is one of the strongest predisposing factors in the development of asthma.

14. EOSINOPHIL PATHOGENESIS Infiltration seen in all acute inflammation & many patients with chronic persistent asthma The granules are the source of inflammatory mediators Injure airway epithelium Enhance bronchial responsiveness Affect acetylcholine release Release cysteinyl leukotrienes to contract airway smooth muscle Eosinophils are produced & released from bone marrow via IL-5, migrate to airway via a number of factors

15. EOSINOPHIL PATHOGENESIS Although its role in pathophysiology is less clear, it is affected by anti-inflammatory therapy.

16. Reversible and variable airflow limitation Reversibility of airways’ obstruction Increased PEF >15% 15-20 minutes after inhaling ß2-agonist Variability of airways’ obstruction PEF varies between morning and evening >20% in patients taking bronchodilator >10% in patients not taking bronchodilator Exercise-induced airways’ obstruction Decreased PEF >15% after 6 minutes of exercise GINA Guidelines 1998

17. ASTHMA UPDATE AIRFLOW LIMITATION Bronchoconstriction occurs secondary to release of multi-mediators (histamine, leukotrienes, prostaglandins, PAF etc. Aeroallergen sensitivity Aspirin ( Non-IgE) Multi-factorial (exercise and cold air-osmotic; airborne irritants, laughing, GERD & sinusitis via neurogenic reflex; infections)

18. GOAL OF MANAGEMENT Minimal (ideally no) chronic (inc. nocturnal) symptoms Minimal (infrequent ) exacerbations No emergency visits Minimal need for prn Beta2-agonists No limitations on activities (inc. exercise) Near normal PEFR & variability <20% Minimal (or no ) adverse effects from medicine

19. Control Day time symptoms Limitation of activities Nocturnal symptoms Nocturnal awakenings Use of rescue medications Objective Ass. Lung F.Test

21. ASTHMA UPDATE EARLY IDENTIFICATION OF HIGH RISK PATIENTS: IMMEDIATE CONCERNS: Improve quality of life Reduce risk for hospitalizations and death. LONG TERM CONCERNS: Prevent irreversible changes in airway structure i.e. remodeling with sub-basement fibrosis, mucus hypersecretion, s.m hypertrophy, & injury of lining (epithelium).

22. SYMPTOM CLASSIFICATION Severe Persistent Moderate Persistent Mild Persistent Mild Intermittent

23. SYMPTOM CLASSIFICATION Severe Persistent Day: continual Night: frequent Moderate Persistent Day: daily Night: >1/week Mild Persistent Day: >2/week (<1/day) [3-6/week] Night: >2/month Mild Intermittent Day: 2/week Night: 2/month

24. ASTHMA UPDATE AIRWAY HYPER-RESPONSIVENESS (TWITCHY LUNGS) Exaggerated bronchoconstrictor response to stimuli- triggers such as exercise, cold air, laughing, stress. Defined by methacholine/adenosine/mannitol responsiveness Rx directed towards reducing inflammation can reduce airway hyper-responsiveness.

25. ASTHMA UPDATE HETEROGENOUS PHENOTYPES OF ASTHMA: Different patterns of inflammation-targets for eventual treatment Many patients have overlapping phenotypes. Intermittent; Persistent Atopic (extrinsic) vs. Intrinsic Exercise induced Aspirin sensitive Late Onset Infection induced (RSV; parainfluenza; adenovirus, rhinovirus) Cough variant asthma Steroid resistant

26. ASTHMA UPDATE ESTABLISH DIAGNOSIS OF ASTHMA: History, physical and PFT to establish there are symptoms of airflow obstruction and/or airway hyperresponsiveness; At least evidence for reversibility Value of history What are the triggers in the home? Outdoor triggers?-pollens, time of year What else triggers asthma- aspirin, NSAIDs, URI’s cold air exercise, forest fires, smoking; positioning, foods, Family history

27. ASTHMA UPDATE Differential diagnosis:co-morbidities GERD; vocal cord dysfunction; foreign body; anatomical abn; hypersensitivity bronchopulmonary aspergillosis; Chronic sinusitis Churg’s syndrome; Samter’s syndrome; Cystic Fibrosis bronchiectasis; sleep apnea with aspiration; occupation and hobbies (birds); wheezing” with COPD

28. ASTHMA UPDATE PHYSICAL EXAM: Nasal exam- polyps Level of wheezing (high, low) High level over trachea: consider vocal cord dysfunction Hyperexpansion of chest Signs of chronicity i.e.(clubbing); consider bronchiectasis, COPD, C.F. Signs of hypoxemia (cyanotic nail beds) Lymphadenopathy or lack of with history of recurring respiratory infections (consider ID workup) Keep in mind undiagnosed adult CF (sweat test is not useful in adults)

29. ASTHMA UPDATE LABORATORY EVALUATION: r/o Atopy: skin tests properly applied and interpreted; Properly performed PFT pre and post BD PEF > FEV1; Expiration plateau for at least 6 seconds Reproducibility with BD- at least 2 measurements with FEV1 within 0.15 L. Reversibility in adults: >250 ml; FEV1> 12% or > 10% increase of pred FEV1% for adults. Later may separate COPD from asthma. May need oral steroids for reversibility. FEV1/FVC% should be included for children .

31. Inspiratory loop for VCD

32. Methacholine challenge

33. Nasal exam/endoscopy- polyps; sinusitis;VCD

34. Chest Xray/ CT of chest on rare occasion Sinus CT Trial with protonics as a diagnostic tool (pH studies) Consider bronchoscopy and lung biopsy for difficult to diagnose and/or treat.

35. ASTHMA UPDATE NIH Guidelines: asthma classification Initially severity assessment: Based on medication usage; history of recent exacerbations, PFT; night time awakenings; persistent or intermittent. Initial Rx based on classification of severity Manage based on control of symptoms i.e. more functional emphasis: Use of rescue meds Night time awakenings Exacerbation rate Objective parameters –PFT; NO measurements

36. ASTHMA UPDATE Goals of Therapy Reduce impairment (current) Prevent troublesome symptoms (cough, breathlessness with exertion and at night) Reduce frequent use of SABA to < 2 days a week Maintain near normal PFT Maintain normal activity Reduce risk (future) Exacerbations Prevent ER visits and hospitalizations Prevent loss of lung function; children-prevent reduced lung growth

37. Managing asthma needs brains !

38. UPDATE ON ASTHMA Therapeutic Strategies to Improve Control: Education: preferably by experienced or certified asthma educator: Peak flows- setting parameters of when to call. Awareness of questions to ask: nocturnal awakenings, use of rescue meds. Asthma treatment plan: what to do when sx develop. How to use medications and when- very important Compliance checks

39. ASTHMA UPDATE Environmental & Personal Health Strategies Eliminate tobacco smoke ( in utero and passive) Associated with severity and dec. response to steroid Rx. Air pollution- forest fires Wood burning stoves Use of air purifier (HEPA) especially near open windows during pollen seasons

40. UPDATE ON ASTHMA Environmental & Personal Health Strategies Encourage breast feeding up to 6 months to minimize food allergy induction Home environmental control Individualize recommendations for aerobics in cold weather and during peak pollen counts. Speculative HYGIENE THEORY but worth noting: early exposure to daycare; rural environment; early exposure to animals- Favor immune responses away from allergy development; antibiotic use; Western lifestyle- Favor immune responses towards allergy responses.

41. UPDATE ON ASTHMA Environmental & Personal Health Strategies Control co-morbidities that can increase asthma: Allergic rhinitis/sinusitis –studies demonstrate that regular use of nasal steroids and/or AH reduce asthma flares and ER visits GERD- use of protonics decreases asthma. Obesity-dieting is important Leptin increases in obesity: inc. IgE sensitization Adiponectin decreases in obesity: enhancing remodeling and increased inflammation. CPAP for sleep apnea can help control obesity, aspiration New concerns: overuse of vitamins, folic acid in pregnancy may be increase incidence of asthma: based on mice studies.

42. ASTHMA UPDATE MONITORING ASTHMA TO ASSESS CONTROL: Symptom retrieval- ACT Spirometrics- frequency Other Monitoring Parameters Peak flow measurements Sputum Eosinophils Nitric Oxide and pH Measurements on Exhaled Air

43. ASTHMA UPDATE Sputum eosinophils : correlates with inflammatory response but impractical NO produced by epithelial and alveoli cells. Correlates with eosinophil bronchial lavage studies Many convincing studies that suggest NO can be used to reflect status of eosinophilic inflammation in asthma. May be best used as a compliance check with inhaled steroids.

44. ASTHMA UPDATE Medications: Rescue medications and long term beta agonists: Controversy re’ LABA. New data supports use with ICS. Xopenex® vs. albuterol Inhaled corticosteroids- reduced decline in lung function (FEV1) Mometasone and ciclesonide –both have minimal or no bioavailability (absorption) Dynamic dosing- use of ICS as a burst to treat exacerbations in well controlled asthma patients and normal lung function

45. ASTHMA UPDATE TARGETED THERAPY: IgE- anti-IgE (Xolair) Leukotrienes (anti-leukotrienes – Singulair; Zyflo Trials with Anti-IL-5- reduce eosinophils Anti- IL-4 trials-reduce IgE

47. ASTHMA UPDATE Approaches Based on Hygiene Theory Shifting Th2 to Th1 to modify asthma. The shift to Th1 induces IL-2 and IFN critical in defense against infection Alter balance between Th1 and Th2- towards Th1 by immunotherapies SLIT vs. SCIT Factors favoring Th1: Older siblings; early exposure to daycare; rural environment; certain infections (TB, measles, hep A); early exposure to animals; Factors favoring Th2: Antibiotic use; Western lifestyle; urban environment; diet; house dust mite and cockroach sensitization; RSV

48. Potential Treatments for Acute Asthma B-agonists Corticosteroids Oxygen Intubation & Mechanical Ventilation Methylxanthines Ipratropium Bromide BiPAP Heliox MgSO4 Infusion Mucolytics Chest Physical Therapy Aggressive Hydration Antibiotics Inhalational Anesthetics ECMO Inhalational Furosemide Inhalational MgSO4

49. Methylxanthines (Theophylline) Used for over 50 years to treat asthma Poorly understood mechanism of action Physiologic effects thought to include bronchodilation, stimulation of diaphragmatic contractility, mucocilliary clearance, and possibly some anti-inflammatory effect. Dose related toxicities include nausea, vomiting, headache, CNS stimulation, seizure, hematemasis, hyperglycemia, and hypokalemia

50. Bottom Line on Methylxanthines "theophylline/aminophylline is not recommended because it appears to provide no additional benefit to optimal inhaled B2-agonist therapy and may increase adverse effects.” Use after admission remains controversial

51. Ipratropium Bromide A synthetic anticholinergic compound Anticholinergic compounds are known to cause bronchodilation Atropine has been used, but often limited due to side effects such as tachycardia, dry mouth, disturbances of visual accommodation, etc. Ipratropium thought to be relatively free of side effects, but with preservation of bronchodilatory properties

52. Ipratropium Bromide Bottom Line Small, early studies tend to favor its use More recent, larger studies fail to find benefit Given ipratropium’s relative lack of toxicity, one “safely” can use it

53. Noninvasive Positive-Pressure Ventilation (BiPAP) Literature is extensive in treatment of COPD, but sparse in treatment of acute asthma Studies using CPAP in asthma have shown it to improve symptoms, but not gas exchange

54. BiPAP BiPAP theoretical benefits: Decreased work of breathing (and CO2 production) Ameliorating large negative intrapleural pressures and accompanying potential for hemodynamic compromise Bronchodilation with decreased airway resistance (due to “splinting” airways open with air pressure) Improved delivery of inhalational medication Problems include: Discomfort with facemask and pressure apparatus Requires very close observation by trained personnel

55. BiPAP Bottom Line Little evidence to guide us Existing evidence seems to support its use Given few known risks with an attempt, would consider BiPAP in patients refractory to conventional therapy (B-agonists and corticosteroids), or facing impending intubation

56. Magnesium Sulfate (Infused) Mechanism of action not well understood but may inhibit bronchial smooth muscle contraction by inhibiting intracellular influx of calcium Side effects are dose and rate related: facial warmth, flushing, decrease in BP, sweating, nausea, emesis, CNS effects (including coma)

57. Bottom Line on MgSO4 Lower doses (2g in 20 min) well tolerated but probably only helpful in severe asthma if at all Weak evidence that higher doses (2g in 2 min or 10-20 g in 1 hour) more effective, but side effects may be more of a problem Doses on the order of 2g in 2 min shown to be safe in obstetrical literature

58. Heliox As described by Gluck: “Helium-oxygen mixtures improve ventilation by reducing the Reynolds number and reducing density dependent resistance. Helium’s beneficial effects are due to its high kinematic viscosity, high binary diffusion coefficient for CO2, and high diffusivity.” In English: Helium flows through airways more “easily” that nitrogen, decreasing work of breathing Not thought to directly promote bronchodilation

59. Heliox: an Ethereal Treatment Few clinical trials mostly consisting of case series, uncontrolled studies, and some pediatric literature No “definitive” study, but seems to be a consensus in the literature supporting its use in some cases - particularly severe asthma

60. Heliox Bottom Line Little available evidence May be helpful (at least in very severe asthma) in “buying time” until other treatments become effective Use unlikely to cause harm unless it delays other necessary treatment such as B-agonists or necessary intubation

61. The Bottom, Bottom Line B-agonists and corticosteroids remain the mainstay treatments for asthma exacerbation Methylxanthines not helpful acutely, but may play a role subacutely and/or in chronic management Ipratropium Bromide not harmful, may help BiPAP and Heliox may spare a patient from more morbid treatments such as intubation MgSO4 is without good evidence of benefit, but high doses may be helpful in severe asthma

63. Short-acting inhaled

65. Systemic (oral)Leukotriene Modifiers Methyl Xanthines Cromolyn and Nedocromil Anticholinergics

66. COMORBID INFECTIONS Most asthma exacerbations are associated with infection by a respiratory virus, especially rhinovirus. Only a small percentage of exacerbations are associated with infection by an atypical bacterium, like Mycoplasma pneumoniae or Chlamydia pneumoniae. It is widely believed that coincident bacterial sinusitis contributes to asthma exacerbations. Airway obstruction due to mucus plugging possibly predisposes patients to bacterial infection of non-draining regions of the lungs. Viral and bacterial infections are both associated with neutrophilic inflammation of the upper and lower airways.

67. RECOMMENDATION Antibiotics are not recommended for the treatment of acute asthma exacerbations except as needed for comorbid conditions – e.g., for the patients with fever and purulent sputum, evidence of pneumonia, or suspected bacterial sinusitis.

68. PROPELLENTS CFC: chlorofluorocarbons Safe to inhale but damaging to the earth’s ozone layer MDIs with CFC are being phased out HFA: hydrofluoroalkane Safe for the environment and the patient Delivers nearly twice as much medication to the patient

69. ORAL CORTICOSTEROIDS Only prednisone needed for PO use Once per day about equivalent to BID May stop med abruptly after ~5 days Used almost exclusively for quick relief, not for supplementing (long term) inhaled steroids or long acting beta2-agonists in step 4

70. INHALED STEROIDSCOMMON PRACTICES Beclomethasone (Beclovent) not in common use in some medical centers Budesonide (Pulmicort)~20% absorbed, but used mostly in nebulizer for children Flunisolide (Aerobid) not used much Fluticasone (Flovent) ~1% absorbed, commonly used & available in 3 strengths Triamcinolone acetonide (Azmacort) not in common use in some medical centers

71. Keep asthma medicine cool !

72. Ciclesonide Newest ICS (About 5 years in use) Small airways effect High level of efficacy of available ICS Safety profile Does not affect circadian rhythm High degree of serum protein binding Rapid clearance rate; reduced systemic effect

74. MINIMAL SYTEMIC ABSORPTION

75. LOW SIDE EFFECTS

76. RETENTION IN LUNG

78. FORMOTEROL Available as Foradil It is both short acting and long acting 12 mcg of Foradil is equivalent to 50 mcg of salmeterol (Serevent) Provided as 12 mcg capsules to be used in aerolizer (not PO) every 12 hours

79. CROMOLYN & NEDOCROMIL Cromolyn is available as Intal Nedocromil is available as Tilade Not commonly used

80. LEUKOTRIENE MODIFIERS Used as adjunctive therapy for asthma Oral treatment available Simultaneously treats allergic rhinits

81. LEUKOTRIENE MODIFIERS Leukotriene Receptor Antagonists (LTRAs) Montelukast is available as Singulair prescribed as one 10 mg tablet per day Zafirlukast is available as Accolate prescribed as 20 mg tablet BID 5-Lipoxygenase Inhibitors Zileuton is available as Zyflo prescribed as 600 mg QID

82. Children and allergy in asthma

83. METHYLXANTHINES Theophylline used very little now and requires blood level monitoring

84. OTHERS Pulse oximetry – most useful in emergency rooms Spirometry – useful to detect degree of obstruction and if it can clear with bronchodilators and or steroids Asthma specialists – useful for step 3 and/or step 4 patients or difficulty with management

85. Other Drugs Surfactant Replacement Therapy New anti-inflammatory Agents Inhaled antibiotics Anticytokine Agents Protease inhibitors immunomodulators

86. Anti-IgE Recombinant humanized monoclonal antibody to treat persons over 12 years with moderate to severe asthma -Omalizumab - Xolair -Inhibits binding of IgE to receptors on mast cells and basophils -Prevents the release of mediators of allergic response that cause bronchospasm -Given subcutaneously q 2-4 weeks, very expensive but effective in reducing hospital visits and steroids use.

87. Special AdministrationTechniques Devices used to deliver aerosol medication -MDI -Jet Nebulizer -UItrasonic Nebulizer -Dry powder inhaler -Spacer

88. Inhalation devices

89. CONSEQUENCES OF POOR ASTHMA CONTROL Social economic waste that is preventable Loss in school/job absenteeism High morbidity Marginalization of Asthmatics in life Family life disruption (divorces and single mother hood) All ADDS up to poor quality of life and early demise

90. Barriers to asthma medication

91. BARRIERS IN ASTHMA Patient Healthcare system Health care provider environmental

92. BARRIERS IN ASTHMA Patient Varying cultural issues Complex treatment regimen Fear of medication Poor adherence – side effects of mediation – poor coping Embarrassment over asthma Low – income – lack of resources Lack of appreciation of severity of asthma

93. BARRIERS IN ASTHMA Health care provider Busy with other respiratory disease Attitude: misdiagnosis and under diagnosis Training and knowledge Managing acute attacks rather than long term control Limited time to give asthma education Lack of awareness of existence of clinical guidelines

94. BARRIERS IN ASTHMA CONT’ Health care system Geographical Poor infrastructure Availability of drugs Low public health Priorities (TB/HIV malaria Private versus public Cost of hospital visits

95. BARRIERS IN ASTHMA CONT’D Environmental factors School Home Workplace Tobacco – smoke Urbanization - pollution

96. BARRIERS IN ASTHMA CONT’D Effects of barriers Socio-economic Frequent symptoms Severe symptoms More emergency room visits More absenteeism Frequent hospitalization Higher mortality

97. The challenges of asthma management Over-reliance on rescue medication1 Suboptimal control1 Poor adherence to maintenance therapy1 Complexity of current treatments1 Lack of education and understanding among patients1 1FitzGerald JM, et al. Can Resp J 2006;13:253–259;2Harrison TW, et al. Lancet 2004;363:271–275.

98. THANK YOU FOR YOUR KIND ATTENTION