ASTHMA

1. ASTHMA

2. Definition Asthma is a clinical syndrome of unknown etiology characterized by three distinct components: (1) recurrent episodes of airway obstruction that resolve spontaneously or as a result of treatment (2) exaggerated bronchoconstrictor response to stimuli that have little or no effect in nonasthmatic subjects (airway hyperresponsiveness) (3) inflammation of the airways

3. Epidemiology • Asthma is an extremely common disorder affecting boys more commonly than girls in childhood and, after puberty, women more commonly than men • Although most cases begin before the age of 25 years, asthma may develop at any time throughout life

4. The worldwide prevalence of asthma has increased more than 45% since the late 1970s. The greatest increases in asthma prevalence have occurred in countries that have recently adopted an “industrialize” lifestyle • Asthma is among the most common reasons to seek medical treatment

5. Pathobiology • Asthma has about 60% heritability, indicating that both genetic and environmental factors are important in its etiology

6. Pathophysiology • Airway hyper-reactivity (AHR)—the tendency for airways to contract too easily and too much in response to triggers that have little or no effect in normal individuals—is integral to the diagnosis of asthma • The degree of airway narrowing

7. With increasing severity and chronicity of the disease, remodelling of the airway occurs, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication

8. Relationship between atopy (tendecy to produce IgE) and asthma is well established • Proved in many individuals by clear relationship between sensitisation (demonstration of skin prick reactivity or elevated serum specific IgE) and allergen exposure

9. Common allergens include house dust mites, pets such as cats and dogs, pests such as cockroaches, and fungi (Aspergillus: allergic bronchopulmonaryaspergillosis) • In aspirin-sensitive asthma, symptoms follow the ingestion of salicylates

10. Intrinsic Asthma • A minority of patients (approximately 10%) have negative skin tests to common inhalant allergens and normal serum concentrations of IgE.\ • These patients, usually show later onset of disease (adult-onset asthma), commonly have concomitant nasal polyps, and may be aspirin-sensitive

11. In exercise-induced asthma, hyperventilation results in water loss from the pericellular lining fluid of the respiratory mucosa, which in turn triggers mediator release • Heat loss from the respiratory mucosa may also be important

12. Hygiene Hypothesis • Lower levels of infection may be a factor in affluent societies that increase the risks of asthma • Children who are exposed to a high level of infection & endotoxin are less likely to develop allergic sensitization than children raised in hygienic environment

13. Intestinal parasite infection may also be associated with a reduced risk of asthma

14. Diet • Diets low in antioxidants such as vitamin C and vitamin A, magnesium, selenium, and omega-3 polyunsaturated fats (fish oil) or high in sodium are associated with an increased risk of asthma • Vitamin D deficiency may also predispose to the development of asthma

15. However, interventional studies with supplementary diets have not supported an important role for these dietary factors • Obesity is also an independent risk factor for asthma, particularly in women, but the mechanisms are unknown

16. In persistent asthma, a chronic and complex inflammatory response ensues • Smooth muscle hypertrophy and hyperplasia, thickening of the basement membrane, mucous plugging and epithelial damage results

17. Clinical features • Typical symptoms include recurrent episodes of wheeze, chest tightness, breathlessness and cough • Not uncommonly, asthma is mistaken for a cold or chest infection that is failing to resolve (e.g. after more than 10 days)

18. Symptoms may be worse at night and patients typically awake in the early morning hours • Prodromal symptoms may precede an attack, with itching under the chin, discomfort between the scapulae, or inexplicable fear (impending doom)

19. Some patients, particularly children, may present with a predominant nonproductive cough (cough-variant asthma) • Typical physical signs are inspiratory, and expiratory, rhonchi throughout the chest • There may be no abnormal physical findings when asthma is under control

20. Classical precipitants Allergens • Inhaled allergens activate mast cells with bound IgE directly leading to the immediate release of bronchoconstrictor mediators

21. The most common allergens to trigger asthma are Dermatophagoides species (house dust mite) and environmental exposure leads to low-grade chronic symptoms that are perennial • Other perennial allergens are derived from cats and other domestic pets, as well as cockroaches

22. Other allergens, including grass pollen, tree pollen, and fungal spores, are seasonal • Pollens usually cause allergic rhinitis rather than asthma, but in thunderstorms the pollen grains are disrupted and the particles that may be released can trigger severe asthma exacerbations (thunderstorm asthma)

23. Virus Infections • Upper respiratory tract virus infections such as rhinovirus, respiratory syncytial virus, and coronavirus are the most common triggers of acute severe exacerbations and may invade epithelial cells of the lower as well as the upper airways

24. Why these viruses cause exacerbations is poorly understood, but there is an increase in airway inflammation with increased numbers of eosinophils and neutrophils • In asthmatic patientsfor production of type I interferons by epithelial cells is reduced, resulting in increased susceptibility to these viral infections and a greater inflammatory response

25. Pharmacologic Agents • Beta-adrenergic blockers commonly acutely worsen asthma, and their use may be fatal • All beta blockers need to be avoided and even selective beta blocker or topical application (e.g., timolol eye drops) may be dangerous • Aspirin may worsen asthma in some patients (aspirin-sensitive asthma)

26. Exercise • Exercise is a common trigger of asthma, particularly in children. The mechanism is linked to hyperventilation, which results in increased osmolality in airway lining fluid and triggers mast cell mediator release, resulting in bronchoconstriction

27. Exercise-induced asthma (EIA) typically begins after exercise has ended, and recovers spontaneously within about 30 minutes • EIA is worse in cold, dry climates than in hot, humid conditions

28. It may be prevented by prior administration ofbeta2-agonists and antileukotrienes, but is best prevented by regular treatment with ICS, which reduce the population of surface mast cells required for this response

29. Physical Factors • Cold air and hyperventilation may trigger asthma through the same mechanisms as exercise • Laughter may also be a trigger • Many patients report worsening of asthma in hot weather and when the weather changes

30. Some asthmatics become worse when exposed to strong smells or perfumes, but the mechanism of this response is uncertain

31. Food • There is little evidence that allergic reactions to food lead to increased asthma symptoms, despite the belief of many patients that their symptoms are triggered by particular food constituents • Exclusion diets are usually unsuccessful at reducing the frequency of episodes

32. Air Pollution • Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated with increased asthma symptoms

33. Hormonal Factors • Some women show premenstrual worsening of asthma, which can occasionally be very severe

34. Stress • Many asthmatics report worsening of symptoms with stress • Psychological factors can induce broncho constriction through cholinergic reflex pathways • Paradoxically, very severe stress such as bereavement usually does not worsen, and may even improve, asthma symptoms

35. Diagnosis • The diagnosis is usually apparent from the symptoms of variable and intermittent airways obstruction, but is usually confirmed by objective measuements of lung function

36. Lung Function Tests • Simple spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and PEF • Reversibility is demonstrated by a >12% and 200-mL increase in FEV1 15 minutes after an inhaled short-acting beta2-agonist

37. > 20% diurnal variation on ≥ 3 days in a week for 2 weeks on PEF diary • FEV1 ≥ 15% decrease after 6 mins of exercise

38. Airway Responsiveness • The increased AHR is normally measured by methacholine or histamine challenge test that reduces FEV1 by 20% (PC20) • This is rarely useful in clinical practice, but can be used in the differential diagnosis of chronic cough and when the diagnosis is in doubt in the setting of normal LFT

39. Skin Tests • Skin prick tests to common inhalant allergens are positive in allergic asthma and negative in intrinsic asthma • Not helpful in diagnosis • Positive skin responses may be useful in persuading patients to undertake allergen avoidance measures

40. Exhaled Nitric Oxide • Exhaled NO is now being used as a noninvasive test to measure eosinophilic airway inflammation • The typically elevated levels in asthma are reduced by ICS • This may be a test of compliance with therapy • It may also be useful in demonstrating insufficient anti-inflammatory therapy

41. Treatment • Asthma is a chronic condition but effective treatment is available for the majority of patients • The goal of management should be to obtain and sustain complete control

42. Patients should be made to understand the nature of the condition, the relationship between symptoms and inflammation, the importance of key symptoms such as nocturnal waking, the different types of medication

43. Avoidance of aggravating factors • Occupational asthma • Atopic patients where removing or reducing exposure to relevant antigens, e.g. a pet animal

44. A stepwise approach • Step 1: Occasional use of inhaled short-acting β2-adrenoreceptor agonist bronchodilators • For patients with mild intermittent asthma (symptoms less than once a week for 3 months and fewer than two nocturnal episodes/month)

45. Step 2: Introduction of regular ‘preventer’ therapy • Regular anti-inflammatory therapy (preferably inhaled corticosteroids (ICS) such as beclometasone,budesonide, fluticasone or ciclesonide) should be started in addition to inhaled β2-agonists taken on an as-required basis

46. In any patient who: • Has experienced an exacerbation of asthma in the last 2 years • Uses inhaled β2-agonists three times a week or more • Reports symptoms three times a week or more • Is awakened by asthma one night per week

47. For adults, a reasonable starting dose is 400 μgbeclometasonedipropionate (BDP) or equivalent per day, although higher doses may be required in smokers

48. Step 3: Add-on therapy • If a patient remains poorly controlled despite regular use of ICS, a thorough review should be undertaken focusing on adherence, inhaler technique and on-going exposure to modifiable aggravating factors

49. In general, add-on therapy should be considered in adults taking 800 μg/day BDP (or equivalent) • Long-acting β2-agonists (LABAs), such as salmeterol and formoterol, with a duration of action of at least 12 hours, should be added

50. Fixed combination inhalers of ICS and LABAs have been developed • These are more convenient, increase compliance, and prevent patients using a LABA as monotherapy alone