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Medicine II 5.5

Dr. Guiang January 13, 2015

Bronchial Asthma

OUTLINE I. Introduction II. Etiology III. Pathogenesis IV. Clinical Features V. Diagnosis VI. Treatment REFERENCES 1. Lecture PPT 2. Recording 3. Harrison’s

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INTRODUCTION The symptoms include chest heaviness, tiredness and difficulty in breathing. If the patient’s condition gets worse, the symptoms will become more prominent, the cough is frequent and laborious. The patient also has a desire to get into open air. However, as the paroxysm ceases, the cough becomes less urgent and less frequent, the voice sonorous, and the body relaxes. Thus, asthmatics escape death, but in the intervals between severe attacks or even when they are walking on ground level, they bear in mind the symptoms of the disease (Arateaus, 2AD) A syndrome characterized by a variable airflow obstruction, both spontaneously and with treatment. Even if they don’t receive treatment, there can be spontaneous resolution and may be variable with treatment like bronchodilators. Asthmatics are more responsive than non-asthmatics to various triggers such as stress, cotton, pollen, leading to narrowing with reduced airflow, wheezing and dyspnea PREVALENCE In developing countries, there is a rising prevalence due to urbanization; in urban areas the prevalence is very high. THE MOST COMMON NONCOMMUNICABLE DISEASE AMONG CHILDREN (WHO). Peak incidence in children is 3 years old; may manifest similarly like bronchitis or pneumonia Risk factors for deaths are “frequent use” of bronchodilator inhalers, lack of corticosteroid therapy and previous admissions with near fatal asthma. The frequent use of bronchodilator inhalers is a risk factor because it means that the asthma is uncontrolled. Lack of corticosteroid is another culprit because people who use bronchodilators don’t feel the relief (of corticosteroids) which make them not use corticosteroids; but it is the main treatment of asthma. Co-morbid diseases such as Heart failure or COPD make the asthma more significant. ETIOLOGY (Interplay between Genetic and Environmental factors) ATOPY Atopy is due to the genetically determined production of specific IgE antibody. A major risk factor for asthma Allergic rhinitis may be found in more than 80% of asthmatics and atopic dermatitis (eczema); other symptoms include morning sneezes and allergic (nasal) salute. Most common allergens are derived from house dust mites, cat and dog fur, cockroaches, pollens and rodents. Atopic triad includes allergic rhinitis, atopic dermatitis and atopic asthma; presence of 2 out of three increases the chances that patient has an atopic triad. INTRINSIC/NONATOPIC ASTHMA 10%, adult onset; usually more severe; unknown mechanism More severe because of co-morbidities

Group 18 | Ally, Jolina, Jianka, Sansan, Margo

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INFECTIONS Common as trigger; uncertain as etiology; Respiratory Syncytial Virus (RSV) infection in infancy is implicated.

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GENETIC High concordance in twins; interaction of many genes (polygenic) Asthma has really strong genetic preponderance.

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ENVIRONMENTAL FACTORS May determine which atopic individuals become asthmatic Diets low in antioxidants such as vitamin C and Vitamin A, magnesium, selenium and omega-3 polyunsaturated fats (fish oil) or high in sodium and omega-6 polyunsaturated are associated with an increased risk of asthma. This theory is still CONTROVERSIAL (with the diet being the etiology); diet is more of a trigger. Air pollution – sulfur dioxide, ozone and diesel particulates may trigger asthma but less certain as etiology ; more of a trigger Allergens – house dust mites in early childhood is a risk factor for allergic sensitization; domestic pets, particularly cats Occupational exposure – 10% of young adults, chemical and animal allergens, symptoms improve during weekends and holidays – example is Monday chest tightness wherein symptoms occur during work. PATHOGENESIS PATHOLOGY Airway mucosa is infiltrated with activated eosinophils, T lymphocytes, mast cells – main players in the pathogenesis of asthma with the dendritic cells, almost the same with COPD. Thickening of the basement membrane due to subepithelial collagen deposition. It renders the basement membrane not friable and elastic which makes it more difficult to treat. Mucous plug, which is comprised of mucous glycoproteins secreted from goblet cells (lines the lumen; they become hyperplastic)

Figure 1. The Pathogenesis of Asthma. The narrowing of the airway in asthma is not just because of bronchospasm but also due to thickening of the membrane and mucous plugging. Bronchodilators will have an effect on the smooth muscle but not on the edema or the inflammation. 

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INFLAMMATION Mucosa of trachea down to terminal bronchioles especially cartilaginous bronchi are the ones that are inflamed. Majority of the lung parenchyma is inflamed. The alveoli are not affected in the same way but through the plugging of the secretions and can be atelectatic due to proximal narrowing. Inflammatory cells seen in asthma and the nasal mucosa in rhinitis are similar. The inflammatory cascade followed by these two disease are the same; treatment may be the same; also they are part of the atopic triad Really a chronic condition, with inflammation persisting over many years in most patients. Page 1 of 5

MEDICINE II 5.5

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INFLAMMATORY CELLS DENDRITIC CELLS (ANTIGEN PRESENTING CELLS) Take up and process allergens present to uncommitted T-lymphocytes to program the production of allergen-specific T cells In the lumen One that comes in contact with the allergens Sensitization process for future reactions As the patient gets more exposed to the pollen, the reaction intensifies because of the program production of these cells MAST CELLS Initiate the bronchoconstrictor responses to allergens, release several bronchoconstrictor mediators including histamine, prostaglandin D2, and cysteinyl-leukotrines EOSINOPHILS Eosinophil infiltration is a characteristic feature of asthmatic airways after allergen inhalation. The release of basic proteins and oxygen-derived free radicals lead to AHR (Airway hyperresponsiveness) In CBC, there is an increase of eosinophils. T-LYMPHOCYTES Coordinate the recruitment of eosinophils and the maintenance of mast cells in the airways Leading to intensification of the reaction.

INFLAMMATORY MEDIATORS Table 1. Inflammatory Mediators Inflammatory cells Mediators Effects Mast cells Histamine Bronchospasm Eosinophils Leukotrienes Plasma exudation Th2 cells Prostanoids Mucus secretion Basophils PAF AHR Neutrophils Kinins Structural changes Platelets Adenosine Endothelins Structural cells Nitric oxide Epithelial cells Cytokines Smooth muscle cells Chemokines Endothelial cells Growth factors Fibroblasts Nerves     

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Many cells and mediators are involved in asthma and lead to several effects on the airways. Each mediator has many effects; it is unlikely that preventing the action of a single mediator that will have a major impact. There is a need for ALL mediators to be present to manifest the effects mentioned above. Patients should use CORTICOSTEROIDS. EFFECTS OF INFLAMMATION AHR due to shedding of airway epithelium, which is due to: o Loss of its barrier function to allow penetration of allergens o Loss of enzymes (such as neutral endopeptidase) that degrade certain peptide inflammatory mediators (mediators go unchecked) o Loss of a relaxant factor Subepithelial fibrosis – depositor of types III and V collagen; may contribute to irreversible narrowing (becomes collagenous; effect of medicines are not as effective as before) Hypertrophy and hyperplasia of airway smooth muscle (presumably the result of stimulation) Vascular responses as an increase in mucosal blood flow and angiogenesis Mucus hypersecretion – hyperplasia of submucosal glands and increased numbers of epithelial goblet cells result in viscid mucus plugs

Group 18 | Ally, Jolina, Jianka, Sansan, Margo

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After use of bronchodilators, there is increase in secretion due to relaxation; able to expel the mucus plugs AIRWAY REMODELING Changes in airway structure leading to irreversible narrowing Accelerated decline in lung function (ability to dilate is lost) Characteristic structural changes are: o Increased airway smooth muscle hypertrophy o Fibrosis o Angiogenesis o Mucus hyperplasia Becomes permanent ASTHMA TRIGGERS Triggers: stress, exercise, pollen, bugs in the home, chemical fumes, cold air, fungus spores, dust, smoke, strong odors, pollution, pets, anger Cold air: Very common in call centers during night shifts Seen as evidence for poor control and an indicator for the need of increase controller (preventive therapy) o You cannot 100% remove these triggers. With continuous reactions to these triggers, there might be a need to increase the dose or use of steroids or a longer-acting beta-2 agonists like Salbutamol. Most common allergen: Dermatophagoides spp. (house dust mite) Most common viruses: rhinovirus, RSV, coronavirus Drugs: B-blockers (metoprolol) increase cholinergic bronchoconstriction, aspirin o Anti-asthma drugs would need to be stepped up when beta blockers are used for patients with heart failure. Exercise-induced asthma: common in children, in cold dry weather, (hyperventilation increases osmolality of airway fluid which activates mast cells) o Because of partial dehydration of the mucosal lining o Can be prevented by pre-medication, use of inhalers; controller (montelukast or steroids) PATHOPHYSIOLOGY Limitation of airflow is due mainly to bronchoconstriction but airway edema, vascular congestion, and luminal occlusion with exudate also contribute. o Cannot be completely cured by just a bronchodilator due to the other factors mentioned above. Results in a reduction in forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF), as well as an increase in airway resistance. Parameters of the spirometry (FEV, PEF) which measure obstruction; the ones that are deranged in asthma. CLINICAL FEATURES OF ASTHMA The characteristic symptoms are variable wheezing, dyspnea and coughing, both spontaneously and with therapy. Chest tightness can also be another characteristic symptom of asthma Symptoms may be worse at night and patients typically awake in the early morning hours. Asthma Control Test: 5 parameters, one of which includes if the patient wakes up at night due to difficulty of breathing or asthma, and is scored accordingly. Typical physical signs are inspiratory, and to a greater extent expiratory, rhonchi throughout the chest, and there may be hyperinflation. This is due to the airways slightly dilating during inspiration and slightly contracting during expiration.

Edited by: JLP

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DIAGNOSIS – CONFIRMATION Lung function tests – spirometry confirms flow 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 shortacting B2-agonist (this implies significant response to the bronchodilator and that you might be an asthmatic; below 12% and 200 ml you might not be an asthmatic but there still may be some reversibility) Airway responsiveness – measured by methacholine or histamine challenge with calculation of the provocative concentration that reduces FEV1 by 20% (PC20)

TREATMENT • AIMS OF ASTHMA THERAPY o Minimal (ideally no) chronic symptoms, including nocturnal o Minimal (infrequent) exacerbations o No emergency visits o Minimal (ideally no) use of required B2-agonist o No limitations on activities, including exercise o Peak expiratory flow circadian variation