ASTHMA

Asthma 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- airway hyperresponsiveness = exaggerated bronchoconstrictor responses to stimuli that have little or no effect in nonasthmatic subjects 3- inflammation of the airways

Asthma Prevalence:
One of the most common chronic disease, affects
approximately 300 million people worldwide The greatest increases in asthma prevalence have occurred in countries that have recently adopted an industrialized lifestyle All ages , predominantly early life with a peak age of 3 years Adults: 10-12% population Children 15% population 2:1 male/female preponderance in childhood but by adulthood the sex ratio has equalized

Asthma Types

Extrinsic (atopic, allergic) asthma Intrinsic (non-atopic, idiosyncratic) asthma

Extrinsic (atopic, allergic) asthma

Most common type Begins in childhood or in early adult life Patients have family history/personal (rhinitis, urticaria, eczema) Hypersensitivity to allergens is usually present Increased IgE concentration in serum (initiating acute immediate response and a late phase reaction)

Intrinsic (non-atopic) asthma

Appears in approximately 10% cases This patients have later onset asthma and have concomitant nasal polyps and may be aspirin-sensitive Negative skin tests to common inhalant allergens Normal IgE concentration in serum

Risk Factors Involved in Asthma

Host Factors:

Genetic predisposition Atopy Airway hyperresponsiveness Gender Race

Environmental Factors:

Indoor allergens Outdoor allergens Occupational sensitizers Passive smoking Respiratory infections Air pollution Socioeconomic factors Family size

 The 2007 Expert Panel Report 3 (EPR-3) of the National Asthma Education and Prevention Program (NAEPP) noted several key changes in pathophysiology of asthma:

The critical role of inflammation + considerable variability in the pattern of inflammation => phenotypic differences that may influence treatment responses

Of the environmental factors, allergic reactions remain important.

The onset of asthma for most patients begins early in life, with the pattern of disease persistence

Current asthma treatment with anti-inflammatory therapy does not appear to prevent progression of the underlying disease severity

Asthma Pathophysiology
The

pathophysiology of asthma is complex and involves the following components:

Airway inflammation Intermittent airflow obstruction Bronchial hyperresponsiveness

Asthma Pathophysiology Airway Inflammation

The mechanism of inflammation in asthma may be : acute, subacute chronic Some of the cells involved in airway inflammation include

mast cells, eosinophils, epithelial cells, macrophages and activated T lymphocytes Structural cells of the airways including fibroblasts, endothelial cells, and epithelial cells, contribute to the chronicity of the disease Other factors such as cell-derived mediators influence smooth muscle tone and produce structural changes and remodeling of the airway.

Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma symptoms.

Asthma Pathophysiology Airway Inflammation

Airway inflammation in asthma may represent a loss

of normal balance between two "opposing" populations of Th lymphocytes (Th1 and Th2)

Th1 cells produce interleukin (IL)-2 and IFN-, which

are critical in cellular defense mechanisms in response to infection Th2 cells generates a family of cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation

Asthma Pathophysiology Airway Obstruction

Airflow obstruction can be caused by a variety

of changes, including acute bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling Airway obstruction causes decreased FEV1, FEV1/FVC ratio, PEF and increased resistance to airflow => decreased ability to expel air and may result in hyperinflation

Asthma Pathophysiology Bronchial Hyperresponsiveness

Describes an exaggerated response to numerous
exogenous and endogenous stimuli The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediatorsecreting cells such as mast cells or nonmyelinated sensory neurons The degree of airway hyperresponsiveness generally correlates with the clinical severity of asthma

Chronic Asthma
Chronic inflammation of the airways is associated
with increased bronchial hyperresponsiveness and bronhospasm and typical symptoms after exposure to allergens, environmental irritants, viruses, cold air, or exercise In chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease

Asthma
Asthma Triggers
Allergens Upper respiratory tract viral infections Exercise and hyperventilation Cold air Sulfur dioxide and irritant gases Drugs (-blockers, aspirin) Stress Irritants (household sprays, paint fumes)

Asthma Triggers Allergens

Dermatophagoides species (the most common) Cats and other domestic pets Crockroaches Grass pollen Ragweed Tree pollen Fungal spores

Asthma Triggers Virus Infections

Rhinovirus, respiratory syncytial virus, and coronavirus are the most common triggers of acute severe exacerbations The mechanism is poorly understood Viruses airway inflammation with increase number of eosinophils and neutrophils Asthmatics patients have a reduced production of type I interferons by epithelial cells increased susceptibility to viral infections and greater inflammatory response

Asthma Triggers Pharmacologic Agents

Beta-adrenergic blockers commonly acutely worsen asthma, and their use may be fatal All beta blockers should to be avoided Selective 2 blocker or topical application (e.g. timolol eye drops) may be dangerous too Angiotensin-converting enzyme inhibitors rarely worsen asthma Aspirin may trigger asthma in some patients

Asthma Triggers Exercise

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. Is more common in sports such as cross-country, running in cold weather, overland skiing, and ice hockey than in swimming It may be prevented by prior administration of 2 agonists and antileukotrienes but is best prevented by regular treatment with ICS

Asthma Triggers Occupational Factors

Occupational asthma : asthma that is caused or worsened by breathing in a workplace with substance such as chemical fumes , gases or dust When diagnosed and treated early (within the first 6 months of symptoms) is usually complete recovery while, long-term exposure can cause lifetime asthma

Asthma Triggers Others

Food: shellfish and nuts, metabisulfite (a food
additive),tartrazine (a yellow food-coloring agent) Physical factors: hyperventilation, cold air, weather changes, laughter, strong smells or perfumes Air pollution: increased ambient levels of sulfur dioxide, ozone and nitrogen oxides Hormonal factors: premenstrual,thyrotoxicosis and hypothyroidism GOR, stress

Asthma Symptoms & Physical Signs

The characteristic symptoms are wheezing, dyspnea,
and coughing, which are variable, both spontaneously and with therapy Increased mucus production , difficult to expectorate Increased ventilation and use of accessory muscles of ventilation Prodromal symptoms such as itching under the chin, discomfort between the scapulae or inexplicable fear may precede an attack Inspiratory rhonchi, hyperinflation No abnormal physical findings in controlled asthma

Asthma Diagnosis
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 inhaling a shortacting bronchodilator Measurements of PEF twice daily may confirm the diurnal variation in airflow obstruction Flow-volume loops show reduced peak flow and reduced maximum expiratory flow

Asthma Diagnosis
Airway Hyperresponsiveness can be measured by:

Methacholine or histamine challenge calculate the provocative concentration that reduces FEV1 by 20% rarely useful in clinical practice can be used in the differential diagnosis of chronic cough or in case of normal pulmonary function tests Exercise testing may demonstrate the postexercise bronchoconstriction if there is a history of EIA Allergen challenge rarely necessary to identify specific occupational agents

Asthma Diagnosis
Chest Radiography is usually normal hyperinflated lungs in severe patients pneumothorax in exacerbations pneumonia or eosinophilic infiltrates in

patients with bronchopulmonary aspergillosis High-resolution CT areas of bronchiectasis in severe asthma

Asthma Diagnosis
Exhaled Nitric Oxide is now used as a

noninvasive test to measure eosinophilic airway inflammation the typically high-levels in asthma are reduced by ICS, so this may be a test of compliance with therapy Skin Prick Tests to common inhalant allergens are positive in allergic asthma and negative in intrinsic asthma

Asthma Differential Diagnosis

Upper airway obstruction by a tumor or laryngeal edema Endobronchial obstruction with a foreign body Left ventricular failure Eosinophilic pneumonias Systemic vasculitis (incl. Churg-Strauss syndr. and polyarteritis nodosa) Chronic obstructive pulmonary disease (COPD)

Asthma - Treatment
Table 254-2 Aims of Asthma Therapy
Minimal (ideally no) chronic symptoms, including nocturnal Minimal (infrequent) exacerbations No emergency visits Minimal (ideally no) use of a required 2-agonist

No limitations on activities, including exercise

Peak expiratory flow circadian variation <20% (Near) normal PEF

Minimal (or no) adverse effects from medicine

Asthma Treatment

The main drugs used for asthma can be divided in two categories: bronchodilators give rapid relief of symptoms through relaxation of airway smooth muscle controllers inhibit the underlying inflammatory process

Asthma Treatment Bronchodilator Therapies

There

are three classes of bronchodilators in current use:

2 agonists (the most effective) Anticholinergics Theophylline

Asthma Treatment Bronchodilator Therapies

Table 254-3 Effects of -2-Adrenergic Agonists on Airways

Relaxation of airway smooth muscle (proximal and distal airways) Inhibition of mast cell mediator release Inhibition of plasma exudation and airway edema Increased mucociliary clearance Increased mucus secretion Decreased cough No effect on chronic inflammation

-2-adrenergic agonists
usually

are given by inhalation to reduce side

effects 1)SABAs = short acting -2-agonistsalbuterol terbutaline

2)LABAs =long acting -2-agonistssalmeterol formoterol

-2-adrenergic agonists SABAs

3-6 hours duration of action Rapid onset of bronchodilation used as needed for symptom relief Increased use of SABAs indicates that asthma is not controlled Used in preventing EIA

-2-adrenergic agonists LABAs

Over 12 hours duration of action Given twice daily by inhalation Used in combination (fixed combination inhalers) with ICS, because alone they do not control the underlying inflammation Added to ICS they reduce exacerbations, improve asthma control at lower doses of corticosteroids

-2-adrenergic agonists
Side

Effects: Muscle tremor and palpitations especially in elderly patients Small potassium fall as a result of increased uptake by skeletal muscle cells but does not usually cause clinical problems Safety: Association between asthma mortality and the use of LABAs is related to the lack of use of concomitant ICS, as the LABAs fails in control the underlying inflammation

Asthma Treatment Anticholinergics

Muscarinic receptor antagonists ipratropium bromide prevent cholinergic nerve-induced bronchoconstriction and mucus secretion Less effective than -2-agonists as they inhibit only the cholinergic reflex component of bronchoconstriction,not all mechanisms as -2agonists May be given by nebulizer in treating acute severe asthma but only after -2-agonists because they have o slower onset of bronchodilation Side effects: dry mouth, urinary retention, glaucom

Asthma Treatment Theophylline

of phosphodiesterases in airway smooth-muscle cells increases cyclic AMPbronchodilator effect anti-inflammatory effects at lower doses Given once or twice daily as a slow-release prep. At plasma concentration of 10-20 mg/L aditional bronchodilator in patients with severe asthma At lower doses (5-10 mg/L)additive effects to ICS Now is rarely used because of side effects , occasionally given to patients with severe exacerbations that are refractory to SABAs
inhibition

Asthma Treatment Theophylline

Side

Effects: are related to plasma concentrations(rarely observed at plasma concentration <10mg/L) nausea , vomiting and headache (most common) diuresis and palpitations cardiac arrhythmias and epileptic seizures (at high doses)

Table 254-4 Factors Affecting Clearance of Theophylline

Increased Clearance Enzyme induction (rifampicin, phenobarbitone, ethanol) Smoking (tobacco, marijuana)

Asthma Treatment Theophylline

High-protein, low-carbohydrate diet Barbecued meat Childhood Decreased Clearance Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, zafirlukast) Congestive heart failure Liver disease Pneumonia Viral infection and vaccination High carbohydrate diet Old age

Asthma-Controller Therapies Inhaled Corticosteroids (ICS)

most effective controller therapy, used now as

first-line therapy for patients with persistent asthma. If do not control symptoms at low doses add a LABA usually given twice daily (once daily in mildly symptomatic patients) withdrawal of ICS results in slow deterioration of asthma control

Asthma-Controller Therapies Inhaled Corticosteroids (ICS)

improve - the symptoms of asthma rapidly - the lung function in several days prevent - asthma symptoms (EIA, nocturnal exacerbations, severe exacerbations) - irreversible changes in airway function that occur with chronic asthma reduce airway hyperresponsiveness in several months Side effects: dysphonia, oral candidiasis

Pharmacokinetics of inhaled corticosteroids

Asthma-Controller Therapies Systemic Corticosteroids

hydrocortisone or methylprednisolone , IV , for acute severe asthma prednisone or prednisolone 3045mg once daily for 510 days in acute exacerbations of asthma ~1% of asthma patients may require maintenance treatment with OCS (determine the lowest dose necessary to maintain control)
systemic

side effects: truncal obesity, bruising, osteoporosis, diabetes, hypertension, gastric ulceration, proximal myopathy, depression and cataracts

Asthma-Controller Therapies
Antileukotrienes:

montelukast, zafirlukast are given orally once or twice daily added to low doses of ICS Cromones: -cromolyn sodium, nedocromil sodium have short duration of action (at least 4 times daily by inhalation) so they have little benefit in the long-term control of asthma -very safe and were popular in the treatment of childhood asthma (now ICS are preferred)

Asthma- Treatment

Steroid-Sparing

Therapies: methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin reduce the requirement for OCS in patients with sever asthma and serious side effects with OCS no long-term benefit and high risk of side effects

Asthma- Treatment
Anti-IgE:omalizumab

reduce the number of severe asthma exacerbations and improve asthma control very expensive and is only suitable for highly selected patients who are not controlled on maximal doses of inhaler therapy given as a subcutaneous injection every 24 weeks for 3 - 4 months

Chronic Asthma Stepwise Therapy

Mild,intermittent asthmaSABAs use for more than 3 times/weekindicates the need for controller therapy add an intermediate dose of ICS if symptoms are controlled after 3 months of therapydecrease the dose if symptoms are not controlledadd LABA If asthma is not controlled with maximal ICS recommended doses check compliance and inhaler technique and add maintenance treatment with OCS Once asthma is controlleddecreased slowly therapy in order to find optimal doses to control symptoms

Stepwise approach to asthma therapy

Acute Severe Asthma

increased chest tightness, wheezing and dyspnea increased ventilation, hyperinflation, tachycardia, pulsus paradoxus reduced spirometric values and PEF, hypoxemia and low Pco2 due to hyperventilation (normal or rising Pco2 impending respiratory failuremonitoring and treatment)

Acute Severe Asthma-Treatment

O2

by face mask oxygen saturation >90% SABAs unsatisfactory response add inhaled anticholinergic In patients who are refractory to inhaled therapies slow infusion of aminophylline (monitor blood levels) Prophylactic intubation in case of impending respiratory failure (Pco2 normal or rises) Respiratory failure intubation and mechanical ventilation. NO sedatives (may depress ventilation). AB only if there are signs of pneumonia

Refractory Asthma
Approximately 5% of asthmatics Factors that cause poor control asthma: noncompliance with medication (particularly ICS) compliance may be improved by giving ICS as a combination with LABA that relieves symptoms Exposure to high ambient levels of allergens or unidentified occupational agents Sever rhinosinusitis,GOR, infection with Mycoplasma pneumoniae, Chlamydophyla pneumoniae, hyper- and hypothyroidism Drugs such as: beta-adrenergic blockers, aspirin and COX inhibitors

Refractory Asthma Corticosteroid-Resistant Asthma

Complete resistance to corticosteroids: = is defined as failure to respond to a high dose of oral prednisone/prednisolone (40mg once daily) over 2 weeks =extremely uncommon (affects less than 1 to 1000 patients) Reduced responsiveness to corticosteroids: =more common, requires OCS to control asthma Many observations suggest that are likely to be heterogeneous mechanisms implicated. Is not yet known if these mechanisms are genetically determined

Refractory Asthma Brittle Asthma

brittle asthma describes patients with asthma who maintained a wide variation in peak expiratory flow (PEF) despite high doses of inhaled steroids Type 1 brittle asthma: characterised by a maintained wide PEF variability (>40% diurnal variation for >50% of the time over a period of at least 150 days) despite considerable medical therapy including a dose of inhaled steroids of at least 1500g of beclomethasone (or equivalent) Type 2 brittle asthma: characterised by sudden acute attacks occurring in less than three hours without an obvious trigger on a background of apparent normal airway function or well controlled asthma

Refractory Asthma Treatment

Check compliance and the correct use of inhalers Identify and eliminate underlying triggers Low doses of theophylline Infusions with -2-agonists Omalizumab is effective in patients with allergic asthma, particularly
when there are frequent exacerbations Subcutaneous epinephrine in patients with type 2 brittle asthma

Special Considerations
Aspirin-Sensitive

Asthma 1-5% of asthmatics becomes worse with aspirin and other COX inhibitors Is usually preceded by perennial rhinitis and nasal polyps Aspirin even in small doses provokes rhinorrhea, conjunctival irritation, facial flushing and wheezing Treatment: - ICS, antileukotrienes - aspirin desensitization

Special Considerations
Asthma

in the Elderly Is more difficult to treat due to the side effects of drugs, the comorbidities which are more frequent at this age group and interactions with drugs such as -2-blockers,COX inhibitors, agents that may affect the theophylline clearance Pregnancy Its important to maintain good control of asthma during pregnancy May be safe treat with SABAs, ICS and theophylline There are less safety informations about drugs such as: LABAs, antileukotrienes, and anti-IgE If an OCS is needed it is better to use prednisone

Special Considerations

Cigarette Smoking Approximately 20% of asthmatics are smokers This patients have more severe disease, more frequent hospital admissions, faster decline in lung function and a higher risk of death Smoking interferes with the anti-inflammatory actions of corticosteroids smokers needs higher doses for asthma control Smoking cessation improves lung function and reduces the steroid resistance

Special Considerations
Surgery

Well-controlled asthma has no contraindication to anesthesia and intubation Patients treated with OCS will have adrenal suppression and should be treated with an increased dose of OCS immediately prior surgery Patients with FEV1<80% of their normal levels should be given OCS before surgery High-maintenance doses of steroids may be a contraindication to surgery because of increased risks of infection and delayed wound healing

Special Considerations
Bronchopulmonary Aspergillosis (BPA) Is a hypersensitivity lung disease due to bronchial

colonization by Aspergillus fumigatus that occurs in susceptible patients with asthma BPA is characterized by: Chest radiographic infiltrates particularly in the upper lobes Allergy prick skin to A. fumigatus always positive Serum Aspergillus precipitins low or undectable Central bronchiectasis Fibrotic stage may be associated with honeycombing Treatment with : OCS, oral antifungal itraconazole