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BRONCHIAL ASTHMA Asthma is defined as a chronic inflammatory disease of airways that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli, in which many cells and cellular elements play a role. This inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. Some of the principal cells identified in airway inflammation include mast cells, eosinophils, epithelial cells, macrophages, and activated T lymphocytes. The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling are present. ETIOLOGY Genetic factors are of major importance in determining a predisposition to the development of asthma. The stimuli that incite acute episodes of asthma can be grouped into seven major categories: • allergenic, •
pharmacologic,
•
environmental,
•
occupational,
• infectious, • exercise-related, and • emotional
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PATHOGENESIS Allergic asthma is dependent on an IgE response controlled by T and B lymphocytes and activated by the interaction of antigen with mast cell–bound IgE molecules. After taking up an immunogen, these cells migrate to the local lymph nodes where they present the material to T cell receptors. This leads to the differentiation of the cell to a TH2 subset and also causes B lymphocytes to switch their antibody production from IgG and IgM to IgE. Once synthesized and released by B cells, IgE circulates in the blood until it attaches to highaffinity receptors on mast cells and low-affinity receptors on basophils. Immune mechanisms appear to be causally related to the development of asthma in 25 to 35% of all cases. The pathophysiologic hallmark of asthma is a reduction in airway diameter brought about by contraction of smooth muscle, vascular congestion, edema of the bronchial wall, and thick, tenacious secretions. All these can cause to airway remodeling, which is associated with structural changes due to long-standing inflammation and may profoundly affect the extent of reversibility of airway obstruction. BA begins to look like COPD. IgE-dependent activation of mast cells leads to release from them big amount of products of arachidonic acid metabolism. These bioactive substances are not all the time in cells like histamine or serotonin, and appear during cells activation and then secreted in extracellular fluid. Free arachidonic acid is used in two metabolic ways: with the help of cyclooxygenase it changes into prostoglandings , and with the help of lipooxygenase into the leukotrienes. Formation of different forms of prostoglandings depends on kind of cells where all these processes happen. One of forms of prostoglandings PgD2 producing a bronchoobstructive action much more strong then histamine does. The typical aspirin-sensitive asthma is most studied. Aspirin inhibits prostaglandin G/H synthase 1 (cyclooxygenase type 1). CLINICAL FEATURES A basic clinical sign of bronchial asthma is an attack of shotness of breath
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because of convertible bronchial obstruction of bronchial tubes due to contraction of smooth muscle, edema of mucous membrane of bronchial tubes and hypersecretion of mucus. The net result is an increase in airway resistance, a decrease in forced expiratory volumes and flow rates, hyperinflation of the lungs and thorax, increased work of breathing, alterations in respiratory muscle function, changes in elastic recoil, abnormal distribution of both ventilation and pulmonary blood flow. During chest examination we can find: o
End-expiratory wheezing or a prolonged expiratory phase is found most commonly, although inspiratory wheezing can be heard.
o
Diminished breath sounds and chest hyperinflation may be observed during acute exacerbations.
o
The presence of inspiratory wheezing or stridor may prompt an evaluation for an upper airway obstruction such as vocal cord dysfunction. Displays of symptoms increase at night or in an early morning.
Symptoms can increase at the physical loadings, viral infections, influence of allergens, smoking, change of external temperature condition, strong emotions, action of chemical aerosols, reception of some medications. Sinusitis, rhinitis, nasal polyposis are preceded aspirin-sensitive asthma. Combination of clinical picture of shortness of breath with unbearableness of aspirin and nasal polyposis is named by aspirin or asthmatic triad. DIAGNOSTICS Diagnosis is based on the presence of special symptoms which characterized by day's and seasonal variability. Thick, stringy mucus, which often takes the form of casts of the distal airways (Curschmann's spirals), when examined microscopically, often shows eosinophils and Charcot-Leyden crystals. The total white blood cell count may be slightly increased during an acute attack, and eosinophilia is common. Pulmonary function tests reveal abnormalities typical of obstractive dysfunction, and partial reversibility (improvement FVC or FEV1
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of at least 12% or improvement in FEF 25-75 of at least 25%) is often demonstrated after an inhaled bronchodilator is administered. An allergist inspection includes: -
collection of allergist anamnesis (presence at patient of eczema, seasonal or whole-year allergic rhinits, food or medicinal allergy, and also BA and atopic diseases of his family members). U should ask about respiratory diseases, age of sick in the moment of beginning disease, seasonality, improvement of the state of house or at work, concomitant diseases).
-
Total serum immunoglobulin E levels greater than 100 IU are frequently observed in patients experiencing allergic reactions, but this finding is not specific for asthma and may be observed in patients with other conditions (eg, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome).
-
Allergy skin testing is a useful adjunct in individuals with atopy. The allergens that most commonly cause asthma are aeroallergens such as house dust mites, animal danders, pollens, and mold spores. Two methods are available to test for allergic sensitivity to specific allergens in the environment: allergy skin tests and blood radioallergosorbent tests (RAST). Allergy immunotherapy may be beneficial in controlling allergic rhinitis and asthma symptoms for some patients.
-
Methacholine- or histamine-challenge testing o
Bronchoprovocation testing with either methacholine or histamine is useful when spirometry findings are normal or near normal, especially in patients with intermittent or exercise-induced symptoms. Bronchoprovocation testing helps determine if hyperreactive airways are present, and a negative test result usually excludes the diagnosis of asthma.
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Differential diagnosis The differentiation of asthma from other diseases associated with dyspnea and wheezing is usually not difficult, particularly if the patient is seen during an acute episode. A personal or family history of allergic diseases such as eczema, rhinitis, or urticaria is valuable contributory evidence. Recurrent episodes of bronchospasm can occur with carcinoid tumors , recurrent pulmonary emboli , and chronic bronchitis. In chronic bronchitis there are no true symptom-free periods, and one can usually obtain a history of chronic cough and sputum production as a background on which acute attacks of wheezing are superimposed. Eosinophilic pneumonias are often associated with asthmatic symptoms, as are various chemical pneumonias and exposures to insecticides and cholinergic drugs. Bronchospasm is occasionally a manifestation of systemic vasculitis with pulmonary involvement. Differential diagnostics of COPD and BA Sign
COPD Not characteristic Periodic or permanent Permanent
BA characteristic paroxysmal Attacks of expiration
Daily allowance changes
Less than, than 10% from
shortness of breath More than 12% from
of FEV1 Bronchial obstruction
normal Making progress decline
normal There is not a making
of function of lungs
progress decline of
Allergy Cough Shortness of breath
function of lungs, convertibility is Eosinophilia of blood and
Not characteristic
characteristic Characteristic
sputum CLINICAL CLASSIFICATION
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Intermittent asthma: 1. Intermittent symptoms occurring less than once a week 2. Brief exacerbations 3. Nocturnal symptoms occurring less than twice a month/ 4. Asymptomatic with normal lung function between exacerbations. 5. FEV1 or PEF rate greater than 80%, with less than 20% variability Mild persistent 1.Symptoms occurring more than once a week but less than once a day 2.Exacerbations affect activity and sleep 3. Nocturnal symptoms occurring more than twice a month 4. FEV1 or PEF rate greater than 80% predicted, with variability of 20-30% Moderate persistent 1. Daily symptoms 2. Exacerbations affect activity and sleep 3. Nocturnal symptoms occurring more than once a week 4. FEV1 or PEF rate 60-80% of predicted, with variability greater than 30% Severe persistent 1.Continuous symptoms 2.Frequent exacerbations 3.Frequent nocturnal asthma symptoms 4.Physical activities limited by asthma symptoms 5.FEV1 or PEF rate less than 60%, with variability greater than 30% TREATMENT The goals for successful management of asthma include the following: •
Achieve and maintain control of symptoms.
•
Prevent asthma exacerbations.
•
Maintain pulmonary function as close to normal levels as possible There are the followings levels of control: complete, partial, uncontrolled Complete control
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Description Daily symptoms Limitation of activity Nightly symptoms Using of в2-agonists for a removal attacks of shortness of breath FVD acute condition
Control flow not not not not normal indexes not
Drug therapy of BA: – the different ways of introduction of drugs are used: - inhalation - peroral - parenterally. Preparations for treatment BA used protractedly for maintenance of BA control. Most preferable way – inhalation. For rapid relief of symptoms short-acting beta-agonists are used . Sometimes more expressed positive answer is observed from short-acting cholinergic antagonist. Drugs
Dose (mcg)
Duration of action
short-acting beta-agonists: salbutamol (Ventolinum),
100
4-6
Fenoterol (Berotek). short-acting cholinergic antagonist:
100
4-6
20, 40
6-8
Ipratropiya bromide (Ipravent) Combined drugs (short-acting beta-agonists + short-acting cholinergic antagonist: Fenoterol + Ipratropiya bromide (berodual) salbutamol + Ipratropiya bromide () Inhaled Glucocorticoids
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These drugs are indicated in patients with persistent symptoms. These drugs share the ability to control inflammation, facilitate the long-term prevention of symptoms, reduce the need for oral glucocorticoids, minimize acute occurrences, and prevent hospitalisations. Drugs Beklometazon (Beklofort, Beklazon) Budesonid (Budekort) Flutikazon (Fliksotid) Mometazon (Asmaneks)
Dose on inhalation 200-500 mcg 200-400 mcg 100-250 mcg 200-400 mcg
The most high type of safety and low system biotavailability is marked at Flutikazon and Mometazon. Cromolyn sodium and nedocromil sodium-their major therapeutic effect is to inhibit the degranulation of mast cells, thereby preventing the release of the chemical mediators of anaphylaxis. Long-acting inhaled β2-agonists should not be used for symptom relief or for exacerbations. Use only with inhaled glucocorticoids.
Long-acting inhaled β2-agonists Drugs
Dose (mcg)
Duration of action
Long-acting inhaled β2-agonists Salmeterol
(Serevent)
Formoterol (Zafiron) Long-acting cholinergic antagonist Tiotropiya bromide (Spiriva)
25, 50
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4, 12
12
18
24
Combination beta-agonist/corticosteroid Inhaled combination medication used frequently in the treatment of asthma consists of a long-acting beta-agonist and inhaled corticosteroid .
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SERETID (salmeterol +fluticasone) has dosages 50/25, 125/25, 250/25. Simbikort (Budesonid + Formoterol) – 200/ 4 There are different deliverable devices – evohaler, дискус, твист-халер, турбухалер, easy breathing. It is better to appoint the high doses of inhalation steroids through spacer (demonstration). Modern deliverable device is NEBULAYZER (nebula means fog). With their help it is possible to inhale long and short acting beta-agonists, inhaled glucocorticoids. Glucocorticoids are the most potent and most effective anti-inflammatory medications available. Systemic steroids are most beneficial in acute illness, when severe airway obstruction is not resolving, and in chronic disease, when there has been failure of a previously optimal regimen with frequent recurrences of symptoms of increasing severity. A preference gives to prednisolone (5 mg=1 tab.) or to Methylprednisolone (4 mg = 1 tab.)
METHYLXANTHINES Theophylline and its various salts are medium-potency bronchodilators with questionable anti-inflammatory propertie. For maintenance therapy, long-acting theophylline compounds are available and are usually given once or twice daily. Single-dose administration in the evening reduces nocturnal symptoms and helps keep the patient complaint-free during the day. They are now considered second-line therapy, and as such they are rarely used in acute situations and infrequently in chronic ones. For basic - the long-term control of asthma inhaled glucocorticoids, inhaled glucocorticoids with long-acting beta-agonists, long-acting cholinergic antagonist, systemic steroids, long-acting theophylline, combined short-acting beta-agonists are used. step approach in treatment of bronchial asthma Intermittent
Mild persistent
Moderate persistent
Severe persistent
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asthma A controller
The controller
The controller
The controller
medication is not medication is an
medication is an
medication is an
needed.
inhaled
inhaled corticosteroid
inhaled
The reliever
corticosteroid
(800-2000 mcg) and a
corticosteroid
medication is a
(200-500 mcg),
long-acting
(800-2000 mcg), a
short-acting beta- cromolyn (adult:
bronchodilator (either
long-acting
agonist as needed 2-4 puffs tid/qid;
beta-agonist or
bronchodilator
for symptoms
child: 1-2 puffs
sustained-release
(beta-agonist
tid/qid),
theophylline) A
and/or
nedocromil, or a
combination
theophylline), and
leukotriene
medication of
long-term oral
antagonist. If
salmeteorol/fluticason
corticosteroid
needed, increase
e (Advair) is a
therapy.
the dose of
preferred choice to
The reliever
corticosteroid and improve compliance.
medication is a
add a long-acting
Other agents may
short-acting beta-
beta-agonist or
include leukotriene
agonist as needed
sustained-release
modifying agents or
for symptoms.
theophylline,
omalizumab.
especially for
The reliever
nocturnal
medication is a short-
symptoms.
acting beta-agonist as
The reliever
needed for symptoms
medication is a short-acting betaagonist as needed for symptoms Mucolytic agents are used in symptomatic therapy (group of bromhexine, ambroxole (lasolvan).
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Information on the clinical course of asthma suggests a good prognosis, particularly for those whose disease is mild and develops in childhood. Prophylaxis Primary – individual and social conditions, directed on avoidance of disease- healthy way of life, improvement of house conditions, effective treatment of rhinosinusitis, chronic infection. Second – full and in time treatment of exacerbations, selection of adequate base therapy, treatment of concomitant diseases.