ASTHMA

Definition by GINA (Global Initiative for Asthma)

 Asthma is a chronic inflammatory disorder of airways. Many cells and mediators are
involved in this process – eosinophils, mast cells and T-lymphocytes. Chronic
inflammation is connected with bronchial hyperresponsivness and leads to episodes
of wheezing, coughing, tightness in the chest, breathlessness, shortage of breath
specially at night and in the morning. This episodes are usually connected with
variable obstruction which is reversible spontaneously or by treatment.

Allergic asthma = asthma induced by immunological mechanisms. IgE induced asthma – IgE
antibodies triggers early and late-phase of response, T-lymphocytes late and delayed
responses.

Non-allergic asthma = asthma induced by non-immunological triggers

Intermittent x persistent

Inflammation causes obstruction of airways by

 Acute bronchoconstriction
 Swelling of bronchial wall
 Chronic production of mucous
 Remodeling of airways walls

Risk factors

 Individual predisposition (genetic variability – 5. a 11. chromosome - atopy,

bronchial hyperreactivity, male or female, nation)
 Environment – exposition to allergens and professional chemicals which lead to
sensitivity, viral and bacterial infection, food, smoking, social and economic society,
number of family members, psychosomatic influence

Inflammation

Remodeling of Chronic
Acute inflammation
airways inflammation

Symptoms Ongoing obstruction of Exacerbation

of bronchoconstriction airways nonspecific
hyperreactivity

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Therapy and obstruction

 Changes of ventilation parameters exist in patients with proper anti-inflammatory

therapy

 the obstruction of airways is not proven in all asthmatic patient.

Remodeling

 Destruction of brush epithelium in airways

 Swelling of the bronchial wall
 Stimulation of proliferation of fibroblasts
 Deposition of collagen in lamina reticularis of basal membrane
 Hypertrophy of smooth muscles
 Hyperplasia of goblet cells

The process of remodeling is involved by

 Th2 lymphocytes (CD25+, production of IL-4,13,5,6,10)

 Antigen presenting cells
 Mast cells (tryptase-converting  angiotensin I to angiotensin II, hypertrophy of
smooth muscles, histamin – fibrogenetic effect)
 Eosinophils long-living in epithelium and submucoses, create lipids –PAF, LTC4,LTD4,
LTB4, peptides, cytokines, TGF-α, TGF-β, IL-1,3, GM-CSF, ECP)
 Alveolar macrophages (production of TNF-α, IL-6)
 Epithelial cells (desquamation of epithelium, lost of integrity, TGF-β, IGF-1, KGF- β,
alteration of differentiation and proliferation of epithelial cells, apoptosis)
 Endothelial cells
 Myocytes (proliferation of myocytes - after stimulation with IL-11, which is produced
by mezenchymal cells after stimulation with allergen, PGDF, EGF, the effect of
gelatinase A (MMP-2) and B (MMP-9), production of IL-6,8, eotaxin, PGE2, RANTES,
MCP-1,2,3, expression of ICAM-1, VCAM-1, production of NO, GM-CSF, IL-5)
 Fibroblasts (activation of fibroblasts, creation of myofibroblasts, release of GM-CSF
and TGF-β, increasing pro-inflammatory activity of eosinophils)

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 Pathogenetic process of inflammation

Increasing Increasing Ongoing of Release of Elastolysis

number of number of inflammatory fibrogenetic
smooth muscles mucous glands cells factors
fibres

Sever Increase of mucous Inflammation Deposition of Decrease of

bronchospasms secretion during collagen in basal elasticity of the
during exacerbation and epithelial wall
exacerbation
membranes

Pathophysiological and clinic consequences

 In some patients the grade of remodeling not necessarily correlates with bronchial
hyperreactivity
 Remodeling correlates with plasma level of eosinophils, but does not correlate with
the grade of bronchial hyperreactivity nor with period and severity of asthma
 Long period of asthma is connected with collagen and fibronectin deposition and
with lowering of bronchial hyperreactivity
 Decrease of FEV1 although the proper therapy
 No correlation between thickening of the reticular membrane and the period of
asthma and decrease of FEV1 in adults

Classification of asthma

A. Atopic (allergic) asthma

 In combination with allergic rhinitis, atopic dermatitis, genetic predisposition
 Confirmation of spec. IgE antibodies, prick tests, inhalation challenge
B. Endogenous asthma
 Without specific known influence, obviously in women after exposition to cold
weather, refract to the standard therapy
C. Exercise induced asthma
 Physical exercising, provocation by inhalation of chemicals, cold or hot weather
D. Aspirin induced asthma
 typical triads-nasal polyps, urticaria and asthma induced by application of aspirin
other drugs

E. Allergic bronchopulmonary aspergillosis

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  aspergillus acts as an allergen challenge in atopic people and induces aspergillus
asthma or alergic bronchopulmonary aspergillosis
 in the chest radiography are intermitent infiltrates in lungs, the viscosity of
mucous is increased and mucous plugs, bronchiectasia
F. Gastroesophageal reflux
 Bronchospasm induced by reflex
G. Sinobronchial syndrome
 Combination of sinusitis with nasal polyps and with asthma
H. Professional asthma
 Induced by inhalation and exposition to industry chemicals
I. CH. Asthmatic equivalent
 Dry cough, irritating, without breathlessness

Classification of asthma severity

Step 1. Intermittent asthma

 Rare symptoms < than 1x per week, short episodes of worsening

 Night symptoms 2x monthly
 No symptoms between attacks
 PEF or FEV1 > 80%, variability < 20%

Step 2. Mild persistent asthma

 Symptoms <1x per day >1x per week

 Night symptoms > 2x per month
 Exacerbation can affect daily activity or sleeping
 PEF or FEV1 > 80%, variability 20-30%

Step 3. Moderate persistent asthma

 Everyday symptoms
 Exacerbation affects daily activity and sleeping
 Night symptoms > 1x per week
 Everyday use of releasing drugs
 PEF or FEV1 between 60- 80%, variability > 30%

Step 4. Severe persistent asthma

 Continuous symptoms
 Frequent exacerbation
 Physical activity is decreased
 Frequent night symptoms
 PEF or FEV1 < 60%, variability > 30%

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Examination methods

History

 Variable – seasonal, diurnal, exercise

 Breathlessness, cough, wheezing, rhinitis
 Physical examination – normal, hyperinflation with sounding se percussion,
prolonged breath-out, dry phenomenon, pulsus paradoxus, running of
supraclavicular area, silent lungs

Spirometry

 Diagnosis, to monitor treatment, estimation and prevention, examination before an

operation
 basic– searching – PEF (Peak Exspiratory Flow)

The Highest−The Lowest ×100

PEF=
0.5 ×(The Highest +The lowest)

 FVC, FEV1, FEV1%FVC

 Enlarged – spirometry, curve of flow-volume, bronchial challenge tests
 puls oxymetry, rhinomanometry
 Pletysmography
 Referential method for measuring of resistance, breathing work, compliance
and DLCO
 Isotherm conditions, two phases- measuring of intrathoracal volume of gas
and measuring of airways resistance
 Bronchomotoric challenge
 bronchodilatation test – test of reversibility of bronchial obstruction
 Salbutamol 200-400 ug, ipratropium 80 ug
 Bronchoconstriction test – bronchial hyperreactivity
 Histamine 1g na 100 ml of 0,9% NaCl, methacholin, acetylcholin, adenosin-5-
monofosfát, hypertonic NaCl
 RTG
 Normal, hyperinflation
 Bronchoscopy
 Endobronchial biopsy – submucosis
 Bronchoalveolar lavage – phenotypic differentiation from peripheral blood,
express CD69
 Induced sputum
 Hypertonic NaCl
 Number of eosinophils in sputum corresponds to bronchial biopsy and BAL

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  ECP
 ECP levels in induced sputum corresponded to symptoms score and inversely
proportional to PEF.
 Significant inflammation –15 µg/l, compensation of asthma - 23 µg/l
 Measuring of breath-out condensated gas
 LTB4, cysteinyl leukotrienes, NO –increased in untreated patients, dependent
on flow, lower flow-higher NO, constantly 50 ml/s
 Low production of NO in cilia dyskinesis, cystic fibrosis, correlation with
findings in biopsy and eosinophils in sputum
 Blood gases

Asthma - Introduction (Cont.)

Drug therapy

ê Airway Inflammation ê Bronchospasm

Glucocorticoids β Adrenergic receptor agonist

Leukotriene inhibitors Methylxanthines
Chromones Muscarinic receptor antagonist
IgE inhibitors

Prophylaxis prevention Symptomatic relief

Long-term (controller medications) Short-term

Basic Pharmacology
Sympathomimetics- Use in Asthma

Adrenoceptor agonists (b2-selective agents preferred)

Short-acting Long-acting
(2-6 hrs) (>12 hrs)
Very lipophilic (persistent membrane
contact)

Symptomatic relief Prophylactically in combination with steroid

Albuterol (Proventil, etc.) Salmeterol (Serevent)

L-albuterol (Xopenex) Formoterol (Foradil)
Metaproterenol (Alupent)
Terbutaline (Brethaire)
Pirbuterol (Maxair)

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Short-Acting Beta2-Agonists

 Most effective medication for relief of acute bronchospasm

 More than one canister per month suggests inadequate asthma control
 Regularly scheduled use is not generally recommended
 May lower effectiveness
 May increase airway hyperresponsiveness

Long-Acting Beta2-Agonists

 Not a substitute for anti-inflammatory therapy

 Not appropriate for monotherapy (sometimes OK with mild asthma)
 Beneficial when added to inhaled corticosteroids
 Not for acute symptoms or exacerbations

Inhaled Corticosteroids

 Most effective long-term-control therapy for persistent asthma

 Small risk for adverse events at recommended dosage
 Reduce potential for adverse events by:
 Using spacer and rinsing mouth
 Using lowest dose possible
 Using in combination with long-acting beta2-agonists
 Monitoring growth in children

Older Adults: Special Considerations (continued)

 Systemic corticosteroids can provoke confusion, agitation, changes in glucose

metabolism
 Inhaled corticosteroids
 May be associated with dose-dependent reduction in bone mineral content
 Treat concurrently with:
 Calcium supplements and
 Vitamin D and, when appropriate,
 Estrogen replacement

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Basic Pharmacology
Cromolyn (Intal) and Nedocromil (Tilade)

 Extremely insoluble salts: inhaled as metered-dose aerosol or microfine powder

 Prophylactic only
 Prevent both antigen- and exercise-induced mild to moderate bronchial asthma
 Reduce bronchial reactivity (chronic application)
 no direct effect on smooth muscle tone

Stepwise Approach to Therapy: Gaining Control

STEP 4
SEVERE PERSISTENT

STEP 3
1 MODERATE PERSISTENT 2

1. Start high and

STEP 2 step down.
MILD PERSISTENT 2. Start at initial
level of Severity;
STEP 1
MILD INTERMITENT

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Clinical Summary

 Mild (intermittent)
 Bronchodilator :used acutely to reverse bronchospasm = “as needed basis”
 Preferred: Short acting (SA) β2- agonist
 Mild (persistent)
 Antiinflammatory drugs to quell bronchial inflammation
 Inhaled steroid if persistent or exercise induced asthma
Can consider chromones but steroids have better outcome
Can consider leukotriene inhibitor
 Bronchodilator as needed
 Moderate (persistent)
 Bronchodilator: “as needed basis”
 Preferred: short acting β2 – agonist
OR long acting β2 if poor control with combo s.a. β2 + steroid
OR if poor control with combo try theophylline in combo
OR in combination with muscarinic antagonist with more
moderate asthma or COPD
 Anti-inflammatory:
 Preferred: Inhaled glucocorticoids
Or a chromone if nonresponder to steroid, want to reduce
steroid dose when used in combination, or when clear cut
inciting stimulus is known
OR leukotriene inhibitor if mild asthma
 Severe Asthma
 Above combinations +
 Short course of oral steroids
 Omalizumab

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Drug List

 Bronchodilators
 Sympathomimetics
 Epinephrine, ephedrine
 Beta 2 – selective agonist
Albuterol (Proventil, etc.)
L-albuterol (Xopenex)
Metaproterenol (Alupent)
Terbutaline (Brethaire)
Pirbuterol (Maxair)
Salmeterol (Serevent)
Formoterol (Foradil)
 Methylxanthine
Theophylline
Caffeine
Theobromine
 Muscarinic antagonist
Ipratropium (Atrovent)
Tiotropium
 Antiinflammatory
 Glucocorticoids
Beclomethasone (Beclovent, etc.)
Triamcinolone (Azmacort)
Flunisolide (AeroBid)
Budesonide (Pulmicort)
Fluticasone (Flovent)
 Leukotriene inhibitors
Zileuton (Zyflo)
Zafirlukast (Accolate)
Montelukast (Singulair)
 Chromones
Nedocromil
Cromolyn
 Anti-IgE
Omalizumab (Xolair)

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