Asthma Lecture 5

Definition of Asthma

chronicinflamatory syndrome of the airways, Involving several cells(eosinophils, limfocytes, macrophages,

mastocytes, epithelial, smooth m cells etc), citokynes and mediators. with increased airway responsiveness resulting in
symptoms such as wheeze, cough and dyspnoea, and airways obstruction which is variable over short periods of time or reversible with
treatment.

-apearing ingenetically susceptible individuals

-Bronchial obstructionreversible partially/completely, spontanously/under treatment

-BHRto various factors

Syndrome
etiopathogenic types
-extrinsic (alergic)

-intrinsic (possibly intricated with COPD)

-sensitive to nonsteroid antiinflamators

-profesional

EPIDEMIOLOGY
Factors influencing prevalence

Air polution (Romania)

intensive polution 12,4 %
rural population 3,3 %
most incriminated polutants: chemical volatile

age
maximal prevalence beetween 1-17 years and 45-64 years
asthmatic children present in 50 % of cases a full remission of de symptoms at puberty

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Hypothetical Representation of the Natural History of Asthma

Asthma
-Heterogeneous condition
-Lack of well-defined markers for the different disease phenotypes grouped under this common label
-Most cases of persistent asthma start in early life (first 5 years of life)

Natural history
-Many children have asthma-like symptoms during viral infections in the preschool years
-Most are transient conditions that subside with age
-Only a minority will have persistent asthma
-Hard to distinguish who will develop asthma

Respiratory syncytial virus:

is a virus that causes respiratory tract infections. It is a major cause of lower respiratory tract infections and
hospital visits during infancy and childhood. A prophylactic medication (not a vaccine) exists
for preterm (under 35 weeks gestation) infants, infants with certain congenital heart defects (CHD)
or bronchopulmonary dysplasia (BPD), and infants with congenital malformations of the airway. Treatment is
limited to supportive care (for example C-PAP), including oxygen therapy.

RSV lower respiratory tract illness was associated with:

-significantly lower measurements of FEV1

-an increased risk of wheeze by the age of 6 (risk decreased with age and became not significant by the age
of 13)

There was no association between RSV lower respiratory tract illnesses and subsequent atopic status

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Phenotypes of wheezing in childhood

Transient wheezing in infancy

Most frequent form of recurrent airway obstruction in infancy (2/3 of infants with asthma-like symptoms)

Predisposing factors
-Maternal smoking during pregnancy
-Lower levels of lung function in the first months of life

Remission factors –unknown (growth of the airways/changes of airway tone?)

Development of asthma
-Inverse relationship between duration of symptoms and level of lung function in school-age children with
asthma1
-Sensitization to local aeroallergens is strongly associated with increased risk of asthma in adult life

Asthma between school years and mid adult life is associated with:
-Sensitization to local aeroallergens
-Elevated total circulating IgE
-Both1
Hypothesis -Sensitization to specific allergens (early life) is the cause of asthma (IgE specific)

-Children with skin-test negative to Alternaria develop asthma-like symptoms in the first year of life
-Children with skin-test positive to Alternaria have peak incidence of asthma-like symptoms at age 2-3

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In both groups –inception of symptoms before age 3
-Non-atopic asthma develop earlier than atopic asthma (different mechanisms)

-Increasing prevalence of pediatric asthma

-“Western” environmental pro-asthmatic factors

-Studies performed in low exposure to house dust mites areas –prevalence of asthma is similar or higher than
in areas with high exposure1

-N. Sweden (low indoor exposure to dust mites/molds ) –similar prevalence of school-age asthma with S.
Sweden (high exposure)2

-Skin-negative children with asthma have higher IgE than non-asthmatic2

Outcome of asthma in adult life

-Asthma remits in early adulthood in a large proportion of patients (~50%)

-Most children with severe symptoms will develop severe symptoms in adulthood

-Most children with mild symptoms will develop mild/no symptoms in adulthood

-Allergic symptoms (rhinitis, eczema) are associated with persistence of asthma into adult life

-Factors associated with relapses of asthma in adulthood with symptoms remitted during teenage period –
unknown (appears to be independent of allergies and smoking)1

-Smoking2produces an excessive rate of decline of FEV1 (overlap asthma –COPD)

MORTALITY
UK, 1982 aparent higher prevalence of deaths among asthmatics by comparison with 1970 (>2 folds)

ANALYSIS of the deceased: 86 % of the cases could be prevented!!!

-current physicians: were not able to appreciate the severity of the cases

-patients noninformed upon their disease

-Insuficient use ofantiinflammatory drugs

-Asthmatics with life threatening forms have to be identified and actively treated and medically surveyed

-1998 for first time the mortalitaty in BA is comparable with the general population

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Social impact
-USA there are 15 millions asthmatics
-In Romania there are 1 million asthmatics!
-Major cost of drugs
-Major costof frequent hospitalizations
-Major social economic cost by losing working days

Pathology: chronic inflammation of the airways

Postmortem studies

Macro: distended lungs , circumscribed atelectasia by mucous plugs that were obstructing subsegmentary
bronchi.

Micro: important thikening of the bronchial wall (edema, glandular hiperplasia, thikening of the basal
membrane, thikening of the smooth muscle cell layer, important cellulear inflammatory infiltration especially
with eosinophils and lymphocytes); extensive necrosisof the bronchial epithelium with mucosal uncovering.

bronchial biopsy:microscopic features met in postmortem studies were found even in mild and medium
severe forms of asthma and even during clinical remission

broncho-alveolar lavage (BAL): a method able to identify and characterize the cells and the mediators
involved in asthmatic inflammation

Asthmatic inflammation: involved cells

Bronchial asthma is a disease determined by an immune pathological mechanism, IgE mediated (group l Gell -
Coombs)

-All the cells involved in the chain of the immune reactions will be also active in bronchial asthma

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Cellular mechanisms in BA Mecanisme celulare in AB

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CONCLUSIONS
1.Chronic inflammation: eosynophils

2.Different inflamatory profile as in COPD, Bronchiectasis, Infectious bronchitis

3.Maximal therapeutic effect: corticosteroids

4.Antibioticotherapy: not indicated

Bronchial Remodeling–Bronchial Hiperreactivity

-Bronchial asthmatic remodeling: morphologic global consequences of chronic inflammation

-The physiopathological consequence of br. remodeling: br. Hyperreactivity

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 BRONCHIAL HIPERREACTIVITY
Definition: the ability of the bronchi to decrease their diameter to stimuli that are usually indifferent

Types of stimuli:

1. Physical: Low temperature, effort

2. Chemical: NO2, SO2, ozone, chlorine, NH3

3. Infectious: respiratory viruses

4. Air polutants: smoke, gases, volatiles

5. Vagal reflexes, psychological negative stimuli

Bronchial remoddeling -BHR

Bronchial progressive fibrosis –late asthma evolution

-Progressive fibrosis of the extra cellular matrix of bronchial wall

-Determines a partially irreversible chronic obstructive sindrome

Relation INFLAMMATION-BHR-SYMPTOMS

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CONCLUSIONS
-Chronic inflammation induces hyperreactivity

-Severe hyperreactivity induces symptoms

-Controlling symptoms means diminishing inflammation

-Viral infections can trigger asthmatic exacerbations (but asthma is not an infection!)

Risk factors in asthma

RF for appearance of the disease:
-predisposition: atopy

-causal: alergens, non-steroid antiinflamatory drugs, work related molecules

-adjuvant: respiratory infections, air polution, smoking (active and second hand)

RF for enhancing the disease: triggers

Risk factors: significance

NOT SCHOLASTIC AB classification
-alergic/extrinsic,

-professional,

-NSAI related,

-intrinsic,

BUT PRAGMATICAL
-Systematic search for a causal factor in the patient’s enviroment

-Build up efficient therapeutic strategies

Allergens
Indoor:
-mytes (main cause for sensitisation)

-animal allergens (cats –high amount of sensitisation, dogs, rodents)

-cockroaches (main cause in some areas)

-fungi

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Outdoor:
-pollens (trees, grass, and ??)

-fungi

ASTHMA DIAGNOSIS
-Asthmatic symptoms

-Physical exam signs of obstruction/hyperinflation

-Variable obstructive syndrome confirms the diagnosis

-Atopy

-Family history

-Identifying causal factors and triggers (interview and prick tests)

Asthmatic symptoms
1-Dyspneea
-Usually dominant, rarely absent

->/< paroxystical

-expiratory

2-Wheezing
-Usually associated with dyspneea

-relatively specific

3-Cough
-rarely dominant, usualy associated to dyspneea

-Dry, non productive, (purulent sputum could be induced by excessive eosynophils)

-sometimes severe

4-Chest tightness
-Associated with dyspneea

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Variable:
-Associated with trigger factors

-Spontaneously or therapeutically improved

-Nocturnal predominance or As a consequence of a trigger (effort

Clinical behaviour of asthmatics

1-Asthmatic crisis

2-Asthmatic exacerbation

3-Continuous symptoms

4-Coughing asthma

Physical examination
-Respiratory rate: normal or mildly enhanced

-Signs of bronchial obstruction:

 Prolonged exhalation (involving the auscultation)

 Diffuse wheezes

 Diffuse diminishing of breath sounds (severe obstruction)

-Hyperinflation signs: increased thoracic diameters (anterior and posterior)

-May not be present –normal physical exam doesn’t exclude asthma

Variable obstructive syndrome –Pulmonary function tests

Spirometry:
-FEV1 (Forced Expiratory Volume in the first second)

-VC (Vital Capacity)

-calculating VEMS/CV% ration (bronchial permeability index)

-Peak-flow-metry

PEF (Peak Expiratory Flow)

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Measuring PEF (peakflow-metry)
-Simple, Available and cheap, Relatively accurate,

depends by:

 Patient effort (ideally maximum)

 Reliability of the technique

Enhanced by:
repeating the measurement

ideal for measuring pulmonary function In the GP office & At home by the patient

Variable Obstructive Syndrome-PEF assessed

-Improvement of PEF by more than 15% at 15-20 (max. 30) minute after bronchodilation (a short acting 2
agonist)
-Variable PEF more than 20% morning/evening and taking a bronchodilator (or more than 10% without taking
a bronchodilator)
-Reduction of PEF with more than 15% at 5-10 minutes after an effort (running) of 6 minutes

PEF chart

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Spirometry
-FEV1, VC si FEV1/VC = most validated functional respiratory parameters

-Necessitates a trained staff

-Relatively expensive and less achievable

-Very important for diagnosis and for follow up

Spirometry Obstructive syndrome:

-FEV1 < 80% of predicted
-VEMS/CVF < 70%
-Reversible after a short acting beta2 agonist
-Improvement of FEV1 by more than 15% vs the initial value

Asthma DIFFERENTIAL diagnosis

1. Bronchoconstriction after viral infectious events

2. Reactive airway disease (RADS)

3. COPD

4. Left ventricle failure

5. Sleep Snorring Apnea (SAS)

6. Benign tracheal tumors

7. Diskynetic vocal cords

8. Anxiety (Tachipnea)

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 Bronchial asthma therapy
1. Patients education

2. Evviction of the allergens

3. Antiasthmatic drugs

4. Therapeutic strategy

5. Treating the exacerbation

6. Life-threatening asthma

1. Educating The Patient establishing a partnership with the patient

Ability to assess and to manage a long-term therapy

-Treating an asthmatic doesnt’comprise an isolated medical gesture

-A chronic disease needs a LONG-TERM MEDICAL ASSISTANCE

-The Physician should represent aPartner/Manager of the Asthmatic patient

First consultation: arguing the diagnosis

-establishing an optimal COMMUNICATION With the patient

-EVALUATION OF THE PSICHOLOGIC Profile

-Level of education: optimal communication

-Degree of interest of the patient in his disease?

-Atitude facing the disease: Depression?Anxiety?

EDUCATING the PATIENT

-Asthma is a chronic diseasebut with an adequate therapy PATIENT’s LIFE could be NORMAL

-Therapy must be understood

-Patient’s compliancefor a long-term therapy

-Good connection Patient/Physician

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-Main objective of the Physician: providing an AUTONOMYto the Patient

Teaching the Patient

-Correct administration ofthe drugs

-Understanding the difference between a “reliever” and a “controller”

-Avoid triggering factors

-Ability to correctly evaluate his clinical state(using peakflowmetry)

-Recognizing signs of clinical worsening

-Asking correctly for help if NEEDED

-Don’t panic!

2. Eviction of the allergens

-Avoid contact with the places previously inducing crisis

-Especially important in professional asthma

-Useless to elliminate pets

-Avoid presence of pets in the bedroom

-Encase bedding in impermeable covers

3. ANTIASTHMATIC DRUGS
-Antiasthmatics
-Controller (control) -Reliever (symptoms)

Antiasthmatics-”controller”
1. Inhaled corticosteroids

2. Systemiccorticosteroids

3. Theofylline

4. Long acting Beta 2 agonists

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 5. Leukotrienemodifiers

6. Anti-IgE

Antiasthmatics-”reliever”
1. Short acting Beta 2 agonists
2. Systemic corticosteroids
3. Short acting Anticholinergics

Significance of the“controller”
-Daily scheduled medication

-Long term therapy; long term control of the disease

-Antiinflammatory agents; allergy blocking agents. Most powerfull agents.

-Active in secondary prophylaxis

-Unable to instantly influence symptoms

Significance of the ”reliever”

-Immediate effect

-Demand administration

-Basic strategy for cutting symptoms

-Short time of action

Inhaled corticosteroids “controller”

A. Beclometasonedipropionate

B. Budesonide

C. Mommetasone

D. Fluticasone propionat

E. Cyclesonide

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-Most important class of “controllers”

-Most active antiinflammatory effect

-Targeting proinflammatory cells, cytokines, mediators etc.

-Improve the Beta 2 agonist effect

-Airways topic effect as a consequence of the inhaled way of administration

-Aerosols MDIor new devices asTurbuhaler,Discushaler,etc

-Excellent tolerance: unjustified anxiety

-Virtuallyeficientindependently of the age or severityof the disease

-Improving: symptoms, hyperreactivity, exacerbations, hospitalizations, mortality

-Improving: function; preventing airways narrowing

-Sparring the necessity of oral corticosteroids

-Reversible effects after tappering

Inhaled corticosteroids: side effects

Local side effects

-dysphonia, hoarseness

-Oropharyngeal candidosys

-pharyngitis

Dependent of: dosage,sensitivity, local deposition

Reduced by: spacer,washing the mouth

NO SYSTEMIC SIDE EFFECTS

Systemic corticosteroids
Orally administered

-prednisone,prednisolone,metilprednisolone,etc.

-Minimal mineralocorticoid effects

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Parenterali.m.,i.v.

-metilprednisoloneetc.

-Hydrocortisone hemisuccinate

Powerfullantiinflamatory activity, Similar ways of action with inhaled cstds

Significant side effects: on long term therapy: metabolic (diabetes, proteic catabolism), digestive,
osteoporosis, immunodeficiency, HTA, cataract, suprarenal suppression, psychological, femoral necrosis,
obesity

Indications:

-Asthma exacerbations

-Short term “induction” therapy

-Long term therapy of severe asthma (step V) corticosteroid-dependent patients

Posology: 0,5-1 mg/kgc/day <40 mg/day

Theophylline
-Modest antiinflamatory activity

-Potentiate the antiinflammatory effect of corticosteroids (reversing cstds resistance)

-Bronchodilator effect

-Improving bronchial hyperreactivity

-Improving diaphragmatic contractility

-Oral administration

-Posology: 10 mg/kgc/day Less than 600 mg

-Plasma concentration: 5-15 g/ml

-Closed toxic amount with therapeutic amount

Side effects: frequent nausea, vomiting, headache, tremor, digestive insomnia, psychological, tachicardia,
cardiac arrhytmia etc

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 Long acting Beta 2 agonists (LABA)
Salmeterol

Formoterol

-Administration: Inhaled

-Timing of action: 12 h Administered 2 times/day

-Very potent bronchodilators

-Administered mandatory in association with corticosteroids

-Formoterol starts its action in 2-3 min; possibly to be administered as a “releaser”

-Late onset of action for Salmeterol

Leukotriene modifiers ”controller”

Relatively new class of drugs
-Montelukast
-Zafirlukast

Action: Blocking of leukotrienereceptors

-Inhibition ofbronchoconstriction

-Reducing the efect ofallergens, effort,cold airandNSAI

-Less antiinflamatory effects than cstds

-Anti-eosinophillic effect

Oral administration, Easy to administer

-Montelukast-1tablet/day10 mg

-Zafirlukast-2 tablets

-NO side effects

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Clinical indication:

1-Mild asthma and in association for more severe asthma

2-Asthma associated with chronic allergic rhinitis and tobacco smoking

3-Respondent patients evident in the first weeks of treatment

Short acting Beta 2 agonists (SABA) -”relievermedication”

-Salbutamol(albuterol)

-Fenoterol

-Terbutaline,etc

Doses:

 Stable asthmaminiman doses 100-200 g

 Asthma experiencing severe obstruction -4000 g–up to 20 puffs
 Dose-response relationship
 Administration as needed
 Tendency to overdose

Very good tolerance–may induce tachyphylaxis

Counterindicated: severe rhythm disturbances
Adverse effects: tremor, tachycardia,palpitations,restlessness
-Hypokaliemia
-Hypoxia (vasodilation)
-May aggravate asthmaat very large doses

Oral Beta 2 agonists have similar side effects, like cardiovascular stimulation, tremon, hypokalemia,
irritability and restlessness, but they can be more significant than for other therapies

They are indicated for patients who cannot use inhaled therapy

-Given prior to exacerbating stimuli-effort,contact with allergen, Immediate relief of symptoms

-Marker of severity (possibleincrease in morbidity, mortality)

-I.V–severe asthma –possibility of death

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Conclusions:

-There is not incompatibility with long acting beta 2 agonists (LABA)

-Pacient’sanxiety regarding inhaled medication is unfounded, when balanced against the effects of parenteral
corticotherapy

Systemic Corticoids-i.v.”reliever”
Mode of action –effects of systemic corticotherapy

-i.v.administration

Dose-200 mg every 4-6 h-hemisuccinate

-100 mg la 6 h –methylprednisolone

Anticholinergics-”reliever”
-Ipratropium bromid(20/40/ g/puf)

-Oxitropium bromid(100 g/puf)

-Association withfenoterol

Uses: nocturnal asthma

In severe asthma, may be used as an alternative to beta 2 agonists

When using large doses of inhaled corticosteroids –additional effects

The elderly –differential diagnosis with COPD

Conclusions:

-Bronchialasthma does represent an elective indication

-Sometimes advantageous to administer concomitantly with beta 2 agonists

-Less efficacious in chronic asthma, acuteasthma

Short acting i.v.theophylines -”reliever”

Mechanism of action: similar to theophylines
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Effects: a lot faster

-Weaker BronchodilatorEffects than beta 2 agonistsFluctuations of serum concentrations

Therapeutic strategy
Control of symptoms, not the cure of asthma
-Minimal symptoms (nocturnal)

-Minimize exacerbations

-Decrease frequency of Emergency Unit Visits

Stepwise treatment in light of disease

Severity Criteria for the change of therapeutic step

Step down
treatment visit at 3-6 months
if symptom cntrol is optained for more than 3 months a step down therapy may be proposed

Step up
if symptom control is not obtained
before everything else: verify if the medication is correctly administered by the patient, the patient‘s
compliance to treatment and check for potential enviromental triggers

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