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ASTHMA
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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
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Asthma Prevalence:
One of the most common chronic disease, affectsapproximately 300 million people worldwide
The greatest increases in asthma prevalence haveoccurred in countries that have recently adopted anindustrialized lifestyle
All ages , predominantly early life with a peak age of 3years
Adults: 10-12% population
Children 15% population2:1 male/female preponderance in childhood but by
adulthood the sex ratio has equalized
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Asthma Types
Extrinsic (atopic, allergic) asthma
Intrinsic (non-atopic, idiosyncratic) asthma
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Extrinsic (atopic, allergic) asthma
Most common type
Begins in childhood or in early adult lifePatients have family history/personal (rhinitis,
urticaria, eczema)
Hypersensitivity to allergens is usually present
Increased IgE concentration in serum (initiatingacute immediate response and a late phase
reaction)
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Intrinsic (non-atopic) asthma
Appears in approximately 10% cases
This patients have later onsetasthma andhave concomitant nasal polyps and may be
aspirin-sensitive
Negative skin tests to common inhalant
allergensNormal IgE concentration in serum
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Risk Factors Involved in Asthma
Host Factors:Genetic predisposition
Atopy
Airway hyperresponsivenessGender
Race
Environmental Factors:
Indoor allergens
Outdoor allergens
Occupational sensitizers
Passive smoking
Respiratory infections
Air pollution
Socioeconomic factors
Family size
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The 2007 Expert Panel Report 3 (EPR-3) of the National AsthmaEducation and Prevention Program (NAEPP) noted several key
changesin pathophysiology of asthma:
The critical role of inflammation + considerable variability in the patternof 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
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Asthma Pathophysiology
The pathophysiology of asthma is complex
and involves the following components:
Airway inflammation
Intermittent airflow obstruction
Bronchial hyperresponsiveness
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Asthma Pathophysiology
Airway Inflammation
The mechanism of inflammation in asthma may be :acute, subacute
chronicSome of the cells involved in airway inflammation include
mast cells, eosinophils, epithelial cells, macrophages andactivated T lymphocytesStructural cells of the airways including fibroblasts,
endothelial cells, and epithelial cells, contribute to thechronicity of the diseaseOther factors such as cell-derived mediators influence
smooth muscle tone and produce structural changes andremodeling of the airway.
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Antigen presentation by the dendritic cell with
the lymphocyte and cytokine response leading to
airway inflammation and asthma symptoms.
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Asthma Pathophysiology
Airway Inflammation
Airway inflammation in asthma may represent a lossof normal balance between two "opposing"
populations of Th lymphocytes (Th1 and Th2)
Th1 cells produce interleukin (IL)-2 and IFN-, whichare critical in cellular defense mechanisms inresponse to infection
Th2 cells generates a family of cytokines (IL-4, IL-5,IL-6, IL-9, and IL-13) that can mediate allergicinflammation
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Asthma Pathophysiology
Airway Obstruction
Airflow obstruction can be caused by a varietyof changes, including acutebronchoconstriction, airway edema, chronicmucous plug formation, and airwayremodeling
Airway obstruction causes decreased FEV1,
FEV1/FVC ratio, PEF and increasedresistance to airflow => decreased ability toexpel air and may result in hyperinflation
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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 mediator-
secreting cells such as mast cells or nonmyelinated
sensory neuronsThe degree of airway hyperresponsiveness generally
correlates with the clinical severity of asthma
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Chronic Asthma
Chron ic inf lammationof the airways is associatedwith increased bronchial hyperresponsiveness and
bronhospasm and typical symptoms after exposure toallergens, environmental irritants, viruses, cold air, orexercise
In chronic asthma, air f low l imi tat ionmay be onlypartially reversible because of airway remodeling
(hypertrophy and hyperplasia of smooth muscle,angiogenesis, and subepithelial fibrosis) that occurswith chronic untreated disease
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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)
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Asthma Triggers
Allergens
Dermatophagoides species (the most common)
Cats and other domestic petsCrockroaches
Grass pollen
Ragweed
Tree pollen
Fungal spores
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Asthma Triggers
Virus Infections
Rhinovirus, respiratory syncytial virus, andcoronavirus are the most common triggers ofacute severe exacerbations
The mechanism is poorly understood
Viruses airway inflammation with increasenumber of eosinophils and neutrophils
Asthmatics patients have a reducedproduction of type I interferons by epithelialcells increased susceptibility to viralinfections and greater inflammatory response
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Asthma Triggers
Pharmacologic Agents
Beta-adrenergic blockers commonly acutelyworsen 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 rarelyworsen asthma
Aspirin may trigger asthma in some patients
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Asthma Triggers
Exercise
Exercise-induced asthma (EIA) typically begins after
exercise has ended and recovers spontaneously within
about 30 minutesEIA 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 swimmingIt may be prevented by prior administration of 2 agonists
and antileukotrienes but is best prevented by regular
treatment with ICS
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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 thefirst 6 months of symptoms) is usually
complete recovery while, long-term exposure
can cause lifetime asthma
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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 andhypothyroidism
GOR, stress
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Asthma
Symptoms & Physical Signs
The characteristic symptoms are wheezing, dyspnea,and coughing, which are variable, both spontaneously
and with therapyIncreased mucus production , difficult to expectorate
Increased ventilation and use of accessory muscles ofventilation
Prodromal symptoms such as itching under the chin,discomfort between the scapulae or inexplicable fearmay precede an attack
Inspiratory rhonchi, hyperinflation
No abnormal physical findings in controlled asthma
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Asthma Diagnosis
Lung Function Tests
Simple spirometry confirms airflow limitation with a
reduced FEV1,FEV1/FVC ratio and PEFReversibility is demonstrated by a >12% and 200-mL
increase in FEV1 15 minutes after inhaling a short-acting bronchodilator
Measurements of PEF twice daily may confirm thediurnal variation in airflow obstruction
Flow-volume loops show reduced peak flow andreduced maximum expiratory flow
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Asthma Diagnosis
Airway Hyperresponsiveness can be measured by:
Methacholine or histaminechallenge 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 testingmay demonstrate the postexercisebronchoconstriction if there is a history of EIA
Allergen challengerarely necessary to identify specificoccupational agents
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Asthma Diagnosis
Chest Radiography
is usually normal
hyperinflated lungs in severe patients
pneumothorax in exacerbations
pneumonia or eosinophilic infiltrates in
patients with bronchopulmonary aspergillosisHigh-resolution CT
areas of bronchiectasis in severe asthma
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Asthma Diagnosis
Exhaled Nitric Oxide is now used as anoninvasive test to measure eosinophilic airway
inflammation the typically high-levels in asthma are reduced by
ICS, so this may be a test of compliance withtherapy
Skin Prick Tests to common inhalant allergensare positive in allergic asthma and negative inintrinsic asthma
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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)
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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
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Asthma Treatment
The main drugs used for asthma can be
divided in two categories:
bronchodilatorsgive rapid relief ofsymptoms through relaxation of airway
smooth muscle
controllers inhibit the underlyinginflammatory process
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Asthma Treatment
Bronchodilator Therapies
There are three classes of bronchodilators in
current use:
2 agonists (the most effective)
Anticholinergics
Theophylline
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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
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-2-adrenergic agonists
usually are given by inhalation to reduce side
effects
1)SABAs = short acting -2-agonistsalbuterol
terbutaline
2)LABAs =long acting -2-agonistssalmeterolformoterol
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-2-adrenergic agonists
SABAs
3-6 hours duration of actionRapid onset of bronchodilation used as
needed for symptom relief
Increased use of SABAs indicates that asthma
is not controlledUsed in preventing EIA
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-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, improveasthma control at lower doses of corticosteroids
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-2-adrenergic agonists
Side Effects:Muscle tremor and palpitations especially in elderly
patientsSmall potassium fall as a result of increased uptake byskeletal muscle cells but does not usually causeclinical problemsSafety:
Association between asthma mortality and the use ofLABAs is related to the lack of use of concomitant ICS,as the LABAs fails in control the underlyinginflammation
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Asthma Treatment
Anticholinergics
Muscarinic receptor antagonists ipratropiumbromide prevent cholinergic nerve-induced
bronchoconstriction and mucus secretionLess effective than -2-agonists as they inhibit onlythe cholinergic reflex component ofbronchoconstriction,not all mechanisms as -2-agonists
May be given by nebulizer in treating acute severeasthma but only after -2-agonists because theyhave o slower onset of bronchodilation
Side effects: dry mouth, urinary retention, glaucom
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Asthma Treatment
Theophylline
inhibition of phosphodiesterases in airway smooth-musclecells increases cyclic AMPbronchodilator effect
anti-inflammatory effects at lower dosesGiven once or twice daily as a slow-release prep.At plasma concentration of 10-20 mg/L aditional
bronchodilator in patients with severe asthmaAt lower doses (5-10 mg/L)additive effects to ICS
Now is rarely used because of side effects ,occasionally given to patients with severeexacerbations that are refractory to SABAs
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Asthma Treatment
Theophylline
Side Effects:
are related to plasma concentrations(rarely
observed at plasma concentration
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Asthma
TreatmentTheophylline
Table 254-4 Factors Affecting Clearance of Theophylline
Increased Clearance
Enzyme induction (rifampicin, phenobarbitone, ethanol)
Smoking (tobacco, marijuana)
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
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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
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Asthma-Controller Therapies
Inhaled Corticosteroids (ICS)
improve - the symptoms of asthma rapidly
- the lung function in several days
prevent - asthma symptoms (EIA, nocturnalexacerbations, severe exacerbations)
- irreversible changes in airway function thatoccur with chronic asthma
reduce airway hyperresponsiveness in several monthsSide effects: dysphonia, oral candidiasis
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Pharmacokinetics of inhaled corticosteroids
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Asthma-Controller Therapies
Systemic Corticosteroids
hyd rocor t isone or methy lpredniso lone, IV , foracute severe asthmaprednisone or predniso lone3045mg once dailyfor 510 days in acute exacerbations of asthma
~1% of asthma patients may require maintenancetreatment with OCS (determine the lowest dosenecessary to maintain control)
systemic side effects: truncal obesity, bruising,osteoporosis, diabetes, hypertension, gastriculceration, proximal myopathy, depression andcataracts
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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)
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Asthma- Treatment
Steroid-Sparing Therapies: methotrexate,
cyclosporin A, azathioprine, gold, and IV gamma
globulin reduce the requirement for OCS inpatients with sever asthma and serious side effects
with OCS
no long-term benefit and high
risk of side effects
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Asthma- Treatment
Anti-IgE:omalizumab reduce the number of
severe asthma exacerbations and improve asthma
control
very expensive and is only suitable for highlyselected patients who are not controlled on maximal
doses of inhaler therapy
given as a subcutaneous injection every 24 weeks
for 3 - 4 months
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Chronic Asthma
Stepwise Therapy
Mild,intermittent asthmaSABAs use for more than3 times/weekindicates the need for controller therapyadd an intermediate dose of ICSif symptoms are controlled after 3 months of
therapydecrease the doseif symptoms are not controlledadd LABA
If asthma is not controlled with maximal ICSrecommended doses check compliance and inhalertechnique and add maintenance treatment with OCSOnce asthma is controlleddecreased slowly therapy inorder to find optimal doses to control symptoms
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Stepwise approach to asthma therapy
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Acute Severe Asthma
increased chest tightness, wheezing anddyspnea
increased ventilation, hyperinflation,tachycardia, pulsus paradoxus
reduced spirometric values and PEF,hypoxemia and low Pco2 due to
hyperventilation (normal or rising Pco2impending respiratory failuremonitoring andtreatment)
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Acute Severe Asthma-Treatment
O2by face mask oxygen saturation >90%
SABAs unsatisfactory response add inhaled
ant ichol inergic In patients who are refractory to inhaled therapiesslow infusion ofaminophy l l ine(monitor bloodlevels)
Prophylactic intubation in case of impendingrespiratory failure (Pco2 normal or rises)
Respiratory failure intubation and mechanicalventilation. NO sedatives (may depress ventilation).
AB only if there are signs of pneumonia
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Refractory Asthma
Approximately 5% of asthmaticsFactors that cause poor control asthma:
noncompliance with medication (particularly ICS)compliance may be improved by giving ICS as acombination with LABA that relieves symptomsExposure to high ambient levels of allergens or
unidentified occupational agentsSever rhinosinusitis,GOR, infection with Mycoplasma
pneumoniae, Chlamydophyla pneumoniae, hyper- andhypothyroidismDrugs such as: beta-adrenergic blockers, aspirin and
COX inhibitors
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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 2weeks=extremely uncommon (affects less than 1 to 1000patients)Reduced responsiveness to corticosteroids:
=more common, requires OCS to control asthmaMany observations suggest that are likely to beheterogeneous mechanisms implicated. Is not yetknown if these mechanisms are geneticallydetermined
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Refractory Asthma
Brittle Asthma
brittle asthma describes patients with asthma whomaintained a wide variation in peak expiratory flow(PEF) despite high doses of inhaled steroids
Type 1 brittle asthma: characterised by a maintainedwide PEF variability (>40% diurnal variation for >50%of the time over a period of at least 150 days) despiteconsiderable medical therapy including a dose ofinhaled 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 anobvious trigger on a background of apparent normalairway function or well controlled asthma
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Refractory Asthma
Treatment
Check compliance and the correct use of inhalers
Identify and eliminate underlying triggersLow 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
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Special Considerations
Aspirin-Sensitive Asthma
1-5% of asthmatics becomes worse with aspirin and
other COX inhibitorsIs 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
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Special Considerations
Asthma in the ElderlyIs more difficult to treat due to the side effects of drugs, the
comorbidities which are more frequent at this age group andinteractions with drugs such as -2-blockers,COX inhibitors,agents that may affect the theophylline clearance
PregnancyIts important to maintain good control of asthma during
pregnancy
May be safe treat with SABAs, ICS and theophyllineThere are less safety informations about drugs such as:
LABAs, antileukotrienes, and anti-IgEIf an OCS is needed it is better to use prednisone
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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 forasthma control
Smoking cessation improves lung function and
reduces the steroid resistance
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Special Considerations
SurgeryWell-controlled asthma has no contraindication to
anesthesia and intubationPatients treated with OCS will have adrenal suppression
and should be treated with an increased dose of OCSimmediately prior surgery
Patients with FEV1
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Special Considerations
Bronchopulmonary Aspergillosis (BPA)Is a hypersensitivity lung disease due to bronchial
colonization by Aspergillus fumigatus that occurs insusceptible patients with asthmaBPA 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 honeycombingTreatment with : OCS, oral antifungal itraconazole
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