3. Asthma New(Er) Version

7/27/2019 3. Asthma New(Er) Version

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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