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Chapter 9. Bronchial Asthma

Khaled O Hadeli MD, FCCP

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of Medici ne

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8

T he def inition of since i t was first

1892. Duri ng the last

clinical an d physiolo gical featur es of rever sible bronc ho-

spasm and bronchial hyper resp onsiveness .

in confusi on because the two fe atures ma y be shared

other chro nic airway

pulmonary

Ini-

bronchial

described

asthma ha s been revi sed by Sir Wi lliam Osle r in

on

century, t he definiti on focused

This resu lted

by

disorders

such as c hronic air way

disease (C OPD).

The lat est definiti on was re ported by t he Global

tiative for

Asthma ( GINA) pro gram in 20 04; a chr onic

m any

chr onic

an associ ated incre ase in air way

to recurre nt episode s of

wheezing,

or in th e early m orning. Th ese

but

episodes

variable a irflow obs truction t hat is of ten revers ible either spo ntaneously or with tre atment.

associate d

cells

inflammat ory disord er of the

airways

a

in

which

The

and

cellular

e lements

pl ay

role.

inflammat ion causes hyper-resp onsiveness

particularl y at night

are

usually

that leads

breathless ness, chest tightness,

with

and cough ing,

w idespread

Air way I nflamation Reversab le Air way obstructi on Asthma
Air way
I nflamation
Reversab le
Air way
obstructi on
Asthma
I nflamation Reversab le Air way obstructi on Asthma Air way hyper ‐ respon sivness Figure

Air way hyperrespon sivness

Reversab le Air way obstructi on Asthma Air way hyper ‐ respon sivness Figure 1. D

Figure 1. D efinition of

Asthma

199

Epidemiology

Asthma

According to WHO statistics, bronchial asthma affects 300 million people; and 255,000 people died of asthma in 2005. Asthma prevalence increases globally by 50% every decade. The most striking increase in asthma prevalence is seen among children. 80% of asthma deaths occurred in low and lower-income countries, and asthma deaths are projected to increase by 20% if ap- propriate actions are not taken. The prevalence of asthma in the developed countries ranges from 10.9% in the United States, to more than 15% in the United King- dom. In developing countries the prevalence of asthma is less. The highest prevalence in Africa (8%) is seen in South Africa, but is increasing at a higher rate in devel- oping countries as they urbanize and westernize. Worldwide, the burden of asthma on the economy ex- ceeds that of tuberculosis and HIV combined. In the United States, asthma-related treatment cost, cost related to loss of work, loss of productivity, and early retirement was estimated to be $12 billion in 2004. These costs are directly related to the severity of the disease. Even though patients with severe asthma consti- tute only 20% of the total asthma population, they are responsible for 50% of the cost of the disease.

Industrialized countries have a higher prevalence of asthma

Developing countries have a higher incidence of asthma

Asthma mortality is higher in poor countries

The cost of asthma treatment is high

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Pathophysiology of Asthma

Asthma is a chronic disease with a complex interaction of cells, mediators, and cytokines that result in inflam- mation. This interaction causes smooth muscle contrac- tion, smooth muscle hypertrophy, micro vascular leakage, bronchial wall oedema, activation of airway neurons, increase in airway responsiveness, stimulation of mucus-secreting cells, mucus plugging of the airways, disruption of the airway epithelium, and ultimately causes widespread airflow limitation. The inflammatory cells involved in the path physiol- ogy of asthma include mast cells, macrophages, eosino- phils, lymphocytes, neutrophils, basophils, and platelets. These cells are capable of generating mediators that can induce bronchospasm “early phase response”, or guide the activation and migration of the eosinophils and neutrophils, and cause a “late phase response” that results in epithelial damage, capillary leak, and mucus hyper secretion. These mediators include histamine, platelet activating factors, leukotrienes LTC4, LTD4, LTE4, prostaglandin D2 and other derivatives of the arachidonic acid cascade.

Complex interaction of cells, me- diators, and cytokines.

Early or Late phase response

Widespread airflow limitation is the ultimate result

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Asthma

Risk Factors for Asthma

The Environment: This is the most important risk factor for asthma attacks. Correlation between the prevalence of asthma and exposure to allergens is docu- mented in several epidemiological studies. Indoor allergens include mites, cat & dog allergens, fungi, cockroach allergens, insect parts and feces, molds, and dander. Outdoor air quality is a major contributor to asthma expression as well. Outdoor allergens (pollens, weeds, and grass) and outdoor pollution (industrial smog, ozone, and nitric oxide) are included in the list of culprits. Another interesting point is that environmental factors in early life influence the development of asthma. Children who grow up in large families, go to day care, or live on farms will have a smaller chance of developing asthma in later life, despite the fact that these same environmental factors may have a negative effect on asthma activity, as described above. Genetics of asthma: Somewhat complex due mainly to the heterogeneity of the asthma phenotype, but is well documented. Gender, Age, & Race: Females are more prone to asthma, but in childhood, boys are more affected than girls. Racial variation in the incidence and mortality of asthma is proven, but geographic location is more im- portant as immigrants acquire the risk of the local population. Extreme weights: Both over weight and under weight people are at a higher risk of developing asthma. In asthmatics, improvement in peak expiratory flow rate (PEFR) variability is seen in patients who correct their weight.

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Triggers of asthma attacks

Allergens

Infections

Environmental endotoxines and irritants

Stress

Pain

Medications

Non-selective B-blockers (oral or ophthalmic)

NSAID

Steroid or other asthma controller withdrawal

Food additives

Gastro-esophageal reflux disease

Clinical Features of Asthma

The most common symptoms of asthma are wheezing, shortness of breath, and cough. Chest tightness, chest pain, and nocturnal awakening are less common, but well described in the literature. Asthmatics may have multiple symptoms, or may present with cough or wheeze only. Most attacks of asthma are preceded by allergen exposure; usually aeroallergens are responsible. As described above in the Pathophysiology of Asthma

a reaction could be immediate and symptomatic, or

delayed where the patient may not appreciate any symp- toms even with a similar degree of spirometric decline in FEV1. The reason for this is thought to be the rapidity of the decline of FEV1. If the decline is rapid the patient will be symptomatic, but if the reaction is slow the attack

may pass unnoticed. Patients with a slow decline in their FEV1 and who have a poor perception of their symptoms are likely to be under medicated and are more likely to

develop fatal or near-fatal attacks. Cough variant asthma

is a common manifestation of asthma where objective

measurements of airflow limitation may be difficult. In

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Asthma

such patients bronchoprovocation testing may be needed to diagnose the disease. A constellation of signs can be seen with bronchial asthma. Most common are tachypnea, prolonged exhala- tion phase, wheeze, use of accessory muscles, and pulsus paradoxus. The degree of wheezing does not predict the severity of the disease; a quiet chest may actually be a late sign of an acute severe attack. Early in the attack, hyperventilation leads to decrease in CO2. Later on, in advanced and severe cases when FEV1 is less than 15%, VQ mismatch leads to “dead space ventilation”, com- bined with increased work of breathing and increased production of CO2 and O2 consumption. Blood levels of CO2 may “normalize” or even rise to high levels, O2 levels continue to drop.

Wheeze, breathlessness, and cough are the most common asthma symptoms

Perception of asthma symptom is variable, depending on the person and the speed of FEV1 declin.

Tachypnea and prolonged exhala- tion phase are the most common physical signs in asthma

Hypercarbia, dead space ventila- tion, and quiet chest in physical examination are advanced find- ings suggesting a severe attack

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Classification of Asthma

Class

Frequency of

Night time

Lung Function

Attacks

attacks

Mild

< 2 attacks weekly

< Two

FEV1 or

Intermittent

times per

PERF>80%predicted,

 

month

but PERF variability

<20%

Mild

> 2 attacks per week,

>

Two

FEV1 or PERF >80% predicted, but PERF variability 20-30%

Persistent

times per

but

<

1

month

attack daily

 

Moderate

Daily attacks

>

One

FEV1 or PERF >60%- <80%, >30% PERF variability

Persistent

time per

week

Severe

Continuous

Frequent/

FEV1 or PERF <60%, >30% PERF variability

Persistent

attacks

 

Daily

Diagnosis and Monitoring of Asthma

Signs and symptoms of asthma are nonspecific, patients often poorly perceive symptoms, and there is a poor correlation between signs and severity, making the diagnosis and management of asthma challenging. Several tests are developed to help with the diagnosis and management of asthma:

Spirometry: FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) are very impor- tant variables that help to quantify the degree of airway obstruction. In acute attacks, the FEV1 usually drops by 30% of the baseline. The finding of 15% reversibility or greater (of FEV1) after the use of short acting bronchodi- lators is suggestive of asthma. Peak expiratory flow rate: This is a good tool to assess the variability in airflow limitation seen in asth-

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Asthma

matics. After establishing an individual’s normal range, the peak flow rates can then be followed to monitor the progression of the disease. The National Institute of Health (NIH) has developed guidelines to help patients monitor disease severity and control (zones of airflow limitation).

Green zone (80% and 100% of person’s best) indicates good con- trol

Yellow (50%-80% of person’s best) indicates poor control and warrants patient attention, and possibly a need to increase treat- ment

Red (less than 50%) indicates very poor control and warrants physician involvement

Arterial Blood Gas (ABG): The most common finding in an asthma attack is hypoxemia due to ventila- tion perfusion (VQ) mismatch. In mild to moderate attacks, hyperventilation leads to hypocarbia and respi- ratory alkalosis. As previously described, severe asthma exacerbations may lead to normalization or hypercarbia and worsening hypoxemia, heralding respiratory failure. Bronchoprovocation testing: In patients with typical features of asthma, but without spirometric or peak flow confirmation, an inhalation challenge test may be helpful. After giving the patient a dose of short-acting bronchodilators to ensure normal airway at the start of the test, standardized escalating doses of inhaled meth- acholine or histamine are given. A 20% decline in FEV1 is diagnostic of asthma. Radiological Features: Most commonly, the chest x-ray of an asthmatic will be normal. The main findings

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6

with sever e airway o bstruction

chest (figu re 2) and a flat diaphr agm.

are hyperi nflation

of the

re 2) and a flat diaph r agm. are hyperi nflation of the Figure asthma Other
re 2) and a flat diaph r agm. are hyperi nflation of the Figure asthma Other

Figure

asthma

Other

2.

H yperinflati on

in

56

ye ar

old

Clinica l Form s of

fem ale

with

se vere

As thma

particula r occupati onal

environme nt precipit ates attac ks in certa in suscept ible

individual s. Animal

workers, a nd spray p ainters are

ciated wit h this form

away from

occupation al history in patients

to be the their asthm

prove in a

few days

grain han dlers, pou ltry some occ upations a sso-

Occup ational a sthma: A

handlers,

of asthm a. Often,

symptoms

im-

the occup ation. Seek ing with asth ma may pr ove in the m anagemen t of

most imp ortant step

a.

Noctu rnal asth ma: Attac ks occur m ore freque ntly

a differe nt expressi on of gen eric

are though t to be du e to

at

asthma. T he nocturn al attacks

night,

perhaps

as

circadian r hythm vari ability in b ronchial in flammatio n.

Exerci se induce d

ma

asthm a: The exa ct mechan ism is not c lear. Evap orative los s of

of this for m of asth

water and

ditioned ai r during ex ercise may

heat by in halation of large volu mes of unc on-

provoke b ronchospa sm.

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Asthma

Cou gh varian t asthma : Cough is tom, an d diagnosi s can be m ade with

tion tes ting. The

treatmen t with bro nchodilato rs and ster oids.

symp-

bronchopro voca-

the main

cough u sually re sponds w ell to

Dru g induced

asthma:

aspirin a nd beta-bl ockers.

Main culp rit drugs in clude

ABP A (allergic

bronchop ulmonary

aspergillo sis or

allergic

bronchopu lmonary m ycosis): A

form of a sthma

thought

to reflec t hyperse nsitivity t o fungi u sually

Aspergil lus fumiga tus. This f orm is char acterized

formatio n of thick

by the

respiratory secretions and mucu s plug

(figure

3),

presen ce

of

eosi nophilia,

high

IgE

l evels,

antibodi es to asper gillus, and

recurrent

lung

infilt rates.

If untre ated this m ay lead to

bronchiec tasis.

Trea tment

includes

medicati ons is less defined.

the

use

of steroids . The rol e of anti- fungal

defined. the use of steroids . The rol e of anti- fungal Figure 3 . Mucus

Figure

3 .

Mucus

pl ug

pulled

of

45

year

old

female

with

ABPA

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Churg-Strauss syndrome: Is a multisystem dis- ease characterized by allergic rhinitis, asthma, and blood eosinophilia. Involvement of other systems could be seen. The gold standard diagnostic procedure is open lung biopsy with findings including eosinophilic infil-

trates, giant cell vasculitis, interstitial granulomas, and eosinophilic lymphadenopathy. Leukotriene modifying agents were implicated in the development of the dis- ease, however, it is believed that the tapering off of the steroids in these patients unmasked the disease rather than the other way around. Treatment is usually with high dose steroids. Fatal or near-fatal asthma: is an important variant of asthma presentation. Despite better under- standing of the pathophysiology of asthma and the availability of effective medications, acute attacks with significant mortality rates still occur. According to the British Thoracic Society, risks of devel- oping near fatal attacks are:

Previous history of near fatal asthma

Previous history of hospitalization due to asthma

Previous history of mechanical ventilation due to respiratory failure from asthma

Patient on 3 or more classes of asthma medication

Heavy use of B-agonist

Behavioral problems (non-compliance, alcohol abuse, drug abuse…etc.)

Social problems (poverty, social isolation, child abuse…etc.)

Other risk factors include:

Marked fluctuations of PERF am/pm readings

People with blunt response to hypoxemia

Lack of prophylactic anti-inflammatory treatment

Death is usually due to hypercarbic respiratory fail- ure. Despite severe hypercarbia and very low pH, severe attacks can be reversed with appropriate management.

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Asthma

When an asthma attack is sudden and respiratory failure occurs fast, the recovery can be quick and complete, compared to attacks that are slow to progress. Patients who require mechanical ventilation pose a significant challenge to the physician. Severe broncho- spasm and limitation of airflow make ventilation very difficult; and old strategies aimed at quick correction of blood gas derangement may lead to increased mortality from barotrauma and decreased cardiac output due to increased intrathoracic pressure and decreased venus return. The use of mechanical ventilation strategies leading to permissive hypercarbia has improved the outcomes. Proper asthma control can significantly reduce near fatal attacks and asthma mortality. Measures like the regular use of peak flow meters, written action plans, better patient-physician communication, better patient compliance, and the use of corticosteroids can help in this regard.

Management of Asthma

Environmental control of asthma

Once a patient is diagnosed with asthma, a detailed environmental and occupational history is essential. General or specific advice about environmental changes is the cornerstone of asthma management and control. Patients need to appreciate that asthma is a clinical syndrome, where the clinical manifestation can be controlled but the condition is likely to be lifelong. Environmental education is important for the patient for the rest of his/her life. Occupational exposures and type of home furnishings, that may influence the disease, may be difficult to change at the time of diagnosis, but may be necessary to improve control of the disease.

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Pharmacological Treatment of Asthma

Short- term objectives: The use of short acting bronchodilators to control an acute attack and to manage a fall in the PERF or FEV1. Long-term objectives: The use of anti- inflam- matory medications and long-acting bronchodilators for daily maintenance and diminished acute exacerbations.

Asthma Treatment By Severity:*

Asthma

Short acting

Long acting

 

Severity/ treatment

“Rescue medication”

“maintainer”

Mild Intermittent

SABA as needed

NON

 

Mild Persistent

SABA

ICS or LMA or Cs

 

Moderate persistent

SABA

LABA and

ICS

vs.

Higher dose ICS with

or

without

LMA/Theo

Severe Persistent

SABA

All

the

above

and

oral steroids

 

Short acting beta-agonist (SABA), Long Acting beta-agonist (LABA), Inhaled corticosteroids (ICS), Leukotriene- modifying agent (LMAs), Cromolyn sodium (Cs), Theophyl- line (Theo)

*If uncontrolled at any severity level, consider pulse treatment with oral steroids.

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Asthma

Medications

Anti-inflammatory Agents

Corticosteroid

Mode of action: Prevent migration and activation of inflammatory cells, interfere with the production of prostaglandins and leukotrienes, and reduce capil- lary leak.

Use: All forms of asthma with severity higher than mild intermittent.

Preparations: Oral and inhaled.

Side effects: Long-term use of inhaled corticostero- ids is associated with a good safety profile; nonethe- less local effects such as hoarseness of voice, dysphonia, cough, and oral candidiasis can be ex- pected. Hypophyseal-pituitary-adrenal suppression, osteoporosis, cataract, hypertension, diabetes melli- tus, and immune suppression can be seen, especially with long-term use of oral preparations.

Cromolyn Sodium

Mode of action: Mast cell stabilization

Use: Allergen-induced asthma

Preparation: Inhalation.

Very good safety profile

Leukotriene Modifying Agent

Mode of action: Inhibit the cysteinyl leukotrienes and Leukotriene C4, D4, and E4.

Use: particularly useful in allergen-induced asthma, exercise- induced asthma, and aspirin- induced asthma.

Preparation: Oral

Side effects: Generally very safe with reports of rare cases of Churge-strauss vasculitis in patients with

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severe steroid-dependent asthma during steroid ta- per while being on LPMs.

Bronchodilators

Short Acting Beta Agonist (SABA)

Mode of action: Airway dilation by producing cAMP, also reduce the release of inflammatory me- diators and improve mucocilliary transport. Used as rescue medication and prophylactic in exercise- induced asthma.

Use: All levels of severity, preferably on “as needed” basis.

Preparation: Oral and inhaled.

Side effects: Despite selectivity, may have systemic adrenergic effects like tremors, arrhythmias, palpi- tation, and paradoxical bronchospasm. Regular use of Beta 2 agonists is thought to be associated with increased mortality. So, these medications are bet- ter used as an “as needed” rescue medication.

Long Acting Beta Agonist (LABA)

Mode of action: Similar to that of short acting bron- chodilators, but due to lipophilicity the duration of action is much longer.

Use: Moderate persistent severity or higher.

Preparation: Inhaler.

Side effects: the safety profile of long acting beta agonists is controversial. The weight of evidence fa- vors their use in moderate persistent severity or higher in combination with corticosteroids.

Methylxanthines

Mode of action: Not defined. Methylxanthines are effective bronchodilators with anti-inflammatory properties.

Use: Moderate persistent asthma or higher.

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Asthma

Preparation: Oral.

Side effects: Narrow therapeutic margin, requires monitoring of therapeutic levels especially in the el- derly. Side effects include GI upset in mild toxicity and serious cardiac arrhythmias seen in high blood levels.

Magnesium Sulfate

Mode of action: Inhibits calcium channel smooth muscle and reduce acetylcholine release.

Use: Acute severe attack.

Preparation: Intravenous.

Side effects: circulatory collapse.

Anticholinergics

Mode of action: Reduce vagal tone, synergistically when used with Beta agonists.

Use: mainly used in COPD, or as a substitute to beta agonists and methylxanthines in patients with car- diac arrhythmias.

Preparation: inhaler.

Side effect: slow-acting. Caution in patients with glaucoma or urinary retention.

The Patient–physician Relationship and its Effect on Asthma Control

The outcome of asthma management and the degree of asthma control are influenced by the patient-physician relationship. Best compliance and outcomes are seen with patient-focused approach, where the physician interacts with the patient in a friendly and open-minded way. The physician listens to the patient’s concerns and develops a trusting two-way communication. This ap- proach will enable the physician to understand the patient, not only his illness. Disease-focused approaches

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may lead to loss of effective communication with the patient, and ultimately poor adherence and outcome.

Summary of Asthma Management

Use of objective measures of lung function to assess the severity of asthma and to monitor the efficacy of treatment.

Identification and elimination of factors that wor- sen symptoms, precipitate attacks, or promote on- going airway inflammation (environmental control).

Comprehensive pharmacological therapy to reverse bronchoconstriction and prevent airway inflamma- tion.

Creating a patient-focused relationship between the patient and health provider.

Further Reading

1. Bethesda MD. Expert panel 2: guidelines for the diagnosis and management of asthma. NIH publication 1997; No.

97-4051.

2. Braman SS. Decreasing the global burden of asthma. Chest 2006; 130(suppl):S4-S12.

3. Masoli M, Fabian D, Holt S, Beasley R, von Hertzen L. GINA program: The global burden of asthma. Allergy

2004;59:469-478.

4. Canonica

GW.

Treating

asthma

as

inflammory

disease.

Chest 2006;130(suppl):S21-S28.

 

5. Hall

IP.

Genetics

and

pulmonary

medicine:

asthma.

Thorax 1999;54:65-69.

6. Kay AB. Pathology of mild, severe, and fatal asthma. Am J Respir Crit Care Med 1996;154(suppl):S66-S69.

2006;

7. Graham

LM.

Classifying

asthma.

Chest

130(suppl):S13-S20.

8. Palma-Carlos AG. Correlation between clinical classifica- tion, PEF and FEV1: guidelines and reality. Allergy Im- munol (Paris) 2003;35:130-132.

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Asthma

9. Corbridge TC, Hall JB. The assessment and management of patient with status asthmaticus. Am J respire Crit Care Med 1995;151:1296-1316.

10. Cockrill BA. ABPA. Annual Rev Med 1999;50:303-316.

11. Jimenez-Friedman G, Beckett W, Szeinuk J, Petsonk E. Clinical evaluation, management, and prevention of work- related asthma. Am J Ind Med 2000;37:121-141.

12. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus high-dose corticosteroids in asthma patients. Lancet 1994;344:219-224.

13. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The anti- inflammatory effects of Leukotriene-modifying drugs and their use in asthma. Chest 2001; 119:1533-1546.

14. Irwin

R.

Patient-Focused

130(suppl):S73-S82.

Care. Chest 2006;

15. The Smart study. Chest. 2006;129:15-26.

Websites

1. http://www.ginasthma.com/

Global Initiative for asthma (GINA).

2. www.who.int/respiratory/gard/en/

Global Alliance against Chronic Respiratory Diseases (GARD).

3. www.who.int/topics/asthma/en/

World Health Organization: Asthma, Fact Sheet.