asthma acro chapter 9

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Chapter 9. Bronchial Asthma

Khaled O Hadeli MD, FCCP



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199 Asthma

Epidemiology

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 asthmaprevalence 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 ahigher incidence of asthma

• Asthma mortality is higher in poor countries

• The cost of asthma treatment ishigh



The Oea Review of Medicine 200

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 isthe ultimate result



201 Asthma

Risk Factors for Asthma

T h e E n v i r o n m en t : 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. Indoorallergens 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 sameenvironmental factors may have a negative effect on

asthma activity, as described above.

Ge n e t i c s of asthma: Somewhat complex due

mainly to the heterogeneity of the asthma phenotype,

but is well documented.

Gen d e r , A g e , & R a c e : 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.E x t r em e w ei g h t s : 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.




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 li terature. 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



203 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, andcough are the most commonasthma symptoms

• Perception of asthma symptom isvariable, depending on the personand 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




Classification of Asthma

Clas s F requency of

Att ack s

Ni gh t t i me

at t acks

Lu ng F u ncti on

Mild

Int e rmit t e nt

< 2 a t t acks

we e kly

< T wo

t ime s pe rmont h

F EV 1 or

PER F >8 0 % pre dic t e d, bu t P ER F v ar iab i l i t y

<20 %

Mild

Pe rs is t e nt

> 2 a t t acks

pe r we e k ,

bu t < 1

at t ack da i ly

> T wo

t ime s pe r

mont h

F EV 1 or PER F >8 0 %

pre dic t e d, but PER F

v ari ab i l i t y 20 -30 %

Mode rat e

Pe rs is t e nt

D ai ly a t t acks > One

t ime pe r

we e k

F EV 1 or PER F >6 0 % -

<8 0 % , >30 % PER F

v ari ab i l i t y

Se v e re

Pe rs is t e nt

Cont inuous

at t acks

F re que nt /

D ai ly

F EV 1 or PER F <6 0 % ,

>30 % PER F v ariabi l i t y

Diagnosis and Monitoring ofAsthma

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:

S p i r o m e t r y : 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.

P ea k ex p i r a t o r y f l o w r a t e : This is a good tool to

assess the variability in airflow limitation seen in asth-



205 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’sbest) indicates poor control andwarrants patient attention, and

possibly a need to increase treat-ment

• Red (less than 50%) indicates

very poor control and warrants physician involvement

A r t e r i a l B l o o d G a s ( A B G ) : 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.

B r o n c h o p r o v o ca t i o n t es t i n g : In patients with

typical features of asthma, but without spirometric orpeak 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.

R a d i o l o g i c a l F ea t u r es : Most commonly, the chest

x-ray of an asthmatic will be normal. The main findings



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207

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Ch u r g - St r a u s s sy n d r o m e: 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, andeosinophilic 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.

F a t a l o r n ea r - f a t a l a s t h m a : 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, childabuse…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.



209 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 clinicalsyndrome, 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.




Pharmacological Treatment of Asthma

Sh o r t - t e r m o b j ec t i v es : The use of short acting

bronchodilators to control an acute attack and to manage

a fall in the PERF or FEV1.

L o n g - t er m o b j ec t i v e s: The use of anti- inflam-

matory medications and long-acting bronchodilators fordaily maintenance and diminished acute exacerbations.

Asthma Treatment By Severity:*

As t hm a

S everi t y / t r eat ment

S hor t act i ng

“R es cue medi cat i on”

Long act i ng

“mai nt ai ner”

Mild Int e rmit t e nt SABA as ne e de d N ON

Mild Pe rs is t e nt SABA ICS or LMA or Cs

Mode rat e pe rs is t e nt SABA LABA and ICS v s .

H igh e r dos e ICS wit h

or wit h out

LMA/T h e o

Se v e re Pe rs is t e nt SABA Al l t h e abov e and

ora l s t e ro ids

Short act ing beta-agonist (SABA), Long Acting beta-agonist

(LABA), Inhaled corticosteroids (ICS), Leukotriene-

modifying agent (LMAs), Cromolyn sodium (Cs), Theophyl-

l ine (Theo)

*If uncontrol led at any severity level , consider pulse

treatment with oral s teroids.



211 Asthma

Medications

Anti-inflammatory Agents

Corticosteroid

• Mode of action: Prevent migration and activation ofinflammatory 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




severe steroid-dependent asthma during steroid ta-

per while being on LPMs.

Bronchodilators

Short Acting Beta Agonist (SABA)

• Mode of action: Airway dilation by producingcAMP, 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 withincreased 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.



213 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-physicianrelationship. 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




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 oftreatment.

• 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: guidel ines for the diagnosis

and management of asthma. NIH publicat ion 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. Al lergy

2004;59:469-478.

4. Canonica GW. Treating asthma as inf lammory 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 mi ld, severe, and fata l asthma. Am J

Respir Cri t Care Med 1996;154(suppl):S66-S69.

7 . Graham LM. Classi fy ing asthma. Chest 2006;

130(suppl):S13-S20.

8. Palma-Carlos AG. Correlat ion between cl inical c lassi f ica-

t ion, PEF and FEV1: guidel ines and real i ty . Al lergy Im-

munol (Paris) 2003;35:130-132.



215 Asthma

9. Corbridge TC, Hall JB. The assessment and management

of patient with status asthmaticus. Am J respire Cri t Care

Med 1995;151:1296-1316.

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

11 . J imenez-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, Northf ield M, S haw G. Added

salmeterol versus high-dose cort icosteroids in asthma

patients . Lancet 1994;344:219-224.

13. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The anti -

inf lammatory ef fects of Leukotriene-modifying drugs and

their use in asthma. Chest 2001; 119:1533-1546.

14. Irwin R. Patient-Focused Care. Chest 2006;

130(suppl):S73-S82.

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

Websites1 . http://www.ginasthma.com/

Global Ini t iat ive for asthma (GINA).

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

Global Al l iance against Chronic Respiratory Diseases

(GARD).

3. www.who.int/topics/asth ma/en/

World Health Organizat ion: Asth ma, Fact Sheet .

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