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CHAPTER I

INTRODUCTION

A. Background

Globally, asthma is one of the most common chronic diseases and

currently affects approximately 300 million people worldwide. The

prevalence of asthma has risen in affluent countries over the last 30 years

but now appears to have stabilized, with approximately 10-12% of adults

and 15% of children affected by the disease (Longo et al, 2012).

Asthma is a syndrome characterized by airflow obstruction that

varies markedly, both spontaneously and with treatment (Longo et al,

2012). Asthma is a disease of increasing prevalence that is a result of

genetic predisposition and environmental interactions; it is one of the

most common chronic diseases of childhood (DiPiro et al, 2008).

Usually, asthma can present at any age, with a peak age of 3 years.

In childhood, twice as many males as females are asthmatic, but by

adulthood the sex ratio is equalized. The commonly held belief that

children "grow out of their asthma" is justified to some extent. Long term

studies that have followed children until they reach the age of 40 years

suggest that many with asthma become asymptomatic during adolescence

but that asthma can reoccur at some point during adulthood, particularly

in those with persistent symptoms and severe asthma (Longo et al, 2012).

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The exact cause of asthma still remains unknown, but it is thought

to be caused by allergy to some foreign substance (allergen) or irritant, no

extrinsic trigger can be found in some types of asthma. Allergens include

(but are not limited to) pollen, dust mites, feathers, animal dander, molds,

some drugs such as aspirin, and rarely foods. Asthma may also occur in

association with other allergic conditions, such as eczema or hay fever.

Other precipitants of asthma attacks include cold or dry air, smoke, air

pollution, bronchitis and other lung infections, vigorous exercise,

emotional excitement, or stress. A predisposition to asthma may be

hereditary (Margolis et al, 2006). Symptoms include difficulty breathing,

wheezing, coughing tightness in the chest. In severe cases, asthma can be

fatal.

Furthermore, the major characteristics of asthma include a

variable degree of airflow obstruction (related to bronchospasm, edema,

and hypersecretion), bronchial hyper-responsiveness (BHR), and airways

inflammation. Evidence of inflammation depicted in the studies of

nonspecific BHR, bronchoalveolar lavage (BAL), bronchial biopsies, and

induced sputum, as well as from postmortem observations of patients with

asthma who died from an attack of asthma or from other causes. List of

the agents and events triggering asthma have been summarized into a

table below:

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Table I. List of Agents and Events Triggering Asthma

To understand the pathogenetic mechanisms that underlie the

many variants of asthma, it is critical to identify factors that initiate,

intensify, and modulate the inflammatory response of the airways and to

determine how these immunologic and biologic processes produce the

characteristic airways abnormalities. Immune responses mediated by IgE

antibodies are of foremost importance (DiPiro et al., 2009).

Treatment is a scientific process which is done by the doctors

against patients based on the findings obtained, and it is one of the major

components of health care. Availability of drugs for some people is an

important indicator in the health care services which is an effort to

improve and enhance the quality of life because basically intervention of

Respiratory infection

Respiratory syncytial virus (RSV), rhinovirus, influenza,

parainfluenza, Mycoplasma pneumonia

Allergens

Airborne pollens (grass, trees, weeds), house-dust mites, animal

Danders, cockroaches, fungal spores

Environment

Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke,

wood smoke

Emotions

Anxiety, stress, laughter

Exercise

Particularly in cold, dry climate

Drugs/preservatives

Aspirin, NSAIDs (cyclooxygenase inhibitors), sulfites, benzalkonium

chloride, β-blockers

Occupational stimuli

Bakers (flour dust); farmers (hay mold); spice and enzyme workers;

printers (arabic gum); chemical workers (azo dyes, anthraquinone,

ethylenediamine, toluene diisocynates, polyvinyl chloride); plastics,

rubber, and wood workers (formaldehyde, western cedar,

dimethylethanolamine, anhydrides)

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a therapy is by using drugs. Drugs are chemical substance that can affect

the process of life. For instance, a drug will enter the body's circulatory

system and produce an effect (Sastramihardja et al, 1997).

Many different medications are used to manage and control

asthma. The two types of asthma medications used to treat asthma include

long-term control medication and short-term, or also known as quick-

relief medication. Though the goal of both medications is to treat asthma

symptoms, they are used for different purposes. Furthermore there is also

presence of surgical methods in controlling asthma apart from

medications such as bronchial thermoplasty. Long-term control

medication is usually taken every day to control asthma symptoms and to

prevent the occurrence of asthma attacks, for example inhaled

corticosteroids, long acting β2-agonist, leukotriene modifiers and Anti Ig-

E. Quick-relief medication is primarily taken to relieve the sudden onset

of asthma symptoms (such as during an asthma attack), and in cases in

which the asthma symptoms only occur occasionally, for example short-

acting beta2-agonists and anticholinergics. Surgery such as bronchial

thermoplasty can reduce the size of the smooth muscle allowing many

patients to cut back on medication and lead more active lives through

inserting a bronchoscope with a thermoplasty device inside into the

asthmatic patient’s mouth or nose as far as possible down each airway.

Electrodes on the tip are then heated with radiofrequency energy,

shrinking the muscle and creating a larger opening in the airway.

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A clear picture of the treatment patterns for asthma in RSUP Dr.

Sardjito, Yogyakarta are hopefully to be used as a reference to increase

the quality of medical services towards asthmatic patients which can

cause improvement in patient’s quality of life.

B. Statement of Problem

Based on the background, the problem in this research can be:

1. What is the characteristics of asthmatic patients seen from their age, sex,

comorbid illness, occupation, level of education and medical history in

RSUP Dr. Sardjito for the period of January 2013 till December 2013?

2. What is the pattern of drug therapy given to asthma patients in RSUP Dr.

Sardjito, Yogyakarta based on the type of drugs for respiratory tract

disorders (anti-inflammatory drugs and broncodilators) and whether the

treatment is polytherapy or monotherapy?

3. How is the outcome of the patient after the therapy?

C. Objective

1. The objective of this study is to understand the characteristics of asthma

patients in RSUP Dr. Sardjito, Yogyakarta from aspects such as their age,

sex, comorbid illness, and medical history for the period of January 2013

till December 2013.

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2. Besides that, the study is also meant to evaluate the drug pattern in asthma

patients and to compare it to Clinical Practice Guideline of The Diagnosis

and Management of Asthma.

3. At the same time, this study will also observe the outcome of the patient

after the treatment with the drugs for respiratory tract disorders (anti-

inflammatory drugs and bronchodilators).

D. Benefit

The benefit of this study is to be able to understand the seriousness

of this new growing disease in our society and the risk factors that

contributes towards the disease which is to help provide information about

asthma with more in depth, so to expect to work together with the

government or related parties in reducing the number of incidence of

asthma cases. Also, this study will help me and others such as health care

providers to have a better understanding on pattern of drugs used in

asthmatic patients and the outcome of the therapy towards the patients.

Furthermore this study will increase the quality of pharmacy healthcare

services in hospitals nevertheless to increase knowledge on medical

sciences and to apply those knowledge obtained.

E. Literature Review

1. Asthma

a. Definition of Asthma

Asthma is defined as a chronic inflammatory disease of the

airways. The chronic inflammation is associated with airway

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hyperresponsiveness (an exaggerated airway narrowing response

to triggers, such as allergens and exercise), that leads to recurrent

symptoms such as wheezing, dyspnea (shortness of breath), chest

tightness and coughing. Symptom episodes are generally

associated with widespread, but variable, airflow obstruction

within the lungs that is usually reversible either spontaneously or

with appropriate asthma treatment (Kim et al, 2011). There are

seven types of asthma which are (Crosta et al, 2013):

1). Child onset Asthma

Asthma that begins during childhood is called child-onset

asthma. This type of asthma happens because a child becomes

sensitized to common allergens in the environment - most likely due

to genetic reasons. The child is atopic – a genetically determined

state of hypersensitivity to environmental allergens. The airway

cells are sensitive to particular materials making an asthmatic

response more likely if the child is exposed to a certain amount of

an allergen.

2). Adult onset Asthma

This term is used when a person develops asthma after

reaching 20 years of age. Adult-onset asthma affects women more

than men, and it is also much less common than child-onset

asthma. It can also be triggered by some allergic material or an

allergy. It is estimated that up to perhaps 50% of adult-onset

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asthmas are linked to allergies. However, a substantial proportion

of adult-onset asthma does not seem to be triggered by exposure

to allergen(s); this is called non-allergic adult-onset asthma. This

non-allergic type of adult onset asthma is also known as intrinsic

asthma. Exposure to a particle or chemical in certain plastics,

metals, medications, or wood dust can also be a cause of adult-

onset asthma.

3). Exercise induced Asthma

If you cough, wheeze or feel out of breath during or after

exercise, you could be suffering from exercise-induced asthma.

As with other types of asthma, a person with exercise-induced

asthma will experience difficulty in getting air in and out of the

lungs because of inflammation of the bronchial tubes (airways)

and extra mucus.

4). Cough induced Asthma

Cough-induced asthma is one of the most difficult asthmas

to diagnose. The doctor has to eliminate other possibilities, such

as chronic bronchitis, post nasal drip due to hay fever, or sinus

disease. In this case the coughing can occur alone, without other

asthma-type symptoms being present. The coughing can happen

at any time of day or night. If it happens at night it can disrupt

sleep.

5). Occupational Asthma

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This type of asthma is triggered by something in the

patient's place of work. Factors such as chemicals, vapors,

gases, smoke, dust, fumes, or other particles can trigger

asthma. It can also be caused by a virus (flu), molds, animal

products, pollen, humidity and temperature. Another trigger

may be stress.

6). Nocturnal Asthma

Nocturnal asthma occurs between midnight and 8 AM. It

is triggered by allergens in the home such as dust and pet dander

or is caused by sinus conditions. Nocturnal or nighttime asthma

may occur without any daytime symptoms recognized by the

patient. The patient may have wheezing or short breath when lying

down and may not notice these symptoms until awoken by them

in the middle of the night - usually between 2 and 4 AM. Nocturnal

asthma may occur only once in a while or frequently during the

week. Nighttime symptoms may also be a common problem in

those with daytime asthma as well. However, when there are no

daytime symptoms to suggest asthma is an underlying cause of the

nighttime cough, this type of asthma will be more difficult to

recognize - usually delaying proper therapy. The causes of this

phenomenon are unknown, although many possibilities are

under investigation.

7). Steroid – resistant Asthma (Severe Asthma)

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While the majority of patients respond to regular inhaled

glucocorticoid (steroid) therapy, some are steroid resistant.

Airway inflammation and immune activation play an important

role in chronic asthma. Current guidelines of asthma therapy have

therefore focused on the use of anti- inflammatory therapy,

particularly inhaled glucocorticoids (GCs). By reducing airway

inflammation and immune activation, glucocorticoids are used to

treat asthma. However, patients with steroid resistant

asthma have higher levels of immune activation in their

airways than do patients with steroid sensitive (SS) asthma.

Furthermore, glucocorticoids do not reduce the eosinophilia (high

concentration of eosinophil granulocytes in the blood) or T cell

activation found in steroid resistant asthmatics. This persistent

immune activation is associated with high levels of the immune

system molecules IL-2 (interleukin 2), IL-4 and IL-5 in the

airways of these patients.

b. Epidemiology of Asthma

According to WHO, Asthma is one of the major non-

communicable diseases. WHO estimates that 235 million

people currently suffer from asthma. Asthma is the most

common non-communicable disease among children.

Asthma is a public health problem not just for high-income

countries; it occurs in all countries regardless of the level of

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development. Most asthma-related deaths occur in low- and

lower-middle income countries.

Based on AAAAI, the number of people with asthma

continues to grow. One in 12 people (about 25 million, or 8% of

the U.S. population) had asthma in 2009, compared with 1 in 14

(about 20 million, or 7%) in 2001. More than half (53%) of people

with asthma had an asthma attack in 2008. More children (57%)

than adults (51%) had an attack. 185 children and 3,262

adults died from asthma in 2007. About 1 in 10 children (10%)

had asthma and 1 in 12 adults (8%) had asthma in 2009.

Women were more likely than men and boys more likely than girls

to have asthma. For the period 2008–2010, asthma prevalence was

higher among children than adults.

Asthma is one of the major causes of death in many

countries. The prevalence of asthma in different countries

varies widely, but the disparity is narrowing due to rising

prevalence in low and middle income countries and plateauing in

high income countries (Anonymous, 2011). An estimated 300

million people worldwide suffer from asthma, with 250,000

annual deaths attributed to the disease. It is estimated that the

number of people with asthma will grow by more than 100 million

by 2025. Workplace conditions, such as exposure to fumes, gases

or dust, are responsible for 11% of asthma cases worldwide. About

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70% of asthmatics also have allergies. Approximately 250,000

people die prematurely each year from asthma. Almost all of

these deaths are avoidable. Occupational asthma contributes

significantly to the global burden of asthma, since the condition

accounts for approximately 15% of asthma amongst adults

(Anonymous, 2007a).

There are still no accurate statistics in Indonesia, but

according on the latest WHO data published in April 2011,

asthma deaths in Indonesia reached 14,624 or 1.03% of total

deaths. The age adjusted death rate is 8.25 per 100,000 of

population and ranks Indonesia as the no 69th in the world and

asthma as one of the top 20 causes of death in Indonesia.

c. Etiology of Asthma

The cause of Asthma has not been clearly identified

till date. The causes of Asthma are multifactorial. Some of them

cannot be changed such as age and genetic. Asthma is a

heterogeneous disease with interplay between genetic and

environmental factors. Several risk factors have been

implicated (Longo et al, 2012):

1). Genetic predisposition

2). Atopy

3). Airway hyperresponsiveness

4). Gender

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5). Ethnicity

6). Obesity

7). Early viral infections

8). Indoor and outdoor allergens

9). Occupational sensitizers

10). Passive smoking

11). Respiratory infections

12). Drugs (β-blockers, aspirin)

13). Stress

14). Irritants (household sprays, paint fumes)

15). Cold air

16). Exercise and hyperventilation

17). Sulfur dioxide and irritant gases

d. Pathogenesis and Pathophysiology of Asthma

1). Pathogenesis

Asthma is associated with a chronic inflammation of the

mucosa of the lower airways. One of the main aims of treatment

is to reduce this inflammation (Longo et al, 2012).

2). Pathology

The pathology of asthma has been revealed through the

examining the lungs at autopsy of patients who have died of

asthma and from bronchial biopsies in patients with usually mild

asthma. The airway mucosa is infiltrated with activated

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eosinophils and T lymphocytes, and there is activation of mucosal

mast cells. The degree of inflammation is poorly related to disease

severity and may be found in atopic patients without asthma

symptoms. The inflammation is reduced by treatment with ICS. A

characteristic finding is thickening of the basement membrane due

to subepithelial collagen deposition. This feature is also found in

patients with eosinophilic bronchitis presenting as cough who do

not have asthma and is therefore, likely to be a marker of

eosinophilic inflammation in the airway as eosinophils release

fibrogenic factors. The epithelial is often shed or friable, with

reduced attachments to the airway wall and increased numbers

of epithelial cells in the lumen. The airway wall itself may be

thickened and edematous, particularly in fatal asthma.

Another common finding in fatal asthma is occlusion of

the airway lumen by a mucous plug, which is comprised of

mucous glycoproteins secreted from goblet cells and plasma

proteins from leaky bronchial vessels. There is also vasodilation

and increased number of blood vessels (angiogenesis). Direct

observation by bronchoscopy indicates that the airways may be

narrowed, erythematous, and edematous. The pathology of asthma

is remarkably uniform in different types of asthma, including

atopic, non-atopic, occupational, aspirin-sensitive, and pediatric

asthma. These pathologic changes are found in all airways, but do

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not extend to the lung parenchyma; peripheral airway

inflammation is found particularly in patients with severe

asthma. The involvement of airways may be patchy and this is

consistent with bronchographic findings of uneven narrowing of

the pathways (Longo et al, 2012).

3). Pathophysiology

Asthma is associated with T helper cell type-2 (TH2)

immune responses, which are typical of other atopic conditions.

Various allergic (e.g., dust mites, cockroach residue, furred

animals, moulds, pollens) and non-allergic (e.g., infections,

tobacco smoke, cold air, exercise) triggers produce a cascade of

immune-mediated events leading to chronic airway inflammation.

Elevated levels of TH2 cells in the airways release specific

cytokines, including interleukin (IL)-4, IL-5, IL-9 and IL-13,

that promote eosinophilic inflammation and immunoglobulin E

(IgE) production by mast cells. IgE production, in turn, triggers

the release of inflammatory mediators, such as histamine and

cysteinyl leukotrienes, that cause bronchospasm (contraction of

the smooth muscle in the airways), edema (swelling) and

increased mucous secretion (mucous hypersecretion), which lead

to the characteristic symptoms of asthma. The mediators and

cytokines released during the early phase of an immune response

to an inciting allergen, trigger a further inflammatory response

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(late-phase asthmatic response) that leads to further airway

inflammation and bronchial hyperreactivity.

Evidence suggests that there may be a genetic

predisposition for the development of asthma. A number of

chromosomal regions associated with asthma susceptibility have

been identified, such as those related to the production of IgE

antibodies, expression of airway hyperresponsiveness, and the

production of inflammatory mediators. However, further study

is required to determine specific genes involved in asthma as well

as the gene-environment interactions that may lead to expression

of the disease (Kim et al, 2011).

Figure 1. The many inflammatory cells which are

known to be involved in Asthma with no

key cell that is predominant (Longo et al,

2012).

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e. Classification of Asthma

Classification of asthma is done based on the severity and

the control of the disease. Firstly, it occurs with an intermittent

stage of asthma and continued by persistent asthma which can be

divided into 3 groups such as mild, moderate and severe whereas

when based on the control of asthma, it can be divided into 3

aspects, which are well controlled, not well controlled and very

poorly controlled (Anonymous, 2012a).

1). Severity of the Disease

a). Intermittent asthma

b). Persistent asthma

(1). Mild

(2). Moderate

(3). Severe

Table II. The classification of Asthma based on severity

of the disease (Anonymous, 2012a)

2). Control of the disease

a). Well controlled

b). Not well controlled

c). Very poorly controlled

Components of

Severity

Classification of Asthma Severity

≥12 years of age

Intermittent

Persistent

Mild

Moderate

Severe

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Table III. The classification of Asthma based on

components of control (Anonymous, 2012a).

f. Sign and Symptoms of Asthma

Presence of any of these signs and symptoms should

increase the suspicion or indicate that the patient is suffering from

asthma (Anonymous, 2012c):

1). Wheezing high-pitched whistling sounds when breathing out

especially in children. (A normal chest examination does not

exclude asthma)

2). History of any of the following:

a). Cough, worse particularly at night

b). Recurrent wheeze

c). Recurrent difficult breathing

d). Recurrent chest tightness

3). Symptoms occur or worsen at night, awakening the patient.

4). Symptoms occur or worsen in a seasonal pattern.

5). The patient also has eczema, hay fever, or a family history of

asthma or atopic diseases.

Components of

Control

Classification of Asthma Control

≥12 years of age

Well

Controlled

Not Well

Controlled

Very Poorly

Controlled

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6). Symptoms occur or worsen in the presence of:

a). Animals with fur

b). Aerosol chemicals

c). Changes in temperature

d). Domestic dust mites

e). Drugs (aspirin, beta blockers)

f). Exercise

g). Pollen

h). Respiratory (viral) infections

i). Smoke

j). Strong emotional expression

7). Symptoms respond to anti-asthma therapy.

8). Patients colds “go to chest” or take more than 10 days to clear

up.

g. Diagnosis

The diagnosis of asthma is based on the recognition of a

characteristic pattern of symptoms and signs and the absence of

an alternative explanation for them (see Table IV). The key is to

take a careful clinical history. In many cases this will allow a

reasonably certain diagnosis of asthma, or an alternative

diagnosis, to be made. If asthma does appear likely, the

history should also explore possible causes, particularly

occupational.

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Table IV. The recognition of a characteristic pattern of

symptoms and signs and the absence of an

alternative explanation.

In view of the potential requirement for treatment over

many years, it is important even in relatively clear cut cases, to try

to obtain objective support for the diagnosis. Whether or not this

should happen before starting treatment depends on the certainty

of the initial diagnosis and the severity of presenting symptoms.

Repeated assessment and measurement may be necessary before

confirmatory evidence is acquired. Confirmation hinges on

demonstration of airflow obstruction varying over short periods of

time.

Spirometry, which is now becoming more widely

available, is preferable to measurement of peak expiratory flow

because it allows clearer identification of airflow obstruction, and

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the results are less dependent on effort. It should be the preferred

test where available (although some training is required to obtain

reliable recordings and to interpret the results). Of note, a normal

spirogram (or PEF) obtained when the patient is not symptomatic

does not exclude the diagnosis of asthma. Results from spirometry

are also useful where the initial history and examination leave

genuine uncertainty about the diagnosis. In such cases, the

differential diagnosis and approach to investigation is different in

patients with and without airflow obstruction (see Figure 2 and

Table V). In patients with a normal or near-normal spirogram

when symptomatic, potential differential diagnoses are mainly

non-pulmonary; these conditions do not respond to inhaled

corticosteroids and bronchodilators. In contrast, in patients with

an obstructive spirogram the question is less whether they will

need inhaled treatment but rather exactly what form and how

intensive this should be.

Other tests of airflow obstruction, airway responsiveness

and airway inflammation can also provide support for the

diagnosis of asthma, but to what extent the results of the tests alter

the probability of a diagnosis of asthma has not been clearly

established, nor is it clear when these tests are best performed.

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Figure 2. The presentation with suspected asthma in

adults (Anonymous, 2012b)

Furthermore, there are also other diagnosis methods such

as hematologic tests, imaging like chest roentgenography, skin

test and also exhaled nitric oxide (Longo et al, 2012).

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Table V. The differential diagnosis in patients with or

without airflow obstruction (Anonymous,

2012b)

h. Follow Up

A careful history should elicit the reasons for the

exacerbation and explore possible actions the patient should take

to prevent future emergency presentations. Medication should be

altered depending upon the assessment and the patient provided

with an asthma action plan aimed at preventing relapse,

optimizing treatment and preventing delay in seeking assistance

in the future.

Follow up should be arranged prior to discharge with the

patient’s general practitioner or asthma nurse within two working

days; and with a hospital specialist asthma nurse or respiratory

physician at about one month after admission (Anonymous,

2012b).

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i. Therapy of Asthma

1). Objective of Therapy

Treatments of asthma can be said as effective if certain

objectives are achieved such as (Anonymous, 2010a):

a). Minimal or no chronic symptoms day or night

b). Minimal or no exacerbations

c). No limitations on activities/no school/parent’s

work missed

d). Maintain (near) normal pulmonary function in

adults and children

e). Minimal use of short-acting inhaled beta2-agonist

f). Minimal or no adverse effects from medications

2). Algorithm of Therapy

The treatment of asthma is straightforward and the

majority of patients are now managed by internists and family

doctors with effective and safe therapies. There are several aims

of therapy. Most emphasis has been placed on drug therapy, but

several non-pharmacologic approaches have also been used

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(Longo et al, 2012). All diseases have their own specific algorithm

so do asthma.

Figure 3. The main algorithm therapy for Diagnosis and

Management of Asthma (Sveum et al, 2012).

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3). Anti-asthmatic Drug

Medications for asthma are categorized into two general

classes: long-term control medication and quick-relief medication.

Selection of medications includes consideration of the general

mechanisms and role of the medication in therapy, delivery

devices, and safety. Long-term control medications are used daily

to achieve and maintain control of persistent asthma. The most

effective are those that attenuate the underlying inflammation

characteristic of asthma.

a). Long-term control medications include the following

(listed in alphabetical order) (Anonymous, 2007b):

(1). Corticosteroids are anti-inflammatory medications

that reduce airway hyperresponsiveness, inhibit

inflammatory cell migration and activation, and block

late phase reaction to allergen. Inhaled

Corticosteriods (ICSs) are the most consistently

effective long-term control medication at all steps of

care for persistent asthma. Short courses of oral

systemic corticosteroids are often used to gain prompt

control of asthma and are used long term to treat

patients with severe persistent asthma.

(2). Cromolyn sodium and nedocromil stabilize mast cells

and interfere with chloride channel function. They are

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used as alternative, but not preferred, medication for

patients with mild persistent asthma. They also can be

used as preventive treatment before exercise or

unavoidable exposure to known allergens.

(3). Immunomodulators. Omalizumab (anti-IgE) is a

monoclonal antibody that prevents binding of IgE to

the high-affinity receptors on basophils and mast

cells. Omalizumab is used as adjunctive therapy for

patients 12 years of age who have sensitivity to

relevant allergens (e.g., dust mite, cockroach, cat, or

dog) and with severe persistent asthma. Clinicians

who administer omalizumab should be prepared and

equipped to identify and treat anaphylaxis that may

occur.

(4). Leukotriene modifiers interfere with the pathway of

leukotriene mediators, which are released from mast

cells, eosinophils, and basophils. These medications

include LTRAs (montelukast and zafirlukast) and a 5-

lipoxygenase inhibitor (zileuton). LTRAs are

alternative, but not preferred, therapy for the

treatment of patients with mild persistent asthma.

(5). LABAs (salmeterol and formoterol) are inhaled

bronchodilators that have a duration of

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bronchodilation of at least 12 hours after a single

dose. LABAs are not to be used as monotherapy for

long-term control of asthma.

(6). Methylxanthines. Sustained-release theophylline is a

mild to moderate bronchodilator used as alternative,

not preferred, therapy for mild persistent asthma or as

adjunctive therapy with ICS in patients ≥5 years of

age. Theophylline may have mild anti-inflammatory

effects. Monitoring of serum theophylline

concentration is essential.

b). Quick-relief medications are used to treat acute symptoms

and exacerbations. They include the following (listed in

alphabetical order) (Anonymous, 2007b):

(1). Anticholinergics inhibit muscarinic cholinergic

receptors and reduce intrinsic vagal tone of the

airway. Ipratropium bromide provides additive

benefit to SABA in moderate or severe exacerbations

in the emergency care setting, not the hospital setting.

Ipratropium bromide may be used as an alternative

bronchodilator for patients who do not tolerate

SABA.

(2). SABAs—albuterol, levalbuterol, and pirbuterol—are

bronchodilators that relax smooth muscle. They are

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the treatment of choice for relief of acute symptoms

and prevention of EIB. Increasing use of SABA

treatment or the use of SABA >2 days a week for

symptom relief (not prevention of EIB) generally

indicates inadequate asthma control and the need for

initiating or intensifying anti-inflammatory therapy.

Regularly scheduled, daily, chronic use of SABA is

not recommended.

(3). Systemic corticosteroids. Although not short-acting,

oral systemic corticosteroids are used for moderate

and severe exacerbations in addition to SABA to

speed recovery and to prevent recurrence of

exacerbations.

4). Surgery

Bronchial thermoplasty (BT), a new concept in the

treatment of asthma, aims to reduce the airway smooth muscle

(ASM) mass with the goal of diminishing bronchial constriction

and ameliorating asthma symptoms. The reduction in ASM is

accomplished by delivering controlled thermal energy to the

airway walls during a series of three bronchoscopies. The thermal

energy is delivered via the Alair system (Boston Scientific,

Natick, MA), which consists of a radiofrequency electrical

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generator and a single-use catheter with an expandable four-

electrode basket at its distal tip (Figure III) (Wahidi et al, 2011).

Bronchial thermoplasty has been shown to reduce the

ASM mass via radiofrequency ablation in healthy animal and

human airways; whether the reduction in ASM mass can be

reproduced in the airways of patients with asthma or is the only

mechanism responsible for the clinical benefits seen in patients

with severe asthma requires further study. Alternative or

contributing mechanisms of BT may include modification in the

extracellular matrix that can lead to fixed airway structure,

reduction of mucus gland hyperplasia with an accompanying

decrease in mucus production, or change in the autonomic tone of

the airway (Wahidi et al, 2011).

Figure 4. The thermoplasty catheter with a distal shaft

marked at 5-mm intervals and an expandable

basket carrying four electrodes (Wahidi et al,

2011).

31

Table VI. The Usual Dosages for Long-Term Control

Medications (Anonymous, 2005).

32

Table VII. The Usual Dosages for Quick-Relief Medications

(Anonymous, 2005)

33

F. Empirical Expectations

1. Characteristics of patients play a vital role in developing asthma.

2. There could be different patterns of treatment for patients based

on effectiveness of drugs used for respiratory disorders (anti-

inflammatory drugs and bronchodilators) in controlling the

severity of asthma.

34

CHAPTER II

RESEARCH METHODOLOGY

A. Study Design

This is an observational study performed retrospectively.

B. Sample

The target population in this study is patients diagnosed with asthma

from the age of 1 to 90 years. Samples will be selected according to the

inclusion and exclusion criteria. Data will be collected retrospectively and

will be obtained from patients’ medical record from RSUP Dr. Sardjito,

Yogyakarta for 1 year (January 2013 – December 2013).

C. Sample Size

To determine the minimum sample size for this study, simple random

sampling method is used (Sudigdo et al, 1995).

To estimate sample size of a population, 3 information needed:

i. Disease proportion that to be found, P (from literature)

ii. Standard error needed. D (estimated)

iii. Confidence level, α (estimated)

Note:

P = 0.5, d = 0.10, zα = 1.960

n = (1.96)2 (0.5)(1-0.5) = 97

(0.1)2

35

Therefore, the minimal sample size is 97.

D. Inclusion Criteria

1. Patients from the age of 1 to 90 years who are having asthma.

2. Patients who received only out-patient treatment from RSUP Dr.

Sardjito.

3. Patients whose medical records have complete data.

E. Exclusion Criteria

1. Patients who are having COPD.

2. Unclear record of therapy.

3. Unclear record of examination and diagnosis.

4. Mistake in classification.

F. Course of Study

The course of study is carried out using 2 steps, which is:

1. Obtaining data based on medical records from the Medical Installation of

that specific hospital.

Data obtained from the patient’s medical records will consist of the

patient’s age, medical history and the history of drugs used. Besides that,

the drugs that are currently being used by the patient and its outcome is

also taken into account. All these data’s are made as the resources of this

study without having to choose a specific sampling method.

2. Analyzing and processing data.

Data obtained from this study will be analyzed descriptively through a

non- experimental design by analyzing with further details such as the

36

characteristic of asthmatic patient, treatment patterns and also the

outcome of the treatment plan.

D. Definition of Operational Variable

1. The asthmatic patients which are being studied are patients whom are

suffering from asthmatic and is currently obtaining their treatment from

RSUP Dr. Sardjito, Yogyakarta.

2. Patient medical record, health record, and medical chart are used

somewhat interchangeably to describe the systematic documentation of a

single patient's medical history and medical care across time. The

medical record includes a variety of types of "notes" entered over time by

health care professionals, recording observations and administration of

drugs and therapies, orders for the administration of drugs and therapies,

lab test results, x-rays, reports, etc.

3. The characteristics of asthmatic patients comprise of age, sex, history of

comorbid illness, occupation, residence, education level, complication,

degree of asthma, and medical history.

4. Treatment patterns are models or forms of therapies which is provided for

the asthmatic patients through local therapy (surgery or radiotherapy).

5. The outcome at the end of a therapy is the condition of the patient after

the treatment plan has ended, or the presence or absence of complains

from the patient and the side effects experienced by the patient after

receiving the treatment (post-treatment).

37

E. Data Analysis

Based on the data obtained from the treatment of Asthma in RSUP Dr.

Sardjito, it was further processed and analyzed as follow:

1. Characteristics of Asthma patient

The distribution of the total percentage were calculated from the

total number of patients according to the distribution of age of the patient,

sex, history of combined illness with asthma, complications, degree of

asthma, and medical history and its divided to the total number of

asthmatic patient which are being treated and being the subject of study

in RSUP Dr. Sardjito, Yogyakarta.

2. Treatment pattern for asthmatic patient

The patients will be divided into groups according to monotherapy

or polytherapy and each group will be analysed for the pattern of

antiasthmatic drug for asthma treatment. The analysis will be in the form

of descriptive according to the group of antiasthmatic drugs and

combination used for each group. Subsequently, the data will be analysed

by comparing the usage of antiasthmatic drugs by asthma patients with

standard guideline which included the parameter of right drugs, right dose

and right patients.

3. Outcome of therapy

Patients grouping were performed based on their therapy outcome

as in those who improved after receiving treatment were grouped as one

and the others who did not show any improvement after receiving therapy

38

and those who died were grouped in separate groupings respectively.

Thus, each groups were calculated the total amount of patient and divided

with the total amount of patients overall before grouping to obtain a

percentage. Side effects from surgery also were analyzed and the side

effects which occurs frequently by the patient is calculated. Furthermore,

patients were also grouped based on their level of control which are

controlled patients and uncontrolled patients where uncontrolled patients

experience exacerbations.

39

CHAPTER III

RESULTS AND DISCUSSION

A. Characteristics Of Asthma Patients

The data collection of this study took exactly two months. As it

was mentioned previously, the subjects of the study were outpatients with

RSUP Dr. Sardjito, Yogyakarta period 2013. A total number of 120

asthma patients have been used in this study. The subjects were matched

according to the inclusion and exclusion criteria as exact as possible.

As can be seen in Table VIII, 120 patients were diagnosed with

asthma according to the degree of asthma and the presence of significant

eosinophil levels. Out of 120 patients, 41.6% (n=50) of them were with

mild intermittent asthma, 42.5% (n=51) patients with mild persistent

asthma, 14.2% (n=17) patients with moderate persistent and 1.7% (n=2)

patients with severe persistent asthma.

To strengthen the diagnosis of asthma, there must be the presence

of test for the levels of eosinophil. In this study out of 120 patients, 70.8%

(n=85) patients were with the level of high eosinophil, 29.2% (n=35)

patients with the level of normal eosinophil and 0% (n=0) with the level

of low eosinophil. Approximate equivalence to the above description are

high = more than 0 – 0.45 [103/µL] for adults, more than 0.2 – 0.3 [103/µL]

for infants aging 1 week to 6 months, more than 0.3 [103/µL] for infants

aging 1 year and more than 0 – 0.6 [103/µL] for children.

40

Therefore this study showed the most common asthma cases were

with the presentation of mild persistent asthma and high level of

eosinophil.

Table VIII. Classifications of Asthma patients in

RSUP Dr.Sardjito, Yogyakarta period

2013

Number of

Patients

(n=)

Percentage

(%)

Degree of Asthma

Mild Intermittent

(Mild symptoms up to 2 days a

week and up to 2 nights a

month)

(FEV1/FVC normal)

(FEV1 > 80% predicted)

50

41.6

Mild Persistent

(Symptoms more than twice a

week, but no more than once in

a single day)

(FEV1/FVC normal)

(FEV1 > 80% predicted)

51

42.5

Moderate Persistent

(Symptoms once a day and

more than 1 night a week)

(FEV1/FVC reduced < 5%)

(FEV1 > 60% t < 80%

predicted)

17

14.2

Severe Persistent

(Symptoms throughout the day

on most days and frequently at

night)

(FEV1/FVC reduced > 5%)

(FEV1 < 60% predicted)

2

1.7

Total 120 100

Level of Eosinophil

High 85 70.8

Normal 35 29.2

Low 0 0

Total 120 100

41

1. Age Group

The classifications of age among asthma patients in RSUP

Dr.Sardjito, Yogyakarta period 2013 is shown in Figure 5. This study

consists of 120 patients aged from 1 to 90 years old. This age range was

chosen because it is more likely for asthma to occur and are divided into

6 classes to differentiate the incidence of asthma.

Figure 5. Frequency and percentage of age group in

RSUP Dr.Sardjito, Yogyakarta period 2013

As can be seen on Figure 5 above, majority of patients belong to

the age group of 16-30 years old, 35.8% (n=43). This is gradually

followed by 31-45 years old with 22.5% (n=27), 46-60 years old with

18.3% (n=22), 61-75 years old with 13.3% (n=16), 1-15 years old with

8.3% (n=10) and finally 76-90 years old with 1.7% (n=2). From this

figure, it is clearly seen that asthma is more prone to occur in people

from the age group of 16-30 years old.

0

5

10

15

20

25

30

35

40

45

50

1 to 15 16 to 30 31 to 45 46 to 60 61 to 75 76 to 90

FREQ

UEN

CY

AGE

AGE

42

The National Health Interview Survey (NHIS) is a multi-purpose

health survey conducted by the National Center for Health Statistics

(NCHS), Centers for Disease Control and Prevention (CDC). It is the

principle source of information on the health of the civilian, non-

institutionalized, household population of the United States. Based on the

2011 NHIS sample, it was estimated that 39.5 million Americans, or

129.1 per 1,000 persons, had been diagnosed with asthma by a health

professional within their lifetime. Since 1999, children 5-17 years of age

have had the highest prevalence rates. In 2011, 8.7 million children ages

5-17 had been diagnosed with asthma in their lifetime (Anonymous,

2012d). Based on another study in Finland, there is a relationship between

age and the incidence of asthma where in the year 1996 to 1993, data was

collected from two national registers which cover practically all new cases

of occupational asthma and persistent asthma showed that the annual

incidence in the age group of 15 to 29 years increased by 87% (Reijula et

al., 1996). So, younger age is a common risk factor for asthma.

2. Gender

As Figure 6 shows below, it is obvious that the incidence of

asthma occurred more in female 69.2% (n=83).

43

Figure 6. Frequency and percentage of gender of

asthma patients in RSUP Dr. Sardjito,

Yogyakarta period 2013

The majority of patients were females. Male patients have shown

to have lower prevalence of asthma than female patients. Based on the

recent findings, the data illustrates striking sex-related differences in

asthma epidemiology and disease expression. Studies however has shown

an increase incidence of asthma in women. Data from this study

demonstrates that asthmatic women have a poorer quality of life and

increased utilization of healthcare compared to their male counterparts

despite similar medical treatment and baseline pulmonary function.

Research continues to explore hypotheses for these differences

including the potential influences of the female sex hormones, altered

perception of airflow obstruction, increased bronchial hyper-

responsiveness, and medication compliance and technique. However, no

30.8%n=37

69.2%n=83

GENDER

Male Female

44

single explanation has been able to fully explain the disparities. A 2009

National Health Interview Survey in the United States demonstrate a

prevalence of asthma in those less than 15 years of age of 11.9% in boys

and 7.7% in girls. In young adults aged 15 to 34 years, the pattern shifts,

with a prevalence of 6.3% in men and 9.6% in women. The difference

continues to widen in adults older than 35 years with prevalence of 5.6

versus 10.1% in men and women respectively (Kynyk et al., 2011).

3. Residence

As Figure 7 shows below, it is obvious that the incidence of

asthma occurred more in rural residence 64.2% (n=77).

Figure 7. Frequency and percentage of residence in

asthma patients in RSUP Dr. Sardjito,

Yogyakarta period 2013

The majority of patients were from ruralized area. Urban residents

have shown to have lower prevalence of asthma than rural residents. This

35.8%n=43

64.2%n=77

RESIDENCE

URBAN RURAL

45

could be due to the beneficial effect of the air humidity, effect of physical

activity, a more sedentary lifestyle, the level of education, the level of

hygiene in the area and a level of stress among the urbanized residents.

4. Types of Occupation

Figure 8 shows that out of 120 patients in RSUP Dr. Sardjito,

29.2% (n=35) were privates. Private has the highest percentage among

other occupations. Due to incomplete information in the patient’s medical

record, it is unclear if the privates were doing any other jobs to earn extra

income for the family and most probably the privates has higher

workloads compared to other occupation thus causing increase in the

stress level causing them to be more prone to asthma.

Figure 8. Frequency and percentage of types of

occupation in asthma patients in RSUP Dr.

Sardjito, Yogyakarta period 2013

23.3%

27.5%29.2%

2.5%

17.5%

0

5

10

15

20

25

30

35

Housewife Student Private Farmer Unknown

FR

EQ

UE

NC

Y

OCCUPATION

OCCUPATION

46

Even though some authors have not found any difference in

asthma outcomes between privates and other occupations, most

publications state that workers have adverse outcomes. Based on an

article by the American Lung Association State of Lung Diseases in

Diverse Communities published in the year 2010 which included four

states in their study which are California, New Jersey, Massachusetts, and

Michigan which tracked cases of occupational asthma over a seven-year

period. During this time, the occupations with the highest percentage of

asthma cases were operators, fabricators, and laborers (32.9%) where they

were most associated with miscellaneous chemicals (19.7%), cleaning

materials (11.6%), mineral and inorganic dust (11.1%) and indoor air

pollutants (9.9%) (Anonymous, 2010b). Therefore we can say that most

probably the patients from RSUP Dr. Sardjito suffering from asthma who

are working in the private sector has the highest percentage of incidence

most probably due to higher association with asthma allergens.

5. Obesity and Overweight

According to the Figure 9 below, showed out of 120 asthma

patients in RSUP Dr. Sardjito, Yogyakarta period 2013 41.7% (n=50)

were in the normal body mass index (BMI), followed by overweight

37.5% (n=45), underweight 15% (n=18) and lastly obese 5.8% (n=7).

47

Figure 9. Frequency and percentage of the body mass

index in asthma patients in RSUP Dr. Sardjito,

Yogyakarta period 2013

Based on a recent study in the United States, the rate of asthma

increased with increasing body mass index (BMI), with obese man or

women having the highest incidence. Compared with normal weight

people, obese people (BMI ≥ 30 kg/m2) had a higher risk for asthma.

Based on a study done is Brazil, it is observed that asthma causes

an alarming concomitant increase in obesity, which prevalence reaches

epidemic proportions (Saude et al., 2011). A survey data (POF

2008/2009) showed that asthma patients being overweight affects 50.1%

of men and 48% of adult women, and of that group, 12.4% of men and

16.9% of women are obese (IBGE et al., 2010). This is because, an

increasing body of literature suggests that there is an association between

obesity and asthma (Nystad et al., 2004). Moreover, studies report that

15%

41.7%

37.5%

5.8%

0

10

20

30

40

50

60

Underweight Normal weight Overweight Obese

FREQ

UEN

CY

BMI

BMI

48

individuals with persistent asthma are significantly limited in the practice

of physical activity, thus reducing energy expenditure, a fact that

contributes to the growing increase in the prevalence of overweight and

obesity (Ford et al., 2005).

Based on my study in asthma patients in RSUP Dr. Sardjito, the

highest number of patients were from the normal body mass index (BMI)

which ranged from 18.5 – 24.9 kg/m2 and this does not tally with the

previous studies. Most probably this is because, most of the asthma

patients in RSUP Dr. Sardjito are from the rural areas and can be

considered as low income people and are not able to spend a lot of money

on food and having heavy workload to earn little amount of money

causing them to have a normal body mass index (BMI) or low body mass

index (BMI) where the underweight (<18.5 kg/m2) and normal as stated

above.

B. Complications in Asthma

Based on an article published in Medline Plus there are certain

possibilities of complications occurring in an asthma patient. The

complications of asthma as stated can be severe and may include death,

decreased ability to exercise and take part in other activities, lack of sleep

due to nighttime symptoms, permanent changes in the function of the

lungs, persistent cough and trouble breathing that requires breathing

assistance such as ventilator (Busse, 2013).

49

However, the study performed were done retrospectively and thus

no interview with the patients were required to obtain the quality of life

of the patients from RSUP Dr. Sardjito and the data were just collected

based on the medical records of the patients. Therefore precise

information of whether there were decreased ability to exercise or lack of

sleep due to nighttime symptoms and other complications were not able

to be obtained. Besides that, based on the medical records, there were no

deaths recorded due to complications in RSUP Dr. Sardjito thus shows us

a 0% (n=0) mortality rate due to asthma complications. On the other hand,

the lack of complete data of the follow ups and visits to the hospital in the

medical record of RSUP Dr. Sardjito was a limiting factor to conduct

further analysis on the complications of asthma.

C. Asthma with other Combined Illness

Figure 10 shows that, out of 120 patients 78 patients were reported

to have combined illness with asthma in RSUP Dr. Sardjito, Yogyakarta.

Hypertension has the highest percentage among the group with 25.8%

(n=31). Hypertension is defined as systolic blood pressure of > or = 140

mmHg and or diastolic blood pressure of > or = 90 mm Hg.

50

Figure 10. Percentage of asthma patients with combined

illness in RSUP Dr. Sardjito, Yogyakarta period

2013

Based on a study, it is stated that both asthma and hypertension

are spastic disorders of smooth muscle, also asthmatics and hypertensives

have been found to be salt sensitive. Therefore, there is a suspicion that

the similarities between these two diseases may predispose the individuals

with one disease to the other, as pulmonary hypertension has been

described during exercise-induced bronchoconstriction. In this study, the

blood pressure pattern during and after acute severe asthma (ASA) along

with the frequency of hypertension in stable asthmatic patients were

studied. Two groups of patients were studied. Group 1 consisted of 12

patients with ASA (2 males, 10 females) with a mean age of 30 +/- 9.9

years. The mean blood pressure during attack of ASA (147 +/- 16.9/100

+/- 8.2 mmHg) was higher than the mean BP (132 +/- 8.3/82 +/- 7 mmHg)

25.80%

6.70%

20.80%

11.70%

8.30%

7.50%

5.80%

35%

Hypertension

Diabetes Mellitus Type 2

Brochitis

Allergic Rhinitis

Heart Diseases

GERD

Dislipidemia

None

CO

MB

INED

ILLN

ESS

Percent (%)

51

2 weeks after discharge from hospital without treatment in all patients (P

< 0.05). Group 2 included 134 asthmatic subjects in stable state (54 males,

80 females) with a mean age of 45 +/- 15 years and a range of 15-90 years.

The overall frequency of hypertension was 37% with a proportion of 39%

in males and 35% in females. There was no difference between the

frequency of attack of ASA in hypertensives (5.7 +/- 5.6 per year) and

non-hypertensives (5.5 +/- 3.8 per year), P < 0.05. From that, it was

concluded that the transient elevation of blood pressure may occur during

ASA. This shows that the frequency of hypertension among asthmatics is

quite high (Salako et al, 2000).

Besides that there are also stress induced asthma, therefore due to

high levels of stress can cause increase in the incidence of hypertension

due to increase in blood pressure.

Based on another study performed in Italy, a population-based

retrospective study using information obtained from the Health Search

Database (HSD) showed that asthma appeared to be also associated with

cardiovascular and hypertensive diseases as hypertension was the second

highest at 28.33% in the demographic characteristics of study population

by prevalence of comorbidities. Although asthma appeared to be weakly

associated with cardiovascular and hypertensive diseases and more

strongly associated with gastro-oesophageal reflux disease (GORD) and,

particularly, allergic rhinitis, it doesn’t mean that the disease prevalence

is not significant thus most probably the focus of study for comorbid

52

illness associated with asthma were more focused on diseases related to

the respiratory system such as bronchitis, allergic rhinitis and pneumonia

and the side effects of the use of anti-asthmatic drug such as theophylline

which is more responsible to the cause of GORD and the higher

prevalence of this disease (Cazzola et al, 2010).

D. Treatment And Management Of Asthma

Below are the results of 120 asthma patients in RSUP Dr. Sardjito,

Yogyakarta period 2013 during their visits to the hospital as outpatients:

1. Pattern of anti-asthmatic therapy based on monotherapy or

polytherapy

Data was taken by observing the pattern of anti-asthmatic

therapy in outpatients and are presented in Figure 11. The main

purpose here is to evaluate the differences in the pattern of therapy

among outpatients. From Figure 11 out of 120 asthma patients

during outpatient, 81.7% (n=98) were on polytherapy (consuming

two or more drugs) while 18.3% (n=22) were on monotherapy

(consuming a single drug). This study shows that most asthmatic

patients are on polytherapy.

The main aim of asthma management is control of the

disease. Therefore complete control of asthma can be defined as

no daytime symptoms, no night-awakening due to asthma, no need

for rescue medication, no exacerbations, no limitations on activity

including exercise, normal lung function (in practical terms FEV1

53

and/or PEF >80% predicted or best) and minimal side effects from

medication (Anonymous, 2012b). Therefore this study shows

that polytherapy is more frequently utilized than monotherapy.

Figure 11. Pattern of therapy in asthma patients in

RSUP Dr. Sardjito, Yogyakarta period

2013

There is a small number of patients on monotherapy and

this could be due to the number of asthma attacks occurred and

how controlled the asthma is in the patients and most probably due

to the effectiveness of a single drug to control the symptoms of

asthma. For patients without underlying medical problems, anti -

asthmatics drug therapy should be used to keep the asthma

symptoms under control as in less number of symptom episodes

per week, less number of nocturnal symptoms per month, and

improvement in the lung function (Anonymous, 2012a).

81.7%

n=98

18.3%

n=22

Type of Therapy

Polytherapy Monotherapy

54

Table IX. Single anti-asthmatics according to group given

to asthma patients in RSUP Dr. Sardjito,

Yogyakarta period 2013

Agent Frequency

(n=)

Percentage

(%)

Glucocorticosteroid

1. Inhaled Corticosteroid

2. Systemic Corticosteroid

69

33

57.5

27.5

Long Acting Beta2-Agonist 35 29.2

Short Acting Beta2-Agonist 99 82.5

Theophylline 52 43.3

For patients without underlying medical problems, anti-asthmatics

drug therapy should be used to keep the asthma symptoms under control

as in less number of symptom episodes per week, less number of

nocturnal symptoms per month, and improvement in the lung function

(Anonymous, 2012a).

In RSUP Dr. Sardjito, short acting beta2-agonist (SABA) was

administered 82.5% (n=99) if the asthma symptoms occurred and act as

relievers in the form of nebulizers or metered dose inhalers (MDI)/spacer

with dosage of 2 to 4 puffs as needed for symptoms every 4 to 6 hours

depending on the severity.

Based on an article in WebMD, it was stated that short-acting

beta2-agonists are bronchodilators and they relax the muscles lining the

airways that carry air to the lungs (bronchial tubes) within 5 minutes. This

55

increases airflow and makes it easier to breathe. They relieve asthma

symptoms for 3 to 6 hours. This group is most used due to the quick relief

symptoms that it provides during asthma attacks and acts as a reliever

before other steps could be taken. Furthermore, it is also stated that fewer

side effects are caused throughout the body than the oral forms

(Anonymous, 2012e). Examples of short acting beta2-agonists used in

RSUP Dr. Sardjito are albuterol/salbutamol, terbutaline and levalbuterol.

In this study, it is observed that inhaled corticosteroid was

administered 57.5% (n=69) in the form of nebulizers and inhalers with the

dosage varying on the severity of the disease, the drugs and the age of the

patient as in there is an adult dose for ≥12 years old and child dose for

<12 years old. The types of inhaled corticosteroid commonly used in

RSUP Dr. Sardjito were Budesonide DPI (Pulmicort Turbuhaler), and

Fluticasone DPI (Flixotide).

In this study, theophylline was administered 43.3% (n=52) in the

form of tablet and a dosage of 150 mg with frequency of three times a

day.

Besides that, long acting beta2-agonist were also one of the drug

groups administered by patients in RSUP Dr. Sardjito 29.2% (n=35) in

the form of nebulizers and inhalers with the dosage varying on the severity

of the disease, the drugs and the age of the patient as in there is an adult

dose for ≥12 years old and child dose for <12 years old. The types of long

56

acting beta2-agonists commonly used in RSUP Dr. Sardjito is formoterol

DPI and salmeterol DPI.

Lastly but not least, systemic corticosteroid was administered

27.5% (n=33) in the form of tablet and a dosage of 8, 16, and 32 mg

with frequency of three to four times a day depending on severity of the

disease.

2. Comparison with British Guideline on the Management of

Asthma 2012: A national clinical guideline

As based on the 2012, British Guideline On The

Management Of Asthma, there are several steps in controlling

asthma symptoms. As for step one which is known as the mild

intermittent asthma, the first drug of choice are the following

medications which act as short-acting bronchodilators which are

inhaled short-acting inhaled short-acting β2 agonists, inhaled

ipratropium bromide (anticholinergics), β2 agonists tablets or

syrup and theophylline. These short acting β2 agonists work more

quickly and/or with fewer side effects than the alternatives. Using

short-acting β2 agonists as required is at least as good as regular (four

times a day) administration. Good asthma control is associated with little

or no need for short-acting β2 agonist. Using two or more canisters of

β2 agonists per month or >10-12 puffs per day is a marker of poorly

controlled asthma that puts patients at risk of fatal or near-fatal asthma.

57

Therefore patients should have their asthma management reviewed

(Anonymous, 2012b).

As for step two, three, and four, treatments have been judged

on their ability to improve symptoms, lung function, and prevent

exacerbations, with an acceptable safety profile. Step two states the

introduction of regular preventer therapy for an asthma patient. In this

step, inhaled steroids can be said as the most effective preventer drug for

adults and older children for achieving overall treatment goals. There is

increasing body of evidence demonstrating that, at recommended

doses, they are also safe and effective in children under five years with

asthma. Inhaled steroids should be considered for adults, children aged 5-

12 and children under the age of five with any of the following features:

using inhaled β2 agonists three times a week or more; symptomatic three

times a week or more; or waking one night a week. In addition, inhaled

steroids should be considered in adults and children aged 5-12 who have

had an exacerbation of asthma requiring oral corticosteroids in the last

two years. In a mild to moderate asthma, starting at very high doses of

inhaled steroids and stepping down confers no benefit, therefore it is said

that patients should be started with a dose of inhaled steroids which is

appropriate to the severity of the disease. In adults, a reasonable starting

dose will usually be 400 micrograms BDP per day and in children 200

micrograms BDP per day. In children under five years, higher doses may

be required if there are problems in obtaining consistent drug delivery.

58

Later the dose of inhaled steroid should be titrated to the lowest dose at

which effective control of asthma is maintained. Regarding the frequency

of dosing of inhaled steroids, most current inhaled steroids are slightly

more effective when taken twice rather once daily, but may be used once

daily in some patients with milder disease and good or complete control

of their asthma (Anonymous, 2012b) .

Comparing the types of inhaled steroids, BDP and budesonide

are approximately equivalent in clinical practice, although there may be

variations with different delivery devices. There is limited evidence from

two open studies of less than ideal design that budesonide via the

turbohaler is more clinically effective. However, at present a 1:1 ratio

should be assumed when changing between BDP and budesonide.

Fluticasone provides equal clinical activity to BDP and budesonide at half

the dosage. The evidence that it causes fewer side effects at doses with

equal clinical effect is limited. Mometasone appears to provide equal

clinical activity to BDP and budesonide at half the dosage. The relative

safety of mometasone is still not fully established.

Based on Table X below, it shows the types of inhaled

steroids with its equivalent doses and the current licensed age

indications. The safety of inhaled steroids for adults shows that there is

little evidence that doses below 800 micrograms BDP per day cause any

short term detrimental effects apart from the local side effects of

dysphonia and oral candidiasis. However, the possibility of long term

59

effects on bone has been raised. One systematic review reported no

effect on bone density at doses up to 1,000 micrograms BDP per day. The

significance of small biochemical changes in adrenocortical function is

unknown. Thus, it is said that the dose of inhaled steroid should be titrated

to the lowest dose at which effective control of asthma is maintained.

Table X. Equivalent doses of inhaled steroids relative to

BDP and current licensed age indications

(Anonymous, 2012b)

60

Based on this guideline, it is also stated that administration of

inhaled steroids at or above 400 micrograms BDP a day or equivalent

may be associated with systemic side effects. These may include growth

failure and adrenal suppression. Isolated growth failure is not a

reliable indicator of adrenal suppression and monitoring growth cannot be

used as a screening test of adrenal function. Clinical adrenal insufficiency

has been identified in a small number of children who have become

acutely unwell at the time of intercurrent illness. Most of these children

had been treated with high doses of inhaled corticosteroids. The dose or

duration of inhaled steroid treatment required to place a child at risk of

clinical adrenal insufficiency is unknown but is likely to occur at ≥800

micrograms BDP per day or equivalent. The low-dose ACTH test is

considered to provide a physiological stimulation of adrenal

responsiveness but it is not known how useful such a sensitive test is at

predicting clinically relevant adrenal insufficiency. In addition, it is

unknown how frequently tests of adrenal function would need to be

repeated if a child remained on high-dose inhaled corticosteroid. At

higher doses, add-on agents, for example, long-acting β2 agonists, should

be actively considered. While the use of inhaled corticosteroids may be

associated with adverse effects (including the potential to reduced bone

mineral density) with careful inhaled steroid dose adjustment, this risk is

likely to be outweighed by their ability to reduce the need for multiple

bursts of oral corticosteroids. Due to this, there should be monitoring of

61

the growth (height and weight centile) of the children with asthma on

annual basis. Furthermore, the lowest dose of inhaled steroids compatible

with the maintaining disease control should be used. As for children

treated with ≥ 800 micrograms BDP per day or equivalent, specific

written advice about steroid replacement (e.g. Steroid Alert Card) in the

event of a severe intercurrent illness or surgery should be part of the

management plan and the child should be under the care of a specialist

pediatrician for the duration of treatment (Anonymous, 2012b).

Other preventer therapies are also available but inhaled steroids

are the first choice preventer drug. It is also known that long-acting β2

agonists should not be used without inhaled corticosteroids. Patients

taking short-acting β2 agonists alone are a less effective preventer

therefore it is suggested that theophylline should be taken as well as

theophylline have some beneficial effect. Moreover, in children under

five years who are unable to take inhaled corticosteroids, leukotriene

receptor antagonists are an effective first line preventer (Anonymous,

2012b).

Step three states the initial add-on therapy for asthma treatment.

A proportion of patients with asthma may not be adequately controlled at

step two. Therefore, before initiating a new drug therapy, practitioners

should recheck adherence, inhaler technique and eliminate trigger factors.

The duration of a trial of add-on therapy will depend on the desired

outcome. For instance, preventing nocturnal awakening may require a

62

relatively short trial of treatment (days or weeks), whereas preventing

exacerbations of asthma or decreasing steroid tablet use may require a

longer trial of therapy (weeks or months). If there is no response to the

treatment the drug should be discontinued. Options for add-on therapy are

summarized in Figure 12 below (Anonymous, 2012b).

Figure 12. Summary of the Add-on therapy in adults and

children > 5 years (Anonymous, 2012b)

Following a review in 2007 of LABA in the treatment of adults,

adolescents, and children with asthma, the Medicines and Healthcare

products Regulatory Agency (MHRA) further reviewed the use of LABA,

specifically in children younger than age 12 years and concluded that the

benefits of these medicines used in conjunction with inhaled

corticosteroids in the control of asthma symptoms outweigh any apparent

risks. Long-acting inhaled β2 agonists should only be started in patients

who are already on inhaled corticosteroids, and the inhaled corticosteroid

63

should be continued. In efficacy studies, where there is generally good

compliance, there is no difference in efficacy in giving inhaled steroid and

a long-acting β2 agonist in combination or in separate inhalers. In clinical

practice, however it is generally considered that combination inhalers aid

compliance and also have the advantage of guaranteeing that the long-

acting β2 agonist is not taken without the inhaled steroids.

As for step four, it is all about poor control on moderate dose of

inhaled steroid plus add-on therapy which means there is an addition of a

fourth drug. In a small proportion of patients, asthma is not adequately

controlled on a combination of short-acting β2 agonist as required, inhaled

steroid (800 micrograms BDP daily), and an additional drug, usually a

long-acting β2 agonist. There are very few clinical trials in this specific

patient group to guide management. The following recommendations are

largely based on extrapolation from trials of add-on therapy to inhaled

steroids alone. If control remains inadequate on 800 micrograms BDP

daily (adults) and 400 micrograms daily (children) with an inhaled steroid

plus a long-acting β2 agonist, the following interventions are considered

as in increasing inhaled steroids to 2000 micrograms BDP/day (adults) or

800 micrograms BDP/day (children 5-12 years), adding a leukotriene

receptor antagonists, a theophylline, and a slow release β2 agonist tablets,

though caution needs to be used in patients already on long-acting β2

agonists. There are no controlled trials indicating which one of these is

the best option, although the potential for side effects is greater with

64

theophylline and β2 agonist tablets. If a trial of an add-on treatment is

ineffective, stop the drug (or in the case of increased dose of inhaled

steroid, reduce to the original dose). Before proceeding to step five, the

patients with inadequately controlled asthma, especially children, should

be referred to specialist care.

The last but not least is step five which is about continuous

or frequent use of oral steroids. The aim of treatment is to control asthma

using the lowest possible doses of medication. Some patients with very

severe asthma which are not controlled at step four with high dose of

inhaled corticosteroids, and who have also been tried on or are still taking

long-acting β2 agonists, leukotriene antagonists or theophylline, require

regular long term steroid tablets. For the small number of patients not

controlled at step four, use daily steroid tablets in the lowest dose

providing adequate control. Figure 13 and 14 below summaries the

stepwise management in adults and children with asthma. As for steroid

formulations prednisolone and methyl prednisolone are the most widely

used steroid for maintenance therapy in chronic asthma. There is no

evidence that other steroids offer an advantage. Patients on long term

steroid tablets (e.g. longer than three months) or requiring frequent

courses of steroid tablets (e.g. three to four per year) will be at risk of

systemic side effects.

65

Figure 13. Stepwise management of Asthma in adults

(Anonymous, 2012b)

66

Figure 14. Stepwise management of Asthma in children

aged 5-12 years (Anonymous, 2012b)

67

Table XI. Combination of anti-asthmatics given to asthma

patients in RSUP Dr. Sardjito, Yogyakarta period

2013

Combinations Frequency

(n=)

Percentage

(%) SABA’s + Theophylline 13 12.7

SABA’s + SCS 7 6.9

LABA’s + ICS 9 8.8

ICS + Theophylline 2 2.0

SABA’s + ICS 12 11.7

SABA’s + Anticholinergic 1 1.0

SABA’s + Theophylline + Anticholinergic 1 1.0

SABA’s + LABA’s + Theophylline 2 2.0

SABA’s + ICS + SCS 8 7.8

SABA’s + ICS + Anticholinergic 1 1.0

SABA’s + SCS + Anticholinergic 2 2.0

SABA’s + ICS + Theophylline 10 9.8

SABA’s + SCS + Theophylline 5 4.9

LABA’s + SCS + ICS 1 1.0

LABA’s +ICS + Theophylline 4 3.9

LABA’s + SABA’s + ICS 7 6.8

LABA’s + SABA’s + ICS + Anticholinergic 1 1.0

SABA’s + LABA’s + Theophylline + SCS 1 1.0

SABA’s + LABA’s + Theophylline + ICS 6 5.8

LABA’s + ICS + SCS + Theophylline 1 1,0

SABA’s + ICS + SCS + Anticholinergic 3 2.9

SABA’s + ICS + SCS + Theophylline 1 1.0

ICS + SCS + Theophylline + Anticholinergic 1 1.0

SABA’s + LABA’s + ICS + SCS 1 1.0

SABA’s + LABA’s + ICS + SCS +

Theophylline

2 2.0

Total 102 100 *ICS = Inhaled Corticosteroid; SCS = Systemic Corticosteroid; SABA’s = Short-acting β2 Agonist;

LABA’s = Long-acting β2 Agonist.

As seen in Table 11 above, in terms of dual anti-asthmatic

therapy, the most widely used combination in RSUP Dr. Sardjito was

short-acting β2 agonist and theophylline, which represented around 12.7%

(n=13) of dual therapy combinations with dosage of short-acting β2

agonist which can vary from 2 to 4 puffs as needed for symptoms and up

to 3 treatments at 20-minute intervals or a single nebulizer treatment as

needed and theophylline 10 mg/kg/day.

68

Based on a recent study, a total of eight studies were included. In

comparing the effect of theophylline combined with beta2-agonists to that

of a placebo, we found a statistically significant improvement in mean

FEV1 (0.27 L; 95% CI: 0.11 to 0.43) and mean dyspnea (-0.78; 95% CI:

-1.26 to -0.29). None of the Meta analyses performed detected any

difference between the results obtained using theophylline combined with

beta2-agonists and those obtained using beta2-agonists alone. When the

administration of theophylline combined with beta2-agonists was

compared to that of theophylline alone, there was a statistically significant

improvement in mean dyspnea (0.19; 95% CI: -0.34 to 0.04) (Zacarias et

al, 2007).

The second highest combination therapy administered in RSUP

Dr. Sardjito was dual combination of short-acting β2 agonist with inhaled

corticosteroid 11.7% (n=12).

As for the triple combination therapy administered in RSUP Dr.

Sardjito, the highest was the combination of short-acting β2 agonist with

inhaled corticosteroid and theophylline 9.8% (n=10).

The addition of theophylline in a combination therapy may be

used as a long term controllers for asthma symptoms as a second or third-

line agent or in patients whose asthma control is still inadequate therefore

trial of other add-on therapy such as leukotriene receptor antagonist or

theophylline is suggested. It is also known that theophylline may improve

69

lung function and symptoms, but side effects occur more commonly

(Anonymous, 2012b).

There were also combination of four types of anti-asthmatic

agents used in RSUP Dr. Sardjito and the highest number of usage were

short-acting β2 agonist with long-acting β2 agonist with inhaled

corticosteroid and theophylline 5.8% (n=6). The addition of the fourth

drug is also due to inadequate control of asthma symptoms (Anonymous,

2012b).

Furthermore, there were also combination of five types of anti-

asthmatics from different groups which consist of short-acting β2 agonist

with long-acting β2 agonist with inhaled corticosteroid, systemic

corticosteroid as well as theophylline 2% (n=2). This treatment was most

probably due to exacerbation of the disease and only two patients were

prescribed with these combinations of five different groups of anti-

asthmatic.

Inhaled corticosteroid are mostly contraindicated in children < 2

years as we can see according to the guideline. Most of the inhaled

corticosteroid are only administered for patients over age 2 because

consuming these group of drugs for infants < 2 years of age might affect

their metabolic organs such as liver due to the lack of full organ function.

Besides that, corticosteroids can also cause systemic side effects such as

growth failure and adrenal suppression (DiPiro et al, 2009).

70

Therefore, since there were one prescription involving inhaled

corticosteroids it can be considered as high risked decision taken by the

responsible physician in RSUP Dr. Sardjito, Yogyakarta.

E. Management On Prevention Of Asthma

Prevention of asthma can be performed by performed by surgery

which is also known as bronchial thermoplasty. This is a new concept in

the management on prevention of asthma, where aims to reduce the

airway smooth muscle (ASM) mass with the goal of diminishing

bronchial constriction and ameliorating asthma symptoms (Wahidi et al,

2011).

Sadly, this procedure has not reached this country and therefore

none have performed the surgery. Therefore, it couldn’t be analyzed

further due to insufficient resources and data.

F. Outcome of Therapy

Since the ultimate treatment for asthma is the control and

management of the symptoms and the quality of life besides

administration of anti-asthmatic drugs, based on Figure 15 within the

visits as outpatient in RSUP Dr. Sardjito 60.8% (n=73) controlled

symptoms were reported and has the highest percentage of outcome.

71

Figure 15. Frequency and percentage on outcome of

therapy in asthma patients in RSUP Dr.

Sardjito, Yogyakarta period 2013

This is followed by uncontrolled 35% (n=42) and 4.2% (n=5) for

non-stated outcomes respectively. Controlled outcomes can be defined as

when there is no daytime symptoms, no night-time awakening due to

asthma, no need for rescue medication, no exacerbations, no limitations

on activity including exercise, normal lung function and minimal side

effects from medication.

Based on a study, the relationship between baseline ACQ-5 and

exacerbations was investigated. A Markov analysis examined the

transitional probability of change in control status throughout the studies.

From this study, the percentage of patients achieving asthma control

increased with time, irrespective of treatment; the percentage

Controlled/Partly Controlled at study end was at least similar to

budesonide/formoterol maintenance and reliever therapy versus the 3

60.8%

35%

4.2%

0

10

20

30

40

50

60

70

80

Controlled Uncontrolled Not Stated

Freq

uen

cy

Outcome

Outcome

72

maintenance therapies: higher dose ICS (56% vs 45%), same dose

ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%).

Baseline ACQ-5 score correlated positively with exacerbation rates. A

Controlled or Partly Controlled week predicted at least Partly Controlled

asthma the following week (≥80% probability). The better the control, the

lower the risk of an uncontrolled week. The probability of an exacerbation

was related to current state and was lower with budesonide/formoterol

maintenance and reliever therapy (Bateman et al, 2010).

Outcome based on quality of life were not been able to be

evaluated due to the type of study carried out which was a retrospective

study and no questionnaire were done and used to carry out interviews to

obtain precise information on the improvement of the patients quality of

life.

73

CHAPTER IV

CONCLUSION AND SUGGESTIONS

A. Conclusion

1. During the 1st of January 2013 to 31st December 2013, common

risk factors of asthma found were at the age of 16 to 30 years

35.8%, gender 69.2% for females, residence 64.2% for rural

residency, and occupation 29.2% for privates. Uncommon risk

factors found were obesity.

2. Evaluation of treatment in asthma patients showed results of

81.7% patients were under polytherapy with the most common

dual anti-asthmatics which are short-acting β2 agonist +

theophylline 12.7% as the most common combination anti-

asthmatic drugs given.

3. Management on prevention of asthma is through the procedure of

having a surgery called Bronchial Thermoplasty but due to

insufficient technology in this country, this procedure is yet to be

introduced therefore it cannot be evaluated.

4. Overall, the drug pattern and management of asthma patients in

RSUP Dr. Sardjito, Yogyakarta were correct according to the

British Guideline On Management Of Asthma (2012) with

outcome therapy of 60.8% controlled symptoms but there were

several high risked decision taken by the responsible physician in

74

RSUP Dr. Sardjito, Yogyakarta prescribing inhaled corticosteroid

for an infant below the age of 2 years.

B. Suggestions

1. For future researcher

For this study it is best to be performed as prospective

study because data collected will be more accurate and

researcher will have detailed information about patient’s

condition.

2. For hospital

a. Regarding the patient’s medical record, physicians should

write in detail of patient’s characteristics, such a family

history and outcome after receiving treatment as the lack

of complete data limits further analysis on risk factors.

This will help researchers in future to obtain complete data

and significant risk factors.

b. Physicians should also fill the treatment and management

sheet with great detail and not leaving any detail blank for

example pharmaceutical form of drugs given. This will help

researchers to understand physicians’ choices and decisions.

75

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