PHILIPPINES Asthma Consensus Guidelines 2009
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PHILIPPINES Asthma Consensus Guidelines 2009
Transcript of PHILIPPINES Asthma Consensus Guidelines 2009
PREFACE
Despite the fact that much is presently known about the clinical, pathologic and cellular mechanisms of asthma, it remains to be a
major cause of chronic morbidity and mortality not only in the Philippines but also throughout the world. It is indeed a complex disease
that lends itself to a wide variation of presentation and response to medication and makes a single approach to treatment virtually
impossible. Hence, the continued efforts of health professionals to update existing guidelines that aimed to rationalize the diagnosis
and approach to treatment of this disease.
The Philippine Consensus Report on Asthma Diagnosis and Management of Asthma (PCRADM), the local consensus report
formulated by the Council of Asthma of the Philippine College of Chest Physicians (PCCP), first saw light in 1996. The updated 2004
evidence-based report took all of three years to complete. After five years, the Council feels the time is right to go over the two
guidelines again, revise and consolidate them, and in the end, come up with an updated document that will address the concerns of
local practitioners tasked with the management of asthma. Applicability of the consensus report to what is the reality in the Philippine
setting is the ultimate goal of this updated report.
The present document is a product of some eight months of hard work. It was the Council decision that the updated report will be
largely based on the 2007 GINA document, with emphasis placed on the inclusion of current local evidence that will make it more
relevant to the Filipino practitioner involved in the asthma care. In this context, the reader will find obvious similarities in the chapter
chronology and discussion of topics between the latest document and our updated report. The relative paucity of published studies on
asthma, however, makes it imperative that each chapter of our updated report should end with recommendations to bridge such gaps in
knowledge on diagnosis and management.
Over and beyond the similarities with GINA, however, the Council is very proud of its differing stand in the classification and
approach to treatment of asthma. We carried over the simpler classification of asthma, which first appeared in the 2004 PCRADM
update. Likewise, the approach to treatment in this current update is a modification of the original GINA recommendation, and an
improvement to what was proposed in the 2004 document. In both instances, the Council is aiming to find greater acceptance and
eventual usage of its updated guidelines by the Filipino physician managing asthmatic patients.
The completion of this updated report would not be possible without the diligence, perseverance, and single-minded determination
of the core group of eighteen Asthma Council members who laboured long hours reviewing voluminous number of journal articles,
research papers and other publications, then adapted them using the GINA as “template” to come up with what you now have in your
hand, the product of Asthma Consensus Report Update (ACRU) Project of the Philippine College of Chest Physicians Council on
Asthma, the new Philippine Consensus Report on Asthma Diagnosis and Management 2009. Much of the credit should go to Dr. Dina
V. Diaz who spearheaded the project and was its moving force from conceptualization to final publication. We likewise acknowledge
the Herculean efforts of our project secretary, Dr. Eloisa S. De Guia, who, despite all odds, managed to meet the set deadlines in
finalizing this update report. Somewhere in this document is the list of the core Asthma Council members, without that invaluable
contribution on this consensus report would not have been possible. Lastly, our heartfelt gratitude goes to AstraZeneca Philippines,
Inc. for their commitment and generous support of this undertaking from start to finish.
We, in the Asthma Council, hope that this document will find wide acceptance not only among the pulmonary specialists, internists,
fellows-in-training, resident physicians, and but also all medical practitioners who manage patients with asthma. With the plans for a
nationwide dissemination process of the updated report already in place, we likewise look forward to this report being a useful tool to
affect a better, more scientific and more rational approach to the diagnosis and management of asthma.
TITO C. ATIENZA, M.D., FPCCP
Chairman, Council on Asthma
Philippine College of Chest Physicians
TABLE OF CONTENTS
Preface.................................................................................................................................................................................................. v
Chapter 1 – Definition and Overview
1. Definition.................................................................................................................................................................................... 2
2. Burden of Asthma...................................................................................................................................................................... 3
3. Pathophysiologic Mechanisms.................................................................................................................................................. 6
4. Pathogenesis............................................................................................................................................................................. 8
Chapter 2 – Diagnosis and Classification
1. Introduction....................................................................................................... ....................................................................... 16
2. Clinical Diagnosis.................................................................................................................................................................... 16
3. Diagnostic Challenges and Differential Diagnosis................................................................................................................... 21
4. Classification of Asthma ......................................................................................................................................................... 22
5. Asthma Severity and Control a new perspective..................................................................................................................... 22
Chapter 3 – Asthma Medications
1. Introduction............................................................................................................................................................................... 32
2. Route of Administration ............................................................................................................................................................ 32
3. Controller Medications .............................................................................................................................................................. 32
4. Reliever Medications ................................................................................................................................................................. 37
Chapter 4 – Patient Education
1. Asthma Education ..................................................................................................................................................................... 48
2. Improving Adherence ................................................................................................................................................................ 50
3. Education of Others ......................................................................................... ......................................................................... 50
Chapter 5 – Identify and Reduce Risk Exposure to Risk Factors
1. Introduction ............................................................................................................................................................................... 54
2. Asthma Preservation ................................................................................................................................................................ 54
3. Prevention of Asthma Symptoms and Exacerbations .............................................................................................................. 55
Chapter 6 – Assess, Threat, and Monitor Asthma
1. Introduction .............................................................................................................................................................................. 66
2. Assessing Asthma Control........................................................................................................................................................ 67
3. Treating to Achieve Control....................................................................................................................................................... 67
4. Monitoring to Maintain Control .................................................................................................................................................. 70
Chapter 7 – Acute Exacerbations
1. Introduction .............................................................................................................................................................................. 78
2. Assessment of Severity ........................................................................................................................................................... 79
3. Home Management of Acute Exacerbation ............................................................................................................................. 80
4. Management: Acute Care Setting ........................................................................................................................................... 84
5. Assessment .............................................................................................................................................................................. 87
6. Laboratory Studies ................................................................................................................................................................... 89
7. Treatment ................................................................................................................................................................................. 90
8. Repeat Assessment .............................................................................................. ................................................................... 92
9. Hospitalization .......................................................................................................................................................................... 92
10. Impending Respiratory Failure ................................................................................................................................................. 92
11. Patient Discharge .................................................................................................. ................................................................... 94
Chapter 8 – Special Considerations
1. Introduction ............................................................................................................................................................................ 106
2. Pregnancy .............................................................................................................................................................................. 106
PREFACE
Despite the fact that much is presently known about the clinical, pathologic and cellular mechanisms of asthma, it remains to be a
major cause of chronic morbidity and mortality not only in the Philippines but also throughout the world. It is indeed a complex disease
that lends itself to a wide variation of presentation and response to medication and makes a single approach to treatment virtually
impossible. Hence, the continued efforts of health professionals to update existing guidelines that aimed to rationalize the diagnosis
and approach to treatment of this disease.
The Philippine Consensus Report on Asthma Diagnosis and Management of Asthma (PCRADM), the local consensus report
formulated by the Council of Asthma of the Philippine College of Chest Physicians (PCCP), first saw light in 1996. The updated 2004
evidence-based report took all of three years to complete. After five years, the Council feels the time is right to go over the two
guidelines again, revise and consolidate them, and in the end, come up with an updated document that will address the concerns of
local practitioners tasked with the management of asthma. Applicability of the consensus report to what is the reality in the Philippine
setting is the ultimate goal of this updated report.
The present document is a product of some eight months of hard work. It was the Council decision that the updated report will be
largely based on the 2007 GINA document, with emphasis placed on the inclusion of current local evidence that will make it more
relevant to the Filipino practitioner involved in the asthma care. In this context, the reader will find obvious similarities in the chapter
chronology and discussion of topics between the latest document and our updated report. The relative paucity of published studies on
asthma, however, makes it imperative that each chapter of our updated report should end with recommendations to bridge such gaps in
knowledge on diagnosis and management.
Over and beyond the similarities with GINA, however, the Council is very proud of its differing stand in the classification and
approach to treatment of asthma. We carried over the simpler classification of asthma, which first appeared in the 2004 PCRADM
update. Likewise, the approach to treatment in this current update is a modification of the original GINA recommendation, and an
improvement to what was proposed in the 2004 document. In both instances, the Council is aiming to find greater acceptance and
eventual usage of its updated guidelines by the Filipino physician managing asthmatic patients.
The completion of this updated report would not be possible without the diligence, perseverance, and single-minded determination
of the core group of eighteen Asthma Council members who laboured long hours reviewing voluminous number of journal articles,
research papers and other publications, then adapted them using the GINA as “template” to come up with what you now have in your
hand, the product of Asthma Consensus Report Update (ACRU) Project of the Philippine College of Chest Physicians Council on
Asthma, the new Philippine Consensus Report on Asthma Diagnosis and Management 2009. Much of the credit should go to Dr. Dina
V. Diaz who spearheaded the project and was its moving force from conceptualization to final publication. We likewise acknowledge
the Herculean efforts of our project secretary, Dr. Eloisa S. De Guia, who, despite all odds, managed to meet the set deadlines in
finalizing this update report. Somewhere in this document is the list of the core Asthma Council members, without that invaluable
contribution on this consensus report would not have been possible. Lastly, our heartfelt gratitude goes to AstraZeneca Philippines,
Inc. for their commitment and generous support of this undertaking from start to finish.
We, in the Asthma Council, hope that this document will find wide acceptance not only among the pulmonary specialists, internists,
fellows-in-training, resident physicians, and but also all medical practitioners who manage patients with asthma. With the plans for a
nationwide dissemination process of the updated report already in place, we likewise look forward to this report being a useful tool to
affect a better, more scientific and more rational approach to the diagnosis and management of asthma.
TITO C. ATIENZA, M.D., FPCCP
Chairman, Council on Asthma
Philippine College of Chest Physicians
TABLE OF CONTENTS
Preface.................................................................................................................................................................................................. v
Chapter 1 – Definition and Overview
1. Definition.................................................................................................................................................................................... 2
2. Burden of Asthma...................................................................................................................................................................... 3
3. Pathophysiologic Mechanisms.................................................................................................................................................. 6
4. Pathogenesis............................................................................................................................................................................. 8
Chapter 2 – Diagnosis and Classification
1. Introduction....................................................................................................... ....................................................................... 16
2. Clinical Diagnosis.................................................................................................................................................................... 16
3. Diagnostic Challenges and Differential Diagnosis................................................................................................................... 21
4. Classification of Asthma ......................................................................................................................................................... 22
5. Asthma Severity and Control a new perspective..................................................................................................................... 22
Chapter 3 – Asthma Medications
1. Introduction............................................................................................................................................................................... 32
2. Route of Administration ............................................................................................................................................................ 32
3. Controller Medications .............................................................................................................................................................. 32
4. Reliever Medications ................................................................................................................................................................. 37
Chapter 4 – Patient Education
1. Asthma Education ..................................................................................................................................................................... 48
2. Improving Adherence ................................................................................................................................................................ 50
3. Education of Others ......................................................................................... ......................................................................... 50
Chapter 5 – Identify and Reduce Risk Exposure to Risk Factors
1. Introduction ............................................................................................................................................................................... 54
2. Asthma Preservation ................................................................................................................................................................ 54
3. Prevention of Asthma Symptoms and Exacerbations .............................................................................................................. 55
Chapter 6 – Assess, Threat, and Monitor Asthma
1. Introduction .............................................................................................................................................................................. 66
2. Assessing Asthma Control........................................................................................................................................................ 67
3. Treating to Achieve Control....................................................................................................................................................... 67
4. Monitoring to Maintain Control .................................................................................................................................................. 70
Chapter 7 – Acute Exacerbations
1. Introduction .............................................................................................................................................................................. 78
2. Assessment of Severity ........................................................................................................................................................... 79
3. Home Management of Acute Exacerbation ............................................................................................................................. 80
4. Management: Acute Care Setting ........................................................................................................................................... 84
5. Assessment .............................................................................................................................................................................. 87
6. Laboratory Studies ................................................................................................................................................................... 89
7. Treatment ................................................................................................................................................................................. 90
8. Repeat Assessment .............................................................................................. ................................................................... 92
9. Hospitalization .......................................................................................................................................................................... 92
10. Impending Respiratory Failure ................................................................................................................................................. 92
11. Patient Discharge .................................................................................................. ................................................................... 94
Chapter 8 – Special Considerations
1. Introduction ............................................................................................................................................................................ 106
2. Pregnancy .............................................................................................................................................................................. 106
Chapter 1
Definition and
Overview
2
KEY POINTS:
Asthma is a chronic inflammatory
disorder of the airways which
contributes to airway
hyperresponsiveness, airflow limitation,
respiratory symptoms, and disease
chronicity.
In some patients, persistent changes in
airway structure occur, including smooth
muscle hypertrophy mucus hyper-
secretion, injury to epithelial cells, sub-
basement fibrosis and angiogenesis.
The critical role of inflammation has
been further substantiated, but evidence
is emerging for considerable variability
in the pattern of inflammation, thus
indicating phenotypic differences that
may influence treatment responses.
Clinical manifestations of asthma can be
controlled with appropriate treatment.
However, current asthma treatment with
anti-inflammatory therapy does not
appear to prevent progression of the
underlying disease severity.
Asthma is a problem worldwide, with an
estimated 300 million affected
individuals.1,2
In the Philippines, there is
a high prevalence of asthma in urban
areas, with 27 to 33% of children and 17
to 22% of adults with definite or
probable asthma.3
Although it would seem that, from the
perspective of both the patient and
society, the cost to control asthma is
high, the cost of not treating asthma
correctly is even higher.4
A number of factors that influence a
person’s risk of developing asthma have
been identified. These can be divided
into host factors (primarily genetic) and
environmental factors.
DEFINITION
Based on clinical, physiological and pathological
characteristics of asthma, an operational
definition of asthma is: 1
Asthma is a chronic inflammatory disorder of the
airways in which many cells and cellular
elements play a role. The chronic inflammation
is associated with airway hyperresponsiveness
that leads to recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing,
particularly at night or in the early morning.
These episodes are usually associated with
widespread, but variable, airflow obstruction
within the lung that is often reversible either
spontaneously or with treatment.1
Asthma has significant genetic and
environmental components, but since its
pathogenesis is not clear, much of its definition
is descriptive.
The main physiological feature of asthma is
episodic airway obstruction characterized by
expiratory airflow limitation. The dominant
pathological feature is airway inflammation,
sometimes associated with airway structural
changes.
The predominant feature of the clinical history is
episodic shortness of breath, particularly at
night, often accompanied by cough. Wheezing
appreciated on auscultation of the chest is the
most common physical finding.
Asthma is a chronic disorder of the airway that is
complex and characterized by variable and
recurring symptoms, airflow obstruction,
bronchial hyperresponsiveness, and an
underlying inflammation (Table 1.1). The
interaction of these features of asthma
determines the clinical manifestations and
severity of asthma and the response to
treatment.
Table 1.1. Features of Asthma
3
The concepts involving pathogenesis of asthma
has evolved greatly over the past 25 years, from
a simple smooth muscle disease to the concept
of airway inflammation. 5,6
More recently, further evaluation of these
concepts reveal that various phenotypes of
asthma exist and that clinical features of asthma
may be linked with genetic patterns.6,7
Such
phenotypic patterns depend on the degree of the
underlying airway inflammation which is
variable. Distinct but overlapping patterns are
observed that reflect different aspects of the
disease, such as intermittent versus persistent
or acute versus chronic manifestations. Acute
symptoms of asthma usually arise from
bronchospasm and require and respond to
bronchodilator therapy. Acute and chronic
inflammation can affect not only the airway
caliber and airflow, but also underlying bronchial
hyperresponsiveness, which enhances
susceptibility to bronchospasm.8
Treatment with anti-inflammatory drugs can, to a
large extent, reverse some of these processes;
however, the successful response to therapy
often requires weeks to achieve and, in some
situations, may be incomplete.9
For some
patients, the development of chronic
inflammation may be associated with
permanent alterations in the airway structure—
referred to as airway remodeling—that are not
prevented by or fully responsive to currently
available treatments.10
Therefore, the paradigm
of asthma has been expanded from
bronchospasm and airway inflammation to
include airway remodeling in some persons.11
The concept that asthma may be a continuum of
these processes that can lead to moderate and
severe persistent disease is of critical
importance to understanding the pathogenesis,
pathophysiology, and natural history of this
disease.12
Although the role of inflammation in
asthma is generally understood, the specific
processes related to the transmission of airway
inflammation to specific pathophysiologic
consequences of airway dysfunction and the
clinical manifestations of asthma have yet to be
fully defined.6
Similarly, much has been learned about the
host–environment factors that determine the
airways’ susceptibility to these processes.
However, the relative contributions of either and
the precise interactions between them that leads
to the initiation or persistence of disease have
yet to be fully established.6
Nonetheless, current science regarding the
mechanisms of asthma and findings from clinical
trials have led to therapeutic approaches that
allow most people who have asthma to
participate fully in activities they choose. As
more scientific information about the
pathophysiology, phenotypes, and genetics of
asthma continue to emerge, treatments will
become available to ensure adequate asthma
control for all persons and, ideally, to reverse
and even prevent the asthma processes.6
BURDEN OF ASTHMA
Asthma is considered as one of the most
common chronic diseases with an estimated 300
million people currently affected worldwide. The
Global Burden report stated that considerably
higher estimates can be obtained with less
conservative criteria for the diagnosis of clinical
asthma.2
Based on the application of standardized
methods to measure the prevalence of asthma
and wheezing illness in children 1,2
and adults, 13
it appears that the global prevalence of asthma
ranges from 1% to 18% of the population in
different countries (Fig.1.1). However, the lack of
a precise and universally accepted definition of
asthma makes reliable comparison of reported
prevalence from different parts of the world
problematic. In the Philippines, the prevalence
listed was 6.2 % (Fig.1.2)
The most recent asthma prevalence data in the
Philippines comes from an unpublished study of
the National Asthma Epidemiology Survey
(NAES) conducted in 2002.3
This survey
involved 1,964 adults and 1,143 children
between 6 to 7 years and 13 to 14 years old
from three urban areas using a pretested Expert
Panel Questionnaire. Three asthma specialists
who evaluated all subjects were blinded to the
subjects’ responses to the screening
questionnaires. The prevalence estimates
through the experts’ consensus was reported at
10.3%. With further investigations to confirm
4
Permission for use of this figure obtained from J. Bouquet
Figure 1-1. Asthma Prevalence and Mortality2,3
diagnosis of asthma, the prevalence rose to
26.7%.
Previous epidemiologic data which included the
Philippines were from the International Survey of
Asthma and Allergy in Children (ISAAC) study in
1998.14
The Philippine survey involved 3,207
children surveyed in Metro Manila aged 13 to 14
years and self-reported asthma symptoms were
noted in 12% of the children.15
In 1998, a prevalence survey of asthma and
asthma- like illnesses involving 1,964 Filipino
adults16
showed that about 7.1% of respondents
reported a prior doctor-diagnosed asthma,
although only 87% of them were confirmed to
have definite or probable asthma by the experts.
About half of the total population self-reported
having experienced at least one symptom in the
last year. Of these, only 35% were confirmed to
have asthma or an asthma-like illness. It was
thus recommended that symptoms suggestive of
asthma are prevalent in the community and
further investigations are necessary to confirm
the disorder or to diagnose another illness.
Based on the expert panel consensus, the
prevalence rate obtained in this study is 4.3%.
This figure is almost similar to the figures
reported in Singapore and Japan. This
prevalence rate may be an underestimation,
since there is an additional 18.1% of the
population who presented with asthma-like
illnesses and were classified as probably
asthmatic by the expert panel. Thus, if the
recent NAES 2002 data is taken into
consideration, it would appear that the local
prevalence of asthma is increasing.
This finding is consistent with current thinking
that asthma prevalence has been increasing in
some countries. However, in others, prevalence
may have stabilized.17,18
The explanation for this
occurrence has not been adequately explained.
Similarly, there are insufficient data to determine
the likely causes of for the described variations
in prevalence within and between populations.
It has been observed, however, that the
increase in the prevalence of asthma has been
associated with an increase in atopic
sensitization, and is paralleled by similar
increases in other allergic disorders such as
eczema and rhinitis. The rate of asthma also
appears to increase as communities adopt
western lifestyles and become more urbanized.
With the projected increase in the proportion of
the world's population that is urban from 45% to
59% in 2025, there is likely to be a marked
increase in the number of asthmatics worldwide
5
Figure 1-2. Global Asthma Prevalence20
over the next two decades. As such, there may
be an estimated additional 100 million persons
with asthma by 2025.20
What may be more disturbing is the burden that
asthma imposes on the sufferer and his or her
family. The World Health Organization (WHO)
has estimated that 15 million disability-adjusted
life years (DALYs) are lost annually due to
asthma. Worldwide, asthma accounts for around
1% of all DALYs lost, which reflects the high
prevalence and severity of asthma. This number
of DALYs lost
due to asthma is similar to that for diabetes,
cirrhosis of the liver, or schizophrenia.1
With regards to mortality, annual worldwide
deaths from asthma have been estimated at
250,000; approximately 1 in every 250 deaths.
Mortality does not appear to correlate well with
prevalence (Figure 1-1).2
Many of the deaths
are preventable, and thought to be due to
suboptimal long-term medical care and delay in
obtaining help during the final attack.
6
Social and economic factors are integral to
understanding asthma and its care, whether
viewed from the perspective of the individual
sufferer, the health care professional, or entities
that pay for health care. Absence from school
and days lost from work are reported as
substantial social and economic consequences
of asthma in studies from the Asia-Pacific
region, India, Latin America, the United
Kingdom, and the United States. 1
The economic cost of asthma is considerable
both in terms of direct medical costs (such as
hospital admissions and cost of
pharmaceuticals) and indirect costs (such as
time lost from work and premature death). This
problem is aggravated by the fact that, in the
Philippines, the monetary cost of purchasing
medicines rests mainly on the patient. Several
observations from comparisons of the cost of
asthma in different regions have led to a clear
set of conclusions : 1
The costs of asthma depend on the
individual patient’s level of control and
the extent to which exacerbations are
avoided.
Emergency treatment is more expensive
than planned treatment.
Non-medical economic costs of asthma
are substantial.
Guideline-determined asthma care can
be cost effective.
Although it would seem that, from the
perspective of both the patient and society, the
cost to control asthma is high, the cost of not
treating asthma correctly is even higher. 1
PATHOPHYSIOLOGIC MECHANISMS
Inflammation
Inflammation has a central role in the
pathophysiology of asthma. As noted in the
definition of asthma, airway inflammation
involves an interaction of many cell types and
multiple mediators with the airways that
eventually results in the characteristic
pathophysiological features of the disease:
bronchial inflammation and airflow limitation that
result in recurrent episodes of cough,
wheeze, and shortness of breath. The
processes by which these interactive events
occur and lead to clinical asthma are still under
investigation. Moreover, although distinct
phenotypes of asthma exist (e.g., intermittent,
persistent, exercise-associated, aspirin-
sensitive, or severe asthma), airway
inflammation remains a consistent pattern. The
pattern of airway inflammation in asthma,
however, does not necessarily vary depending
upon disease severity, persistence, and duration
of disease. The cellular profile and the response
of the structural cells in asthma are quite
consistent. 6
The immunohistopathologic features of asthma
include inflammatory cell infiltration with
eosinophils, lymphocytes, neutrophils (especially
in sudden-onset, fatal asthma exacerbations;
occupational asthma, and patients who smoke),
along with mast cell activation and epithelial cell
injury. 6
Inflammatory cells
Eosinophils release basic proteins that may
damage airway epithelial cells, growth factors
that may have a role in airway remodeling. T-
lymphocytes release specific cytokines (IL-4, IL-
5, IL-9, IL-13) that orchestrate eosinophilic
inflammation and Ig-E production by B-
lymphocytes. There may also be an increase in
natural killer (NK) cells which release large
amounts of Th1 and Th
2 cytokines. Increased
numbers of neutrophils may be seen but their
role is uncertain. Activated mast cells release
bronchoconstrictor mediators (histamine,
cysteinyl leukotrienes, PGD2). These cells are
activated by allergens through high-affinity IgE
receptors and osmotic stimuli (as seen in
exercise-induced bronchoconstriction).
Increased mast cell numbers in airway smooth
muscle may be linked to airway
hyperresponsiveness. Other inflammatory cells
are dendritic cells that interact with regulatory T
cells and stimulate Th2 production and
macrophages which release inflammatory
mediators and cytokines that amplify the
inflammatory response.1
Airway structural cells
There are also airway structural cells that are
involved in asthma pathogenesis : epithelial
cells, smooth muscle cells and endothelial cells.
Fibroblasts and myofibroblasts produced
7
connective tissue components, such as
collagens and proteoglycans that are involved in
airway remodeling. Airway nerves are also
involved. Cholinergic nerves may be activated
by reflex triggers in the airways and cause
bronchoconstriction and mucus hypersecretion.
Sensory nerves, which may be sensitized by
inflammatory stimuli may release inflammatory
neuropeptides and cause reflex changes and
symptoms such as cough and chest tightness. 1
Mediators in Asthma
The characteristic pattern of inflammation is also
found in allergic diseases, with resultant
increase in mediators that contribute to asthma
symptoms. Over 100 different mediators are
now recognized to be involved in asthma (e.g.
cysteinyl leukotrienes, cytokines, chemokines,
histamine, nitric oxide, prostaglandin D2) and
mediate the complex inflammatory response in
the airways.1
Airway narrowing
Airway narrowing is the final common pathway
leading to symptoms and physiological changes
in asthma. Several factors contribute to the
development of airway narrowing in asthma,
namely : airway smooth muscle contraction,
airway edema due to increased microvascular
leakage, airway thickening (airway remodeling),
and mucus hypersecretion (mucus plugging).1
Airway hyperresponsiveness
Airway hyperresponsiveness, the characteristic
functional abnormality of asthma, results in
airway narrowing in a patient with asthma in
response to a stimulus that would be innocuous
in a normal person In turn, this airway narrowing
leads to variable airflow limitation and
intermittent symptoms. Airway
hyperresponsiveness is linked to both
inflammation and repair of the airways and is
partially reversible with therapy. Its mechanisms
are incompletely understood.1
Special Mechanisms
Acute exacerbations
Transient worsening of asthma may occur as a
result of exposure to risk factors for asthma
symptoms, or “triggers,” such as exercise, air
pollutants ,20
and even certain weather
conditions, e.g.,thunderstorms.21
More
prolonged worsening is usually due to viral
infections of the upper respiratory tract
(particularly rhinovirus and respiratory syncytial
virus) or allergen exposure which increase
inflammation in the lower airways (acute on
chronic inflammation) that may persist for
several days or weeks.22
Nocturnal asthma. The mechanisms
accounting for the worsening of asthma at night
are not completely understood but may be
driven by circadian rhythms of circulating
hormones such as epinephrine, cortisol, and
melatonin and neural mechanisms such as
cholinergic tone. An increase in airway
inflammation at night has been reported. This
might reflect a reduction in endogenous anti-
inflammatory mechanisms.23
Irreversible airflow limitation. Some patients
with severe asthma develop progressive airflow
limitation that is not fully reversible with currently
available therapy. This may reflect the changes
in airway structure in chronic asthma.24
Difficult-to-treat asthma. The reasons why
some patients develop asthma that is difficult to
manage and relatively insensitive to the effects
of glucocorticosteroids are not well understood.
Common associations are poor compliance with
treatment and psychological and psychiatric
disorders. However, genetic factors may
contribute in some. Many of these patients have
difficult to-treat asthma from the onset of the
disease, rather than progressing from milder
asthma. In these patients airway closure leads
to air trapping and hyperinflation. Although the
pathology appears broadly similar to other forms
of asthma, there is an increase in neutrophils,
more small airway involvement, and more
structural changes. 25
Smoking and asthma. Tobacco smoking
makes asthma more difficult to control, results in
more frequent exacerbations and hospital
admissions, and produces a more rapid decline
in lung function and an increased risk of death.
Asthma patients who smoke may have a
neutrophil-predominant inflammation in their
airways and are poorly responsive to
glucocorticosteroids. 26
8
Figure 1-3. Host Factors and Environmental Exposures (adapted from NAEPR2)6
Key: LRI, lower respiratory infections, RSV respiratory syncytial virus, PIV parainfluenza virus
PATHOGENESIS
A number of factors that influence a person’s
risk of developing asthma have been identified.
These can be divided into host factors (primarily
genetic) and environmental factors. The
expression of asthma is a complex, interactive
process that depends on the interplay between
these two major factors that occur at a crucial
time in the development of the immune system.
(Figure 1.3) 6
Innate Immunity
Research has uncovered the role of innate and
adaptive immune response in the development
and regulation of inflammation.27
Evidence
points to an imbalance between Th1 and Th
2
cytokine profiles predisposing an individual to
development of allergy or asthma. Airway
inflammation is characterized by a shift toward a
Th2 cytokine-like disease, either as
overexpression of Th2 or underexpression of
Th1. (Figure 1.4) Th
1 cells produce interleukin
(IL-2) and interferon-γ (IFN-γ), which are critical
in cellular defense mechanisms in response to
infection. Th2, in contrast, generates a family of
cytokines (IL-4, -5, -6, -9, and -13) that can
mediate allergic inflammation. 6
The current “hygiene hypothesis” of asthma
illustrates how this cytokine imbalance may
explain some of the dramatic increases in
asthma prevalence in westernized countries.
This hypothesis is based on the assumption that
the immune system of the newborn is skewed
toward Th2 cytokine generation. Following birth,
environmental stimuli such as infections will
activate Th1 responses and bring the Th
1/Th
2
relationship to an appropriate balance. 6
Certain conditions appear to reduce the
incidence of asthma, such as certain infections
(M. tuberculosis, measles, or hepatitis A),
exposure to other children (e.g., presence of
older siblings and early enrolment in childcare),
and less frequent use of antibiotics .6
Furthermore, the absence of these lifestyle
events is associated with the persistence of a
Th2 cytokine pattern. Under these conditions, the
child who has a genetic cytokine imbalance
toward Th2 will set the stage to promote the
production of Ig-E antibodies to key
environmental antigens, such as house-dust
mite, cockroach, Alternaria, and possibly cat. 6
There also appears to be a reciprocal interaction
between the two subpopulations in which Th1
cytokines can inhibit Th2 generation and vice
versa. Allergic inflammation may be the result of
an excessive expression of Th2 cytokines.
Alternatively, recent studies have suggested the
9
Numerous factors, including alterations in the number of type of infections early in life, the widespread use of antibiotics, adoption of the western
lifestyle, and repeated exposure to allergens, may affect the balance between Th1 type and Th
2 type cytokine responses and increase the
likelihood that the immune response will be dominated by the Th2 cells and thus will ultimately lead to the expression of allergic diseases such as
asthma. (Adapted from NAEPR2)
Figure 1-4. Cytokine Balance
Th1
possibility that the loss of normal immune
balance arises from a cytokine dysregulation in
which Th1 activity in asthma is diminished. The
focus on actions of cytokines and chemokines to
regulate and activate the inflammatory profile in
asthma has provided ongoing and new insights
into the pattern of airway injury that may lead to
new therapeutic targets. 6
Therefore, a gene-by-environment interaction
occurs in which the susceptible host is exposed
to environmental factors that are capable of
generating Ig-E, and sensitization occurs.
Precisely why the airways of some individuals
are susceptible to these allergic events,
however, has not been established.
Genetics
It is well recognized that asthma has an
inheritable component to its expression, but the
genetics involved in the development of asthma
remains a complex and incomplete picture.28,29
To date, many genes have been found that are
either involved in or linked to the presence of
asthma and some of its features. The
complexity of the genetic involvement in clinical
asthma is related to certain phenotypic
characteristics, but not necessarily the
pathophysiologic disease process or clinical
picture itself. The role of genetics in Ig-E
production, airway responsiveness and
dysfunctional regulation of the generation of
inflammatory cytokines has captured much
10
attention. Current studies are investigating the
genetic polymorphism in the beta-adrenergic
and corticosteroid receptors that may determine
response to therapy. Although the relevance of
these genetic variations is of increasing interest,
their widespread application remains to be fully
established. 6
Sex
In early life, the prevalence of asthma is higher
in boys. At puberty, however, the sex ratio shifts
and asthma appears predominantly in women. 30
It is not clear how sex and sex hormones, or
related hormone generation, are specifically
linked to asthma but they may contribute to the
onset and persistence of the disease.
Obesity
Obesity has also been shown to be a risk factor
for asthma. Certain mediators such as leptins
may affect airway function and increase the
likelihood of asthma development.31,32
Environmental Factors
The two major environmental factors that are
most important in the development, persistence
and severity of asthma in the susceptible host
are: airborne allergens and viral respiratory
infections.6
It is also apparent that allergen
exposure, allergic sensitization, and respiratory
infections are not separate entities but function
interactively in the eventual development of
asthma.
Allergens
The role of allergens in the development of
asthma has yet to be fully defined or resolved,
but it is obviously important. Sensitization and
exposure to house-dust mite and Alternaria are
important factors in the development of asthma
in children. Early studies showed that animal
danders, particularly dog and cat, were
associated with the development of asthma.
However, recent data suggest that, under some
circumstances, dog and cat exposure in early
life may actually protect against the
development of asthma. The determinant of
these diverse outcomes has not been
established. 6
Studies to evaluate house-dust mite and
cockroach exposure have shown that the
prevalence of sensitization and subsequent
development of asthma are linked.33,34
Exposure
to cockroach allergen is an important cause of
allergen sensitization, a risk factor for the
development of asthma.35
In addition, allergen
exposure can promote the persistence of airway
inflammation and likelihood of an exacerbation.
Occupational sensitizers
Over 300 substances have been associated with
occupational asthma,36,37
which is defined as
asthma caused by exposure to an agent
encountered in the work environment. These
substances include highly reactive small
molecules such as isocyanates, irritants that
may cause an alteration in airway
responsiveness, known immunogens such as
platinum salts, and complex plant and animal
biological products that stimulate the production
of Ig-E.
Occupational asthma arises predominantly in
adults, 38,,39
and occupational sensitizers are
estimated to cause about 1 in 10 cases of
asthma among adults of working age.40
Asthma
is the most common occupational respiratory
disorder in industrialized countries. 41,42
Most
occupational asthma is immunologically
mediated and has a latency period of months to
years after the onset of exposure.43
IgE-
mediated allergic reactions and cell mediated
allergic reactions are involved.44,45
Levels above
which sensitization frequently occurs have been
proposed for many occupational sensitizers.
However, the factors that cause some people
but not others to develop occupational asthma in
response to the same exposures are not well
identified. 1
Atopy and tobacco smoking may increase the
risk of occupational sensitization, but screening
individuals for atopy is of limited value in
preventing occupational asthma.46
Very high
exposures to inhaled irritants may cause “irritant
induced asthma” (formerly called the reactive
airways dysfunctional syndrome) even in non-
atopic persons.
The most important method of preventing
occupational asthma is elimination or reduction
of exposure to occupational sensitizers.1
11
Respiratory infections
During infancy, a number of respiratory viruses
have been associated with the inception or
development of the asthma. In early life,
respiratory syncytial virus (RSV) and
parainfluenza virus in particular, cause
bronchiolitis that parallels many features of
childhood asthma.47,48
A number of long-term
prospective studies of children admitted to
hospital with documented RSV have shown that
approximately 40 percent of these infants will
continue to wheeze or have asthma in later
childhood.48
Symptomatic rhinovirus infections in
early life also are emerging as risk factors for
recurrent wheezing. On the other hand,
evidence also indicates that certain respiratory
infections early in life—including measles and
even RSV 49
or repeated viral infections (other
than lower respiratory tract infections) 50,51
can
protect against the development of asthma. The
“hygiene hypothesis” of asthma suggests that
exposure to infections early in life influences the
development of a child’s immune system along a
“non-allergic” pathway, leading to a reduced risk
of asthma and other allergic diseases. Although
the hygiene hypothesis continues to be
investigated, this association may explain
observed associations between large family
size, later birth order, daycare attendance, and a
reduced risk of asthma.27,,50
The influence of viral
respiratory infections on the development of
asthma may depend on an interaction with
atopy. The atopic state can influence the lower
airway response to viral infections, and viral
infections may then influence the development
of allergic sensitization. The airway interactions
that may occur when individuals are exposed
simultaneously to both allergens and viruses are
of interest but are not defined at present.6
Tobacco Smoke
Tobacco smoke, air pollution, occupations, and
diet have also been associated with an
increased risk for the onset of asthma, although
the association has not been as clearly
established as with allergens and respiratory
infections. 52,53,54
In utero exposure to environmental tobacco
smoke increases the likelihood for wheezing in
the infant, although the subsequent
development of asthma has not been well
defined. In adults who have asthma, cigarette
smoking has been associated with an increase
in asthma severity and decreased
responsiveness to inhaled corticosteroids
(ICSs). 55
Air Pollution
The role of outdoor air pollution in causing
asthma remains controversial.56
Similar
associations have been observed in relation to
indoor pollutants, e.g., smoke and fumes from
gas and biomass fuels used for heating and
cooling, molds, and cockroach infestations, as
such, risk for asthma development may be
related to allergic sensitization.
Children raised in a polluted environment have
diminished lung function,57
but the relationship of
this loss of function to the development of
asthma is not known. One recent epidemiologic
study showed that heavy exercise (three or
more team sports) outdoors in communities with
high concentration of ozone was associated with
a higher risk of asthma among school-age
children.58
The relationship between increased
levels of pollution and increases in asthma
exacerbations and emergency care visits has
been well documented.
Diet
The role of diet, particularly breast-feeding, in
relation to the development of asthma has been
extensively studied. In general, the data reveal
that infants fed formulas of intact cow's milk or
soy protein have a higher incidence of wheezing
illnesses in early childhood compared with those
fed breast milk.59
Some data also suggest that
certain characteristics of Western diets, such as
increased use of processed foods and
decreased antioxidant (in the form of fruits and
vegetables), Increased n-6 polyunsaturated fatty
acid (found in margarine and vegetable oil), and
decreased n-3 polyunsaturated fatty acid (found
in oily fish) intakes have contributed to the
recent increases in asthma and atopic disease.60
An association of low intake of antioxidants and
omega-3 fatty acids has been noted in
observational studies, but a direct link as a
causative factor has not been established. 6
Increasing rates of obesity have paralleled
increasing rates in asthma prevalence, but the
interrelation is uncertain. 61
Obesity may be a
risk factor for asthma due to the generation of
12
unique inflammatory mediators that lead to
airway dysfunction. 6
In summary, our understanding of asthma
pathogenesis and underlying mechanisms now
includes the concept that gene-by-environmental
interactions are critical factors in the
development of airway inflammation and
eventual alteration in the pulmonary physiology
that is characteristic of clinical asthma.6
RECOMMENDATIONS:
There is a need to establish local systematic
monitoring protocols on asthma prevalence,
morbidity and mortality.
The economic impact of the cost of asthma
care on the Filipino population should be
determined.
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14
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52. Malo JL, Lemiere C, Gautrin D, Labrecque
M. Occupational asthma. Curr Opin Pulm
Med 2004; 10(1):57–61. Review.
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passive smoking. 5. Parental smoking and
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Chapter 2
Diagnosis and
Classification
16
KEY POINTS:
A clinical diagnosis of asthma is often
prompted by symptoms such as
episodic breathlessness, wheezing,
cough, and chest tightness.
Measurements of lung function
(spirometry or peak expiratory flow)
provide an assessment of the severity of
airflow limitation, its reversibility, and its
variability, and provide confirmation of
the diagnosis of asthma.
Measurements of allergic status can
help to identify risk factors that cause
asthma symptoms in individual patients.
For patients with symptoms consistent
with asthma, but normal lung function,
measurement of airway responsiveness
may help establish the diagnosis.
There remains a need to define the
concept of asthma severity, one that is
based on the intensity of treatment
required to achieve good asthma control
i.e. severity is assessed during
treatment. This is prompted by the
recognition of patients with “severe” and
“mild” asthma.
To aid in clinical management, a
classification of asthma by level of
control is recommended.
Clinical control of asthma is defined as:
o No (twice or less/week) daytime
symptoms
o No nocturnal symptoms or
awakenings because of asthma
o No (twice or less/week) need for
reliever treatment
o Normal or near-normal lung
function
o No exacerbations
INTRODUCTION
A correct diagnosis of asthma is essential if
appropriate drug therapy is to be given1. Asthma
symptoms may be intermittent and their
significance may be overlooked by patients and
physicians, or, because they are non-specific,
they may result in misdiagnosis (for example of
wheezy bronchitis, COPD, or the breathlessness
of old age). This is particularly true among
children, where misdiagnoses include various
forms of bronchitis or croup, and lead to
inappropriate treatment1.
CLINICAL DIAGNOSIS
Medical History
Symptoms1. A clinical diagnosis of asthma is
often prompted by symptoms such as episodic
breathlessness, wheezing, cough, and chest
tightness1. Episodic symptoms after an
incidental allergen exposure, seasonal variability
of symptoms and a positive family history of
asthma and atopic disease are also helpful
diagnostic guides. Asthma associated with
rhinitis may occur intermittently, with the patient
being entirely asymptomatic between seasons
or it may involve seasonal worsening of asthma
symptoms or a background of persistent
asthma. The patterns of these symptoms that
strongly suggest an asthma diagnosis are
variability; precipitation by non-specific irritants,
such as smoke, fumes, strong smells, or
exercise; worsening at night; and responding to
appropriate asthma therapy. Useful questions to
consider when establishing a diagnosis of
asthma are described in Figure 2-1.
In some sensitized individuals, asthma may be
exacerbated by seasonal increases in specific
aeroallergens2. Examples include Alternaria, and
birch, grass, and ragweed pollens.
17
Figure 2-1. Questions to consider in the
diagnosis of Asthma
Cough-variant asthma. Patients with cough-
variant asthma3 have chronic cough as their
principal, if not only, symptom. It is particularly
common in children, and is often more
problematic at night; evaluations during the day
can be normal. For these patients,
documentation of variability in lung function or of
airway hyperresponsiveness, and possibly a
search for sputum eosinophils, is particularly
important4. Cough-variant asthma must be
distinguished from so-called eosinophilic
bronchitis in which patients have cough and
sputum eosinophils but normal indices of lung
function when assessed by spirometry and
airway hyperresponsiveness5
. Other diagnoses
to be considered are cough-induced by
angiotensin-converting-enzyme (ACE) inhibitors,
gastroesophageal reflux, postnasal drip, chronic
sinusitis, and vocal cord dysfunction6
.
Exercise-induced bronchoconstriction.
Physical activity is an important cause of asthma
symptoms for most asthma patients, and for
some it is the only cause. Exercise-induced
bronchoconstriction typically develops within 5-
10 minutes after completing exercise (it rarely
occurs during exercise). Patients experience
typical asthma symptoms, or sometimes a
troublesome cough, which resolve
spontaneously within 30-45 minutes. Some
forms of exercise, such as running, are more
potent triggers7. Exercise-induced
bronchoconstriction may occur in any climatic
condition, but it is more common when the
patient is breathing dry, cold air and less
common in hot, humid climates8.
Rapid improvement of post-exertional symptoms
after inhaled β2-agonist use, or their prevention
by pre-t reatment with an inhaled β2-agonist
before exercise, supports a diagnosis of asthma.
Physical Examination
Because asthma symptoms are variable, the
physical examination of the respiratory system
may be normal. The most usual abnormal
physical finding is wheezing on auscultation, a
finding that confirms the presence of airflow
limitation. However, in some people with
asthma, wheezing may be absent or only
detected when the person exhales forcibly, even
in the presence of significant airflow limitation.
Occasionally, in severe asthma exacerbations,
wheezing may be absent owing to severely
reduced airflow and ventilation. However,
patients in this state usually have other physical
signs reflecting the exacerbation and its severity,
such as cyanosis, drowsiness, difficulty
speaking, tachycardia, hyperinflated chest, use
of accessory muscles, and intercostal retraction.
Other clinical signs are only likely to be present
if patients are examined during symptomatic
periods. Features of hyperinflation result from
patients breathing at a higher lung volume in
order to increase outward traction of the airways
and maintain the patency of smaller airways
(which are narrowed by a combination of airway
smooth muscle contraction, edema, and mucus
hypersecretion). The combination of
hyperinflation and airflow limitation in an asthma
exacerbation markedly increases the work of
breathing.
Tests for Diagnosis and Monitoring
Measurements of lung function. The
diagnosis of asthma is usually based on the
18
presence of characteristic symptoms. However,
measurements of lung function, and particularly
the demonstration of reversibility of lung function
abnormalities, greatly enhance diagnostic
confidence. This is because patients with
asthma frequently have poor recognition of their
symptoms and poor perception of symptom
severity, especially if their asthma is long-
standing10
. Assessment of symptoms such as
dyspnea and wheezing by physicians may also
be inaccurate. Measurement of lung function
provides an assessment of the severity of airflow
limitation, its reversibility and its variability, and
provides confirmation of the diagnosis of
asthma. Although measurements of lung
function do not correlate strongly with symptoms
or other measures of disease control11
, these
measures provide complementary information
about different aspects of asthma control.
Two methods have gained widespread
acceptance for use in diagnosis of patients, (1)
spirometry, particularly the measurement of
forced expiratory volume in 1 second (FEV1) and
forced vital capacity (FVC), and (2) peak
expiratory flow (PEF) measurement.
Predicted values of FEV1, FVC, and PEF based
on age, sex, and height have been obtained
from population studies. These are being
continually revised, and with the exception of
PEF for which the range of predicted values is
too wide, they are useful for judging whether a
given value is abnormal or not. The terms
reversibility and variability refer to changes in
symptoms accompanied by changes in airflow
limitation that occur spontaneously or in
response to treatment. The term reversibility is
generally applied to rapid improvements in FEV1
(or PEF), measured within minutes after
inhalation of a rapid-acting bronchodilator—for
example after 200-400 g salbutamol13
—or more
sustained improvement over days or weeks after
the introduction of effective controller treatment
such as inhaled glucocorticosteroids13
.
Variability refers to improvement or deterioration
in symptoms and lung function occurring over
time. Variability may be experienced over the
course of one day (when it is called diurnal
variability), from day to day, from month to
month, or seasonally. Obtaining a history of
variability is an essential component of the
diagnosis of asthma. In addition, variability forms
part of the assessment of asthma control.
Spirometry is the recommended method of
measuring airflow limitation and reversibility to
establish a diagnosis of asthma. Measurements
of FEV1 and FVC are undertaken during a forced
expiratory maneuver using a spirometer.
Recommendations for the standardization of
spirometry have been published13-15
. The degree
of reversibility in FEV1 which indicates a
diagnosis of asthma is generally accepted as ≥
12% and ≥ 200 ml f rom the pre-bronchodilator
value13
. However most asthma patients will not
exhibit reversibility at each assessment,
particularly those on treatment, and the test
therefore lacks sensitivity.
Repeated testing at different visits is advised.
Spirometry is reproducible, but effort-dependent.
Therefore, proper instructions on how to perform
the forced expiratory maneuver must be given to
patients, and the highest value of three
recordings taken. As ethnic differences in
spirometric values have been demonstrated,
appropriate predictive equations for FEV1 and
FVC should be established for each patient.
Predictive equations and values for Filipinos
have been determined and published61
but have
not yet been widely used.
The normal range of values is wider and
predicted values are less reliable in young
people (< age 20) and in the elderly (> age 70).
Because many lung diseases may result in
reduced FEV1, a useful assessment of airflow
limitation is the ratio of FEV1 to FVC. The
FEV1/FVC ratio is normally > 0.80, and any
value less than this suggests airflow limitation.
19
Figure 2-2. Measuring PEF Variability*
*PEF chart of a 27-year old man wi th long -standing, poorly
controlled asthma, before and after the star t of inhaled
glucocorticosteroid treatment. Wi th treatment, PEF levels
increased, and PEF variability decreased, as seen by the
increase in Min%Max (lowest morning PEF/Highest PEF %) over
one week .
Peak expiratory flow measurements are made
using a peak flow meter and can be an
important aid in both diagnosis and monitoring of
asthma. Modern PEF meters are relatively
inexpensive, portable, plastic, and ideal for
patients to use in home settings for day-to-day
objective measurement of airflow limitation.
However, measurements of PEF are not
interchangeable with other measurements of
lung function such as FEV1
16. PEF can
underestimate the degree of airflow limitation,
particularly as airflow limitation and gas trapping
worsen. Because values for PEF obtained with
different peak flow meters vary and the range of
predicted values is too wide, PEF
measurements should preferably be compared
to the patient’s own previous best
measurements18
using his/her own peak flow
meter. The previous best measurement is
usually obtained when the patient is
asymptomatic or on full treatment and serves as
a reference value for monitoring the effects of
changes in treatment.
Careful instruction is required to reliably
measure PEF because PEF measurements are
effort-dependent. Most commonly, PEF is
measured first thing in the morning before
treatment is taken, when values are often close
to their lowest and last thing at night when
values are usually higher. One method of
describing diurnal PEF variability is as the
amplitude (the difference between the maximum
and the minimum value for the day), expressed
as a percentage of the mean daily PEF value,
and averaged over 1-2 weeks19
. Another method
of describing PEF variability is the minimum
morning pre-bronchodilator PEF over 1 week,
expressed as a percent of the recent best (Min%
Max) (Figure 2-2)19
. This latter method has been
suggested to be the best PEF index of airway
lability for clinical practice because it requires
only a once-daily reading, correlates better than
any other index with airway hyper
responsiveness , and involves a simple
calculation.
PEF monitoring is valuable in a subset of
asthmatic patients and can be helpful:
To confirm the diagnosis of asthma. Although
spirometry is the preferred method of
documenting airflow limitation, a 60 L/min (or
20% or more of prebronchodilator PEF)
improvement after inhalation of a
bronchodilator20
, or diurnal variation in PEF of
more than 20% (with twice daily readings,
more than 10%21
) suggests a diagnosis of
asthma.
To improve control of asthma, particularly in
patients with poor perception of symptoms10
.
Asthma management plans which include self-
monitoring of symptoms or PEF for treatment
of exacerbations have been shown to improve
asthma outcomes22
. It is easier to discern the
response to therapy from a PEF chart than
from a PEF diary, provided the same chart
format is consistently used23
.
To identify environmental (including
occupational) causes of asthma symptoms.
This involves the patient monitoring PEF daily
or several times each day over periods of
suspected exposure to risk factors in the home
or workplace, or during exercise or other
activities that may cause symptoms, and
during periods of non-exposure.
20
Figure 2-3. Measuring Airway Responsiveness
*Airway responsiveness to inhaled methacoline or histamine in a
normal subject, and in asthmatics with mild, moderate, and severe
airway hyperresponsiveness. Asthmatics have an increased
sensitivity and an increased maximal broncho- constric tor response
to the agonist. The response to the agonist is usually expressed as
the provocative concentration causing a 20% decline in FEV1 (PC
20)
Figure 2-3. Measuring Airway Responsiveness
Other tests for Airway Obstruction. There
have been attempts in the local setting to
explore the use of low-technology maneuvers
like the candle light and lighted matchstick
blowing tests. These have not been rigorously
evaluated, much less validated, but offer
potential use in a resource-poor country like the
Philippines.24
Measurement of airway responsiveness. For
patients with symptoms consistent with asthma,
but normal lung function, measurements of
airway responsiveness to methacholine,
histamine, mannitol, or exercise challenge may
help establish a diagnosis of asthma24
.
Measurements of airway responsiveness reflect
the “sensitivity” of the airways to factors that can
cause asthma symptoms, sometimes called
“triggers,” and the test results are usually
expressed as the provocative concentration (or
dose) of the agonist causing a given fall (often
20%) in FEV1 (Figure 2-3). These tests are
sensitive for a diagnosis of asthma, but have
limited specificity25
. This means that a negative
test can be useful to exclude a diagnosis of
persistent asthma in a patient who is not taking
inhaled glucocorticosteroid treatment, but a
positive test does not always mean that a patient
has asthma26
. This is because airway
hyperresponsiveness has been described in
patients with allergic rhinitis27
and in those with
airflow limitation caused by conditions other than
asthma, such as cystic fibrosis28
, bronchiectasis,
and chronic obstructive pulmonary disease
(COPD)29
.
Non-invasive markers of airway
inflammation. The evaluation of airway
inflammation associated with asthma may be
undertaken by examining spontaneously
produced or hypertonic saline-induced sputum
for eosinophilic or neutrophilic inflammation30
. In
addition, levels of exhaled nitric oxide (FeNO)31
and carbon monoxide (FeCO)32
have been
suggested as non-invasive markers of airway
inflammation in asthma. Levels of FeNO are
elevated in people with asthma (who are not
taking inhaled glucocorticosteroids) compared to
people without asthma, yet these findings are
not specific for asthma. Neither sputum
eosinophilia nor FeNO has been evaluated
prospectively as an aid in asthma diagnosis, but
these measurements are being evaluated for
potential use in determining optimal
treatment33,34
.
Measurements of allergic status. Because of
the strong association between asthma and
allergic rhinitis, the presence of allergies, allergic
diseases, and allergic rhinitis in particular,
increases the probability of a diagnosis of
asthma in patients with respiratory symptoms.
Moreover, the presence of allergies in asthma
patients (identified by skin testing or
measurement of specific IgE in serum) can help
to identify risk factors that cause asthma
symptoms in individual patients. Deliberate
provocation of the airways with a suspected
allergen or sensitizing agent may be helpful in
the occupational setting, but is not routinely
recommended, because it is rarely useful in
establishing a diagnosis, requires considerable
expertise and can result in life-threatening
bronchospasm35
. Skin tests and measurement of
serum IgE are methods used to determine
allergic status. Their main limitation is that a
21
positive test does not necessarily mean that the
disease is allergic in nature or that it is causing
asthma, as some individuals have specific IgE
antibodies without any symptoms and it may not
be causally involved.
DIAGNOSTIC CHALLENGES AND
DIFFERENTIAL DIAGNOSIS
A careful history and physical examination,
together with the demonstration of reversible
and variable airflow obstruction (preferably by
spirometry), will in most instances confirm the
diagnosis. The following categories of alternative
diagnoses need to be considered:
• Hyperventilation syndrome and panic
attacks
• Upper airway obstruction and inhaled
foreign bodies43
• Vocal cord dysfunction44
Other forms of obstructive lung disease,
particularly COPD
• Non-obstructive forms of lung disease (e.g.,
diffuse parenchymal lung disease)
• Non-respiratory causes of symptoms (e.g.,
left ventricular failure)
Because asthma is a common disease, it can be
found in association with any of the above
diagnoses, which complicates the diagnosis as
well as the assessment of severity and control.
This is particularly true when asthma is
associated with hyperventilation, vocal cord
dysfunction, or COPD. Careful assessment and
treatment of both the asthma and the co-
morbidity is often necessary to establish the
contribution of each to a patient’s symptoms.
The Elderly
Undiagnosed asthma is a frequent cause of
treatable respiratory symptoms in the elderly,
and the frequent presence of co-morbid
diseases complicates the diagnosis. Wheezing,
breathlessness, and cough caused by left
ventricular failure is sometimes labelled “cardiac
asthma,” a misleading term, the use of which is
discouraged. The presence of increased
symptoms with exercise and at night may add to
the diagnostic confusion because these
symptoms are consistent with either asthma or
left ventricular failure. Use of beta-blockers,
even topically (for glaucoma) is common in this
age group. A careful history and physical
examination, combined with an ECG and chest
X-ray, usually clarifies the picture. In the elderly,
distinguishing asthma from COPD is particularly
difficult, and may require a trial of treatment with
bronchodilators and/or oral/inhaled
glucocorticosteroids.
Asthma treatment and assessment and
attainment of control in the elderly are
complicated by several factors: poor perception
of symptoms, acceptance of dyspnea as being
“normal” in old age, and reduced expectations of
mobility and activity.
Occupational Asthma
Asthma acquired in the workplace is a diagnosis
that is frequently missed. Because of its
insidious onset occupational asthma is often
misdiagnosed as chronic bronchitis or COPD
and is therefore either not treated at all or
treated inappropriately. The development of new
symptoms of rhinitis, cough, and/or wheeze
particularly in non-smokers should raise
suspicion. Detection of asthma of occupational
origin requires a systematic inquiry about work
history and exposures. The diagnosis requires a
defined history of occupational exposure to
known or suspected sensitizing agents; an
absence of asthma symptoms before beginning
employment; or a definite worsening of asthma
after employment. A relationship between
symptoms and the workplace (improvement in
symptoms away from work and worsening of
symptoms on returning to work) can be helpful in
establishing a link between suspected
sensitizing agents and asthma45
. Since the
management of occupational asthma frequently
requires the patient to change his or her job, the
diagnosis carries considerable socioeconomic
implications and it is important to confirm the
22
diagnosis objectively. This may be achieved by
specific bronchial provocation testing46
, although
there are few centers with the necessary
facilities for specific inhalation testing. Another
method is to monitor PEF at least 4 times a day
for a period of 2 weeks when the patient is
working and for a similar period away from
work47-50
. The increasing recognition that
occupational asthma can persist, or continue to
deteriorate, even in the absence of continued
exposure to the offending agent51
, emphasizes
the need for an early diagnosis so that
appropriate strict avoidance of further exposure
and pharmacologic intervention may be applied.
Evidence based guidelines contain further
information about the identification of
occupational asthma52
.
Distinguishing Asthma from COPD
Both asthma and COPD are major chronic
obstructive airways diseases that involve
underlying airway inflammation. COPD is
characterized by airflow limitation that is not fully
reversible, is usually progressive, and is
associated with an abnormal inflammatory
response of the lungs to noxious particles or
gases. Individuals with asthma who are exposed
to noxious agents (particularly cigarette
smoking) may develop fixed airflow limitation
and a mixture of “asthma-like” inflammation and
“COPD-like” inflammation. Thus, even though
asthma can usually be distinguished f rom
COPD, in some individuals who develop chronic
respiratory symptoms and fixed airflow limitation,
it may be difficult to differentiate the two
diseases. A symptom-based questionnaire for
differentiating COPD and asthma for use by
primary health care professionals is
available53,54
.
CLASSIFICATION OF ASTHMA
Etiology
Many attempts have been made to classify
asthma according to etiology, particularly with
regard to environmental sensitizing agents.
However, such a classification is limited by the
existence of patients in whom no environmental
cause can be identified. Despite this, an effort to
identify an environmental cause for asthma (for
example, occupational asthma) should be part of
the initial assessment to enable the use of
avoidance strategies in asthma management.
Describing patients as having allergic asthma is
usually of little benefit, since single specific
causative agents are seldom identified.
ASTHMA SEVERITY and CONTROL:
A NEW PERSPECTIVE
Recently, there has been increasing awareness
of heterogeneity of the underlying processes in
asthma. Reviews have highlighted the
importance of different asthma phenotypes, their
natural history and varying treatment responses.
These phenotypes may alter the intensity of the
treatment required (severity) and, in turn,
contribute to the patient’s level of asthma
control. Figure 2-4 shows the current
perspective on the relationships between
phenotype, severity and control.60
Asthma Control: Refers to the extent to which
the manifestations of asthma have been
reduced or removed by treatment. Its
assessment should incorporate the dual
components of current clinical control (e.g.
symptoms, reliever use and lung function) and
future risk (e.g. exacerbations and lung functions
decline).
Asthma Severity: The most clinically useful
concept of asthma severity is based on the
intensity of treatment required to achieve good
asthma control, i.e. severity is assessed during
treatment. Severe asthma is defined as the
requirement for (not necessarily just prescription
or use of) high-intensity treatment.
Asthma Severity
While asthma control is important, quantification
of severity of asthma needs to be maintained.
Clinical experience indicates that patients have
23
a tendency to seek consult mostly during times
of increasing symptoms when treatment
regimens are not adhered to and control of
triggers are at their lowest. While initial
aggressive treatment based on level of control
may be adequate to get them to a higher level or
even total control, some patients may actually
require less drugs to achieve the same clinical
outcome.
Moreover, in a population of stable asthmatics,
there are varying levels of severity based on the
medications required to maintain control.
Quantification of severity is still important
because in clinical practice there exists a wide
spectrum of patients whose asthma ranges from
mild to severe. Severity may not only dictate the
choice of initial treatment but also maintenance
therapy based on clinical response.
Thus, there is clinical need in describing patients
not only in relation to their level of asthma
control but also their asthma severity, in terms of
the intensity of required treatment to treat the
patient’s asthma and to achieve good control.
We recommend using the PCRDMA severity
classification (Table 2-1) because it addresses
local concerns and realities, including the
problems of low ICS use and overreliance on
reliever bronchodilator medications.
24
The level of asthma control results from the interaction of the underlying phenotype, the environment (genetic and external) and the
response to treatment. The assessment of asthma control has two components: current clinical control (including symptoms, reliever use
and simple “bedside” measures of lung function) and future risks of adverse outcomes (e.g. exacerbations, rapid decline of lung function,
and side-effects). Treatment choice may be governed by the underlying phenotype, and the intensity of the treatment is usually modified
by the clinician as the patient responds to treatment. Severity is described by the intensity of the treatment required to ac hieve good
control. Severe asthma includes situations in which good control is still not achieved despite maximal therapy. Pathological and
physiological markers provide information about the underlying phenotype and the level of residual disease activity on treat ment and may
serve as surrogate markers for future risk. Exacerbations are events that are more common in poorly controlled asthma but may occur at
any level of clinical asthma control.
Figure 2-4. Relationship between Asthma Phenotypes, Severity and Control.
25
Asthma Control
Asthma control may be defined in a variety of
ways. In general, the term control may indicate
disease prevention, or even cure. However, in
asthma, where neither of these are realistic
options at present, it refers to control of the
manifestations of disease. Ideally this should
apply not only to clinical manifestations, but to
laboratory markers of inflammation and
pathophysiologic features of the disease as well.
There is evidence that reducing inflammation
with controller therapy achieves clinical control.
However, because tests such as endobronchial
biopsy and measurement of sputum eosinophils
and exhaled nitric oxide30-34
,are generally
unavailable and costly, it is recommended that
treatment be aimed at controlling the clinical
features of disease, including lung
function abnormalities. Table 2-2 provides the
characteristics of controlled, partly controlled
and uncontrolled asthma. This is a working
scheme based on current opinion and has not
been validated.
*Objective measures take precedence over subjective complaints . The higher severi ty level o f any domain will be t he basis of the final severity level.
**Patients who are high risk for as thma-related deaths are ini tially classified here
Table 2-1. Chronic Asthma Severity While on Treatment
*Any exacerbation should prompt review of maintenance treatment to ensure that i t is adequate.
By defini tion, an exacerbation in any week makes that an uncontrolled as thma week.
++
Lung function is not a re liable test for children 5 years and younger .
Table 2-2. Levels of Asthma Control, adapted from GINA 2008
26
Complete control of asthma is commonly
achieved with treatment, the aim of which should
be to achieve and maintain control for prolonged
periods55
with due regard to the safety of
treatment, potential for adverse effects, and the
cost of treatment required to achieve this goal.
Validated measures for assessing clinical control
of asthma score goals are continuous variables
and provide numerical values to distinguish
different levels of control. Examples of validated
instruments are the Asthma Control Test (ACT)
(http://www.asthmacontroltest.com)56
, the
Asthma Control Questionnaire (ACQ)
(http://www.qoltech.co.uk/Asthma1.htm)57
, the
Asthma Therapy Assessment Questionnaire
(ATAQ) (http://www.ataqinstrument.com)58,
and
the Asthma Control Scoring System59
. Not all of
these instruments include a measure of lung
function. They are being promoted for use not
only in research but for patient care as well,
even in the primary care setting. Some, suitable
for self-assessments by patients, are available in
many languages, on the internet, and in paper
form and may be completed by patients prior to,
or during consultations with their health care
provider. They have the potential to improve the
assessment of asthma control, providing a
reproducible objective measure that may be
charted over time (week by week or month by
month) and representing an improvement in
communication between patient and health care
professional. Their value in clinical use as
distinct from research settings has yet to be
demonstrated but will become evident in coming
years.
RECOMMENDATIONS:
In patients suspected of having
bronchial asthma, all efforts should be
made to confirm the diagnosis through
spirometry.
In the local setting, previously published
predicted values for Filipinos should be
used.
Recognizing their potential to improve
assessment of asthma control,
instruments such as ACT, should be
translated in the vernacular and
validated.
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asthma. N Engl J Med 2005;352(21):2163-
73.
35. Hoeppner VH, Murdock KY, Kooner S,
Cockcroft DW. Severe acute "occupational
asthma" caused by accidental allergen
exposure in an allergen challenge laboratory.
Ann Allergy 1985;55:36-7.
36. Wilson NM. Wheezy bronchitis revisited.
Arch Dis Child 1989;64(8):1194-9.
37. Martinez FD. Respiratory syncytial virus
bronchiolitis and the pathogenesis of
childhood asthma. Pediatr Infect Dis J
2003;22 (2 Suppl):S76-82.
38. Castro-Rodriguez JA, Holberg CJ, Wright
AL, Martinez FD. A clinical index to define
risk of asthma in young children with
recurrent wheezing. Am J Respir Crit Care
Med 2000;162 (4 Pt 1):1403-6.
39. Sears MR, Greene JM, Willan AR, Wiecek
EM, Taylor DR, Flannery EM, et al. A
longitudinal, population-based, cohort study
of childhood asthma followed to adulthood. N
Engl J Med 2003;349(15):1414-22.
40. Guilbert TW, Morgan WJ, Zeiger RS,
Mauger DT, Boehmer SJ, Szefler SJ, et al.
Long-term inhaled corticosteroids in
preschool children at high risk for asthma. N
Engl J Med 2006;354(19):1985-97.
41. Frey U, Stocks J, Sly P, Bates J.
Specification for signal processing and data
handling used for infant pulmonary function
testing. ERS/ATS Task Force on Standards
for Infant Respiratory Function Testing.
European Respiratory Society/ American
Thoracic Society. Eur Respir J
2000;16(5):1016-22.
42. Sly PD, Cahill P, Willet K, Burton P.
Accuracy of mini peak flow meters in
indicating changes in lung function in
children with asthma. BMJ
1994;308(6928):572-4.
43. Mok Q, Piesowicz AT. Foreign body
aspiration mimicking asthma. Intensive Care
Med 1993;19(4):240-1.
44. Place R, Morrison A, Arce E. Vocal cord
dysfunction. J Adolesc Health
2000;27(2):125-9.
45. Tarlo SM, Liss GM. Occupational asthma: an
approach to diagnosis and management.
CMAJ 2003;168(7):867-71.
46. Tarlo SM. Laboratory challenge testing for
occupational asthma. J Allergy Clin Immunol
2003;111(4):692-4.
47. Chan-Yeung M, Desjardins A. Bronchial
hyperresponsiveness and level of exposure
in occupational asthma due to western red
cedar (Thuja plicata). Serial observations
before and after development of symptoms.
Am Rev Respir Dis 1992;146(6):1606-9.
48. Cote J, Kennedy S, Chan-Yeung M.
Sensitivity and specificity of PC20 and peak
expiratory flow rate in cedar asthma. J
Allergy Clin Immunol 1990;85(3):592-8.
49. Vandenplas O, Malo JL. Inhalation
challenges with agents causing occupational
asthma. Eur Respir J 1997;10(11):2612-29.
50. Bright P, Burge PS. Occupational lung
disease. 8. The diagnosis of occupational
asthma from serial measurements of lung
function at and away from work. Thorax
1996;51(8):857-63.
51. Chan-Yeung M, MacLean L, Paggiaro PL.
Follow-up study of 232 patients with
occupational asthma caused by western red
cedar (Thuja plicata). J Allergy Clin Immunol
1987;79(5):792-6.
52. Nicholson PJ, Cullinan P, Taylor AJ, Burge
PS, Boyle C. Evidence based guidelines for
the prevention, identification, and
management of occupational asthma. Occup
Environ Med 2005;62(5):290-9.
53. Price DB, Tinkelman DG, Halbert RJ,
Nordyke RJ, Isonaka S, Nonikov D, et al.
Symptom-based questionnaire for identifying
COPD in smokers. Respiration
2006;73(3):285-95.
54. Tinkelman DG, Price DB, Nordyke RJ,
Halbert RJ, Isonaka S, Nonikov D, et al.
Symptom-based questionnaire for
differentiating COPD and asthma.
Respiration 2006;73(3):296-305.
55. Bateman ED, Boushey HA, Bousquet J,
Busse WW, Clark TJ, Pauwels RA, et al.
Can guideline-defined asthma control be
achieved? The Gaining Optimal Asthma
ControL study. Am J Respir Crit Care Med
2004;170(8):836-44.
56. Nathan RA, Sorkness CA, Kosinski M,
Schatz M, Li JT, Marcus P, et al.
Development of the asthma control test: a
survey for assessing asthma control. J
Allergy Clin Immunol 2004;113(1):59-65.
29
57. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie
PJ, King DR. Development and validation of
a questionnaire to measure asthma control.
Eur Respir J 1999;14:902-7.
58. Vollmer WM, Markson LE, O'Connor E,
Sanocki LL, Fitterman L, Berger M, et al.
Association of asthma control with health
care utilization and quality of life. Am J
Respir Crit Care Med 1999;160(5 Pt 1):1647-
52.
59. Boulet LP, Boulet V, Milot J. How should we
quantify asthma control? A proposal. Chest
2002;122(6):2217-23.
60. Taylor DR, Bateman ED ,Boulet L-P. A new
perspective on concepts of asthma severity
and control. Eur Respir J 2008; 32 :545-554.
30
Chapter 3
Asthma
Medications
32
KEY POINTS:
Medications to treat asthma are
classified as either controllers or
relievers.
Inhaled therapy has the advantage
of delivering drugs directly into the
airways, producing higher local
concentrations with significantly less
risk of systemic side effects.
Inhaled glucocorticosteroids are the
most effective controller medications
currently available.
Rapid-acting β2-agonists are the
medications of choice for relief of
bronchoconstriction and for the pre-
treatment of exercise-induced
bronchoconstriction.
Increased use, especially daily use
of reliever medication is a warning
of deterioration of asthma control
and indicates the need to reassess
treatment.
INTRODUCTION
The goal of asthma treatment is to achieve
and maintain clinical control. Medications to
treat asthma can be classified as controllers
or relievers. Controllers are medications
taken daily on a long-term basis to keep
asthma under clinical control chiefly through
their anti-inflammatory effects. They include
inhaled and systemic glucocorticosteroids,
leukotriene modifiers, inhaled long-acting β2-
agonists (iLABA) in combination with inhaled
glucocorticosteroids, sustained-release
theophylline, cromones, anti-IgE, and other
systemic steroid-sparing therapies. Inhaled
glucocorticosteroids are the most effective
controller medications currently available.
Relievers are medications used on an as-
needed basis that act quickly to reverse
bronchoconstriction and relieve its
symptoms. They include rapid-acting inhaled
β2-agonists, inhaled anticholinergics, short-
acting theophylline, and oral short-acting β2-
agonists (SABA).
ROUTE OF ADMINISTRATION
Inhaled medications for asthma are
available as pressurized metered-dose
inhalers (MDIs), breath-actuated MDIs, dry
powder inhalers (DPIs), soft mist inhalers,
and nebulized or “wet” aerosols. Table 3-1
lists the advantages and disadvantages of
various aerosol devices1
.
Inhaler devices differ in their efficiency of
drug delivery to the lower respiratory tract
and ease with which the device can be used
by the majority of patients.
Jet nebulizers, MDIs, and DPIs all produce
equal results in acute situations when the
doses are matched and when the latter two
devices are used under direct supervision2,3
.
Intravenous salbutamol does not appear to
provide any benefit over nebulization even
in severe cases4
.
CONTROLLER MEDICATIONS
Inhaled Glucocorticosteroids
Inhaled corticosteroids (ICS) are the
mainstay therapy for persistent asthma and
are currently the most effective anti-
inflammatory medications for the treatment
of persistent asthma.
Long term treatment with ICS suppresses
the disease by affecting the underlying
airway inflammation. Several studies
demonstrate that ICS are effective in
reducing symptoms, improving quality of life,
decreasing frequency and severity of
exacerbations, decreasing the need for
bronchodilator rescue therapy,
improving
lung function, and reducing asthma
mortality.
A reduction of airway
inflammation, manifested both by airway
histology findings and improved airway
hyperresponsiveness has also been
33
documented.5-9
The outcome parameter
responding most rapidly to the initiation of
ICS is symptom relief. However, these
drugs do not cure asthma and when they
are discontinued, deterioration of clinical
control follows within weeks to months in a
proportion of patients 10,11
.
Table 3.1. Advantages and Disadvantages of Various Aerosol Devices1
34
Anti-inflammatory therapy, specifically ICS when
started early in the course of asthma, diminishes
the adverse effects of airway inflammation. Long
standing uncontrolled asthma is associated with
lower levels of lung function, greater airway
hyper-reactivity, more symptoms and greater
use of β2 agonists
12
.
Studies suggest that ICS
therapy, in addition to suppressing the disease,
may also modify the disease outcome if
prescribed early enough and given long enough
12-14
. In mild persistent asthma early intervention
with inhaled budesonide was associated with
improved asthma control and less additional
asthma medication use and was shown to be a
cost-effective and safe treatment 15
.
Side Effects. Inhaled steroids are relatively
safe. At low to moderate doses, inhaled steroids
do not frequently exhibit clinically important side
effects and provide asthmatics a good risk-
benefit profile.
Local adverse effects from ICS include
oropharyngeal candidiasis, dysphonia, and
occasionally coughing from upper airway
irritation. For pressurized MDIs, the prevalence
of these effects may be reduced by using certain
spacer devices16
. Oral candidiasis may be
reduced by mouth washing (rinsing with water,
gargling, and spitting out) after inhalation.
ICS are absorbed from the lung, accounting for
some degree of systemic bioavailability. The
occurrence and magnitude of adrenal
suppression is the most extensively studied
systemic effect of ICS. However, even if
moderate and high doses of exogenous
corticosteroids affect the hypothalamic-pituitary-
adrenal (HPA) axis, the resulting adrenal
suppression does not appear to be clinically
important, as there were no cases of adrenal
crisis reported in adults using only ICS. Other
systemic side effects of long-term treatment with
high doses of ICS include easy bruising, and
decreased bone mineral density 17-19
. ICS have
also been associated with cataracts and
glaucoma in cross-sectional studies20,21,22
but
there is no evidence of posterior-subcapsular
cataracts in prospective studies 23
.
There is no
evidence that use of ICS increases the risk of
pulmonary infections, including tuberculosis, and
ICS are not contraindicated in patients with
active tuberculosis 24
.
The risk of systemic adverse effects from an ICS
depends upon its dose and potency, the delivery
system, systemic bioavailability, first-pass
metabolism (conversion to inactive metabolites)
in the liver, and half-life of the fraction of
systemically absorbed drug (from the liver and
possible gut)25
. Therefore, the systemic effects
differ among the various ICS. Table 3.2 lists
approximately equipotent doses of different
inhaled glucocorticosteroids based upon the
available efficacy literature.70
Several comparative studies have demonstrated
that ciclesonide, budesonide, and fluticasone
propionate at equipotent doses have less
systemic effect 25-28
. Current evidence suggests
that in adults, systemic effects of ICS are not a
problem at doses of 400 g or less budesonide
or equivalent daily.
Long-acting Inhaled β2-agonists
Long-acting inhaled β2-agonists, including
formoterol and salmeterol, should not be used
as monotherapy in asthma as these medications
do not appear to influence the airway
Table 3.2. Estimated Equipotent Daily
Dose of Inhaled Glucocorticosteroids for
Adults70
35
inflammation in asthma. They are most effective
when combined with ICS 29-31
.
Salmeterol and formoterol provide a similar
duration of bronchodilation and protection
against bronchoconstrictors, but there are
pharmacological differences between them.
Formoterol has a more rapid onset of action
than salmeterol 32,33
which may make formoterol
suitable for symptom relief as well as symptom
prevention34
. The regular use of rapid acting
Long-acting β2-agonists (LABA) as a
monotherapy for symptom relief however may
lead to relative refractoriness to β2-agonists
35
and a possible increased risk of asthma-related
death and should only be used in combination
with an appropriate dose of ICS.
ICS + LABA. Combination treatment of ICS and
LABA improves symptom scores, decreases
nocturnal asthma, improves lung function,
decreases the use of rapid-acting inhaled β2-
agonists36-38
, reduces the number of
exacerbations19,36-41
, and achieves clinical
control of asthma in more patients, more rapidly,
and at a lower dose of ICS than ICS given
alone42
. In treating patients with mild persistent
asthma, initial therapy with ICS+LABA, may be
more advantageous in the local setting as it may
provide greater improvements in lung function
and asthma control, improve compliance and
has comparable safety to ICS alone.
The greater efficacy of combination treatment
has led to the development of fixed
combination inhalers that deliver both
glucocorticosteroid and LABA simultaneously
(fluticasone propionate plus salmeterol,
budesonide plus formoterol). Controlled studies
have shown that delivering this therapy in a
combination inhaler is as effective as giving
each drug separately43,44
. The additional clinical
benefit derived from the fixed combination
therapy results not only from the LABA-
glucocorticoid interaction but also from the
steroid-induced transcription of β2-adrenoceptor
gene with the resultant increased synthesis of
the β2-receptor protein. This interaction between
the LABA and the ICS increases the efficacy of
both drugs.
Fixed combination inhalers are more convenient
for patients, may increase compliance45
, and
ensure that the LABA is always accompanied by
a glucocorticosteroid. In addition, combination
inhalers containing formoterol and budesonide
may be used for both rescue and maintenance.
Both components of budesonide-formoterol
given as needed contribute to enhanced
protection from severe exacerbations in patients
receiving combination therapy for maintenance
46,47
and provide improvements in asthma control
at relatively low doses of treatment 34,47,48,49
.
Side effects. The regular use of rapid acting β2-
agonists in both short and long acting forms may
lead to relative refractoriness to β2-agonists
50
.
Therapy with inhaled LABA causes the following
systemic adverse effects: cardiovascular
stimulation, skeletal muscle tremor, and
hypokalemia. Data indicating a possible
increased risk of asthma-related death
associated with the use of salmeterol in a small
group of individuals51
led to advisories from the
US Food and Drug Administration (FDA)‡
and
Health Canada§
that long-acting 2-agonists are
not a substitute for inhaled or oral
glucocorticosteroids, and should only be used in
combination with an appropriate dose of ICS as
determined by a physician.
Leukotriene modifiers
Leukotriene modifiers may be given as controller
drugs for mild persistent asthma whenever ICS
are not in use. However, when used alone, their
effects are generally less than that of low dose
ICS52
.
In patients already on inhaled steroids,
leukotriene modifiers cannot substitute for this
treatment without risking the loss of asthma
control53
. For moderate-to- severe persistent
asthma, they may be used as an add-on therapy
to reduce the dose of ICS required by patients54
,
and may improve asthma control in patients
whose asthma is not controlled with low or high
doses of ICS55
.
36
Leukotriene modifiers include cysteneinyl-
leukotriene-1 receptor antagonists (montelukast,
pranlukast, and zafirlukast) and a 5-
lipooxygenase inhibitor (Zileuton). Clinical
studies have demonstrated that they have a
small and variable bronchodilator effect, reduce
symptoms including cough56
, improve lung
function and reduce airway inflammation and
asthma exacerbations57
.
These drugs are beneficial across a range of
asthma severities and may have a particular role
in exercise-induced asthma, aspirin-sensitive
asthma, and individuals with concomitant
allergic rhinitis, cough variant asthma,
premenstrual asthma58
.
Side effects. Leukotriene modifiers are safe
drugs even for prolonged use. Few, if any class-
related effects have so far been recognized.
They should be used with caution among
patients with liver disease, although more recent
studies failed to implicate direct hepatotoxicity
with leukotriene modifiers. The apparent
association of of leukotriene modifiers with
Churg-Strauss Syndrome (CSS) was proposed
to be due to the unmasking of the underlying
disease noted particularly during the period of
oral steroid tapering59
. Currently available
evidence suggests an association between
leukotriene modifiers and CSS that may be
causal60
.
Methylxanthine and Derivatives
Theophylline is used primarily for
bronchodilation. Data on its relative efficacy as a
long-term controller is lacking.
It is preferably prescribed by some physicians
because of the oral administration and relatively
low cost. It is available in sustained release
formulation that is suitable for once or twice daily
dosing. However, its potential for serious
toxicities and drug interactions and the need for
serum concentration monitoring limit its
usefulness in chronic therapy.
Available evidence suggests that it may provide
benefit as add-on therapy, although less
effective, than LABA in patients who do not
achieve control on ICS alone.61-63
The rationale
for this recommendation may arise from findings
that low concentrations of theophylline can
restore the anti-inflammatory action of
corticosteroids in oxidant exposed cells. The
exact mechanism however, remains unknown64
.
Studies on doxofylline, (7-(1,3-dioxalan-2-
ylmethyl) theophylline) a methylxanthine
derivative, have shown better or at least
equivalent results to those of theophylline to
relieve bronchial obstruction with less adverse
effects.65
Doxofylline differs from theophylline in
that it contains a dioxalane group in position 7.
Similarly to theophylline, its mechanism of action
is related to the inhibition of phosphodiesterase
activity, but in contrast, it appears to have
decreased affinity towards adenosine A1 and A2
receptors, which may account for its better
safety profile65-68
.
Side effects. Adverse effects of theopylline
include nausea and vomiting, which are the
most common early events, loose stools, cardiac
arrhythmias, seizures and even death. 69
Monitoring is advised when a high dose is
started, if the patient develops an adverse effect
on the usual dose, when expected therapeutic
aims are not achieved, and when conditions
known to alter theophylline metabolism exist70
.
Anti-IgE
Omalizumab71-72
, as add-on therapy with ICS, is
an effective and well tolerated agent for the
treatment of moderate to severe allergic asthma
in adolescents and adults.73-77
In addition to its
symptomatic and quality of life benefits,
omalizumab therapy allows ICS dosage
reduction or discontinuation of ICS in many
patients.
Omalizumab has been investigated extensively
in the treatment of patients with allergic diseases
and is approved for the treatment of patients
with moderate-to-severe persistent asthma.(78-79)
.
37
In such patients, omalizumab reduces the
frequency and incidence of asthma
exacerbations. Asthma control was well
maintained even with reduced ICS dose.
Comparisons of omalizumab with other asthma
therapies have yet to be conducted. However,
clinical efficacy and tolerability data indicate that
omalizumab is a valuable option in the treatment
of allergic asthma. In the local setting, its use is
severely limited because of its prohibitive cost.
Systemic glucocorticosteroids
The use of long-term oral glucocoticosteroid
therapy in the control of asthma is not
recommended because of the risk of significant
adverse side effects.
The systemic side effects of long-term oral or
parenteral glucocorticosteroid treatment include
osteoporosis, arterial hypertension, diabetes,
hypothalamic-pituitary-adrenal axis suppression,
obesity, cataracts, glaucoma, skin thinning
leading to cutaneous striae and easy bruising,
and muscle weakness. These side effects may
be present even on low doses80
.
Long-acting oral β2-agonist
Long-acting oral β2-agonists are used only on
rare occasions when additional bronchodilation
is needed. Long acting oral β2-agonists include
slow release formulations of salbutamol,
terbutaline, and bambuterol, a prodrug that is
converted to terbutaline in the body.
Regular use of long-acting oral β2-agonists as
monotherapy is likely to be harmful and these
medications must always be given in
combination with inhaled glucocorticosteroids.70
Side effects. The side effect profile of long
acting oral β2-agonists is higher than that of
inhaled β2-agonists, and includes cardiovascular
stimulation (tachycardia), anxiety, and skeletal
muscle tremor. Adverse cardiovascular
reactions may also occur with the combination of
oral β2-agonists and theophylline.
70
Antihistamines
The role of antihistamines is limited to providing
relief of allergic symptoms in some asthmatics81
.
Several studies however have shown that these
drugs may be more useful for allergic rhinitis
rather than bronchial asthma as there is no
decrease in bronchial responsiveness to
methacholine after antihistamine treatment.
Allergen-specific immunotherapy
Allergen specific immunotherapy, also known as
hyposensitization or desensitization, has long
been a controversial treatment for asthma. It
involves having injections of increasing amounts
of the allergen under the skin, and carries a risk
of severe allergic reactions and sometimes fatal
anaphylaxis.
A Cochrane review that examined 75
randomized controlled trials (RCTs), allergen
immunotherapy significantly reduced allergen
specific bronchial hyperreactivity, with some
reduction in non-specific bronchial hyper-
reactivity as well. However, there was no
consistent effect on lung function 82
.
There were also no studies that compare
specific immunotherapy with pharmacologic
therapy for asthma. The role of specific
immunotherapy in adult asthma is therefore
limited.
RELIEVER MEDICATIONS
Rapid-acting inhaled β2-agonists
Moderately short-acting β2-adrenergic agonists
such as salbutamol and terbutaline have rapid
onsets of action and provide three to four times
more bronchodilatation than do methylxanthines
and anticholinergics, making them the first-line
treatment for acute illness.
Salbutamol works poorly in some patients. This
phenomenon does not appear to be a function of
the medications taken before treatment,
permanent changes in β2-receptor physiology, or
the presence of fixed obstruction.83-87
38
Rapid-acting inhaled β2-agonists should be used
only on an as-needed basis at the lowest dose
and frequency required. Increased use,
especially daily use, is a warning of deterioration
of asthma control and indicates the need to
reassess treatment. Similarly, failure to achieve
a quick and sustained response to β2-agonist
treatment during an exacerbation mandates
medical attention, and may indicate the need for
short-term treatment with oral
glucocorticosteroids.
Side effects. Use of oral β2-agonists given in
standard doses is associated with more adverse
systemic effects such as tremor and tachycardia
than occur with inhaled preparations.
Systemic glucocorticosteroids
In acute asthma, systemic glucocorticosteroids,
can effectively treat the airway edema and
increased secretions associated with the
inflammation. They are important in the
treatment of severe acute exacerbations
because they prevent progression of the asthma
exacerbation, reduce the need for referral to
emergency departments and hospitalization,
prevent early relapse after emergency
treatment, and reduce the morbidity of the
illness. Corticosteroids should be administered
as soon as possible after initiation of
bronchodilator therapy88
since the onset anti-
inflammatory effects of corticosteroids are not
seen for several hours. Oral and intravenous
routes of corticosteroid administration are
equally efficacious89
. The parenteral route is
preferred if patients are unable to take
medication orally or if they are unable to absorb
an oral dose.
Patients discharged from the Emergency
Department (ED) who require corticosteroid
therapy should be given 30 to 60 mg of
prednisone orally (or equivalent) per day for 7 to
14 days. No tapering is required over this
period.90-93
When symptoms have subsided and lung
function has approached the patient’s personal
best value, the oral glucocorticosteroids can be
stopped or tapered, provided that treatment with
inhaled glucocorticosteroids continues.93
Intramuscular injection of glucocorticosteroids
has no advantage over a short course of oral
glucocorticosteroids in preventing relapse.93
Adverse effects of short-term high-dose
systemic therapy are uncommon but include
reversible abnormalities in glucose metabolism,
increased appetite, fluid retention, weight gain,
rounding of the face, mood alteration,
hypertension, peptic ulcer, and aseptic necrosis
of the femur.
Anticholinergics
The use of anticholinergic drugs as the initial
bronchodilator has been consistently reported to
be inferior to the use of a β-agonist on improving
airflow in acute severe asthma. It has a slow
onset of action (60–90 minutes to peak) and
medium potency (about 15% increase in PEFR).
Consequently, it is used as second-line therapy,
particularly in patients resistant to β2 agonists.
94-
97
The addition of nebulized ipratropium bromide to
salbutamol, further improves the FEV1, or PEFR
in the initial treatment of acute asthma attacks.
The benefits offered however, are still a matter
of debate. A meta-analysis of trials of inhaled
ipratropium bromide used in association with an
inhaled β2-agonist in acute asthma showed that
the anticholinergic produces a statistically
significant, albeit modest, improvement in
pulmonary function, and significantly reduces
the risk of hospital admission.98
The benefits of ipratropium bromide in the long-
term management of asthma have not been
established, although it is recognized as an
alternative bronchodilator for patients who
experience such adverse effects as tachycardia,
arrhythmia, and tremor from rapid acting β2-
agonists.
39
Side effects. Inhalation of ipratropium can
cause a dryness of the mouth and a bitter taste.
There is no evidence for any adverse effects on
mucus secretion.99
Methylxanthines
Short-acting theophylline may be considered for
relief of asthma symptoms.100
Recent guidelines
have relegated its use as third line treatment in
acute asthma. Furthermore, it has no proven
additive bronchodilator effect over adequate
doses of rapid-acting 2-agonists. A few studies
have shown that it may benefit respiratory drive.
Theophylline has the potential for significant
adverse effects, although these can generally be
avoided by appropriate dosing and monitoring.
Short-acting theophylline should not be
administered to patients already on long-term
treatment with sustained-release theophylline
unless the serum concentration of theophylline
is known to be low and/or can be monitored.
Intravenous methylxanthine (aminophylline)
does not result in any additional bronchodilation
compared to standard care with beta-agonists.
The frequency of adverse effects is higher with
aminophylline. No subgroups in which
aminophylline might be more effective could be
identified. 101
IV Magnesium
The use of magnesium to improve pulmonary
function should be considered when treating
acutely ill asthmatics in the Emergency Room
(ER) with severe airway obstruction.102
IV
magnesium may be useful for severe
exacerbations unresponsive to the initial
treatment in the ER to decrease the likelihood of
intubation. There has been insufficient evidence
to support the routine use of magnesium in
acute asthma and further studies are still
recommended.
The administration of 2 g of magnesium sulfate
as an adjunct to standard therapy to patients
presenting to the ER with severe asthma causes
improvement in pulmonary function. The
improvements were restricted to patients with
the most severe airway obstruction, and the
lower the initial FEV1 the greater the
improvement in FEV1. The hospital admission
rates, however, did not improve after treatment
with magnesium.102
Magnesium is relatively inexpensive, readily
available, and easy to administer. Minor side
effects can include transient flushing,
lightheadedness, lethargy, nausea, or burning at
the IV site. Transient urticaria resolving with
discontinuation of magnesium has been
reported. Serious side effects at the infusion
rate and dose administered of 2 g are extremely
uncommon in patients with adequate renal
function.
Heliox
Heliox may be useful for severe exacerbations
unresponsive to the initial treatment in the ER to
decrease the likelihood of intubation. Heliox, a
blend of helium and oxygen, reduces airway
resistance and may be a therapeutic option for
severe refractory asthma. In intubated patients,
there is a decrease in peak inspiratory pressure
and PaCO
2. Its temporary use, however, may
lower respiratory resistive work long enough to
forestall muscle fatigue and/or improve
ineffective mechanical ventilation until
bronchodilators and steroids can take effect.
The mixture may improve the distribution of
inhaled agents and lead to a faster rate of
resolution of obstruction. In non-intubated
individuals, some studies have shown a
reduction in dyspnea, improved gas exchange,
increased PEFR, and a diminution in pulsus
paradoxus103-104
whereas others have not found
any benefit. 105,106
The effects of heliox are
transitory and disappear when air is once again
inhaled.
Complementary and Alternative Medicine
The roles of complementary and alternative
medicine in adult asthma treatment are limited
because these approaches have been
insufficiently researched and their effectiveness
40
is largely unproven. Complementary and
alternative therapies include herbal medicine,
dietary supplements, Ayurvedic medicine,
acupuncture, chiropractic manipulation, Butyeko
breathing method or retraining exercises, Sahaja
yoga, and psychotherapy-related methods such
as relaxation, hypnosis, autogenic training,
speleotherapy, and biofeedback.
A systematic review107
was conducted to
determine the study quality of articles
investigating ayurvedic/collateral herbs, the
effectiveness/efficacy and safety profile, as
reported in the studies. The review concluded
that there is insufficient evidence to make
recommendations for the use of these herbals.
There is also insufficient evidence on the benefit
of Vitex vigonensis (lagundi), an herbal cough
preparation, for asthma. In a small randomized
double blind study involving 40 subjects,
Lagundi tablets improve peak expiratory flow
rate108
. At this time, however, there is insufficient
evidence to recommend it as part of the
standard therapeutic regimen for asthma.
In a prospective randomized crossover
controlled study in 18 asthma patients,
acupuncture treatment resulted in immediate
improvement of FEV1, but the degree of
improvement is less than that from inhalation
bronchodilator.109
A single controlled trial of
chiropractic spinal manipulation failed to show
benefit of this therapy in asthma110
.
At present there is no definitive evidence to
recommend any of the breathing techniques
such as the Buteyko breathing method or
retraining exercises. Although one study of the
Buteyko breathing method suggested minor
benefit, a later study of two physiologically-
contrasting breathing techniques showed similar
improvements in reliever and ICS use in both
groups, suggesting that perceived improvement
with these methods are the result of non-
physiological factors.111
A randomized controlled
trial indicated that the practice of Sahaja yoga
has limited beneficial effects on asthma for
some objective and subjective measures,
although there were no significant differences
between the intervention and control groups at
the 2-month follow-up assessment.112
Psychotherapy-related methods such as
relaxation, hypnosis, autogenic training,
speleotherapy, and biofeedback might have a
small effect in selected cases, but have not
proven to be superior to placebo.113
Side effects. Acupuncture-associated hepatitis
B, bilateral pneumothorax, and burns have been
described. Side effects of other alternative and
complementary medicines are largely unknown.
However, some popular herbal medicines could
potentially be dangerous, as exemplified by the
occurrence of hepatic veno-occlusive disease
associated with the consumption of the
commercially available herb comfrey sold as
herbal teas and herbal root powders. Side
effects of Lagundi include vomiting,
desquamation of the skin over the palms and
increased urination.108
RESEARCH RECOMMENDATIONS
A well-designed study should be
conducted to determine how low dose
inhaled corticosteroids alone compare
with combined low dose inhaled
corticosteroid with LABA in controlling
the symptoms and improving the lung
function of patients with mild persistent
asthma as well as their cost-
effectiveness and safety.
A cost-effectiveness study between
strategies using different combination
inhaled LABA and corticosteroids.
Bigger randomized placebo controlled
trials investigating the bronchodilator
effects and safety of local herbal
preparations are needed.
41
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104. Manthous CA, Hall JB, Melmed A, Caputo
MA, Walter J, Klocksieben JM, Schmidt GA,
Wood LDH. Heliox improves pulsus
paradoxus and peak expiratory flow in
nonintubated patients with severe asthma.
Am J Respir Crit Care Med 1995;151:310–
4.
105. Carter ER, Webb CR, Moffitt DR. Evaluation
of heliox in children hospitalized with acute
severe asthma: a randomized crossover trial.
Chest 1996;109:1256–61.
106. Henderson SO, Acharya P, Kilaghbian T,
Perez J, Korn CS, Chan LS. Use of heliox-
driven nebulizer therapy in the treatment of
acute asthma. Ann Emerg Med
1999;33:141–6.
107. Singh BB, Khorsan R, Vinjamury SP, Der-
Martirosian C, Kizhakkeveettil A, Anderson
TM. Herbal treatments of asthma: a
systematic review. J Asthma 2007
Nov;44(9):685-98.
108. Chu, RP. The Effect of “Lagundi” (a local
herb) Tablets on Bronchial Asthma in Adults:
A Randomized Double Blind Study with
Theophylline.
http://www.pascuallab.com/altermed/s_lagun
di1.htm.
109. Chu KA, Wu YC, Ting YM, Wang HC, LU JY.
Acupuncture therapy results in immediate
bronchodilating effect in asthma patients. J
Chin Med Assoc 2007 Jul;70(7):265-8.
110. Balon JW, Mior SA. Chiropractic care in
asthma and allergy. Ann Allergy Asthma
Immunol 2004;93(2 Suppl 1):S55-S60.
111. Slader CA, Reddel HK, Spencer LM,
Belousova EG, Armour CL, Bosnic-
Anticevich SZ, Thien FC, Jenkins CR.
Double blind randomised controlled trial of
two different breathing techniques in the
management of asthma. Thorax 2006
Aug;61(8):651-6.
112. Manocha R, Marks GB, Kenchington P,
Peters D, Salome CM. Sahaja yoga in the
management of moderate to severe asthma:
a randomised controlled trial. Thorax
2002;57:110-5.
113. Györik SA, Brutsche MH Complementary
and alternative medicine for bronchial
asthma: is there new evidence? Curr Opin
Pulm Med 2004 Jan;10(1):37-43.
46
Chapter 4
Patient
Education
48
Table 4.1. Essential Features of the Doctor -
Patient Partnership to Achieve Guided Self-
Management in Asthma
KEY POINTS:
Patient education is of prime importance
in the management and control of
asthma. This can be achieved either
through individualized or group
education.
Development of a good doctor-patient
relationship facilitates patient education.
The aim of patient education is guided
self-management.
ASTHMA EDUCATION
Patient education is of prime importance in the
management and control of asthma. In the GINA
2007 guidelines, asthma education is the first
step in the treatment recommendations.
Because of non-adherence to medication, it has
been recognized that the adolescent asthmatic
is considered difficult to manage1.
Communicative skills have been pointed out as
one of the key factors for good adherence or
compliance of patients2-3
(Evidence B). Thus, the
ability of the healthcare professionals to be good
communicators should not be overlooked. It is
thus of prime importance that healthcare
professionals be educated to improve their
communication skills which can result into better
outcomes – including increased patient
satisfaction, better health, and reduced use of
health care. Such benefits can be achieved
without any increase in consultation times4.
Table 1 enumerates the essential features of the
doctor-patient partnership needed to achieve
guided self-management in asthma5.
The main aim for asthma education is to provide
the person with asthma, their family and other
caregivers with suitable information and training
so that they can keep well and adjust treatment
according to a medication plan developed with a
health care professional. All individuals require
core information and skills, however, education
is best with a personalized approach and given
in a number of steps.
Table 4.2 enumerates the key components of
asthma education.
At the INITIAL CONSULTATION6
During the first consultation, the patient needs
information about:
1. Diagnosis
- Asthma and its nature should be
defined
- The signs and symptoms of the
patient should be explained
- It should be stressed that
spirometry be done to have an
objective parameter for the
diagnosis of asthma
49
Table 4.2. Education and the patient/Doctor
Partnership
2. Triggers
- It should be stressed to patients
that avoidance of triggers is
important in the prevention of
acute attacks
- Exercise should not be avoided
3. Peak flow meter
- The patient must be taught the
proper way to use a peak flow
meter
- The patient must know how to
interpret the values obtained
4. Drugs needed for management of
asthma
- Medicines used to control
symptoms
- Medicines used to relieve
symptoms
- Specific instructions about
medication use
5. Proper use of inhaler devices
- The patient must be taught the
correct technique of using their
inhaler devices so as to
maximize medication effect
6. Management of acute exacerbations
- Personal Asthma Action Plan :
individualized asthma action
plans help asthmatic patients
tailor their treatment in response
to changes in their level of
asthma control based on their
symptoms and peak flow
measures, in accordance with
written predetermined
guidelines
- Individual patient’s asthma
action plan should contain the
following:
a. How to identify
deteriorating asthma
control/exacerbations
b. Steps to take in the
management of
exacerbations
c. When to seek
emergency care
Follow-Up Care:
1. PEFR diary – included are symptoms
and home peak flow monitoring noted in
the diary.
2. Check inhaler device technique and
correct if inadequate.
50
Table 4.3. Factors Involved in Non-adherence
3. Check adherence or compliance to
medication plan and recommendations
for reducing exposure to risk factors or
triggers.
4. Review of asthma action plan should be
done.
.
An option for busy practitioners would be to refer
to the different asthma clubs available in their
locality for their patients’ asthma education.
Asthma clubs provide a good venue where the
patients can express their feelings and fears
about asthma. This will enable them to
communicate more effectively to their
physicians, participate in planning strategies for
controlling their asthma and eventually
normalize their day-to-day activities. The
curriculum should cover all those items that
should be discussed in an individualized
education.
IMPROVING ADHERENCE
Studies of adults have shown that around 50%
of those on long term therapy failed to take
medications as directed at least part of the time.
Patient concern about side effects of inhaled
glucocorticosteroids whether real or perceived
may influence adherence. Non-adherence may
be defined in a non-judgemental way as the
failure of treatment to be taken as agreed upon
by the patient and the health care professional.
Non-adherence may be identified by prescription
monitoring, pill counting or drug assay. But at a
clinical level it is best detected by asking about
therapy in a way that acknowledges the
likelihood of incomplete adherence, (e.g., “So
that you can plan therapy, do you mind telling
me how often you actually take the medicine?”)
Specific drug and non-drug factors involved in
non-adherence are listed in Table 4-3. 5
EDUCATION OF OTHERS
Not only is it important to educate patients,
parents, caregivers about asthma, it is likewise
important to educate the general public as well.
This way, the people would be made aware of
asthma symptoms and its consequences, for
better medical seeking attention of afflicted
individuals, to help dispel misconceptions, and
reduce stigmatization on the part of the patient.5
Specific advice about asthma and its
management should be offered to school
teachers and physical education instructors, and
several organizations produce materials for this
purpose. Schools may need advice on improving
51
the environment and air quality. It is also helpful
for employers to have access to clear advice
about asthma. Most occupations are as suitable
for those with asthma as for those without, but
there may be some circumstances where
caution is needed.5 Further readings on
occupational asthma can be found in Chapter 8
on Special Considerations.
RECOMMENDATIONS:
Investigate the impact of asthma clubs
on the quality of life of asthmatic
patients in the local setting.
How to encourage the wide availability
of asthma clubs, with sustenance of the
different asthma clubs.
References
1. Shah s. Peat JK, Mazurki EJ, Wang H,
Sindhusake D, Bruce C, et al. Effect of peer
led programme for asthma education in
adolescents: cluster randomized controlled
trial. BMJ 2001; 322(7286):583-5
2. Ong LM, de Haes JC, Hoos AM, Lammes
FB. Doctor-patient communication: a review
of the literature. Soc Sci Med
1995;40(7):903-18.
3. Stewart MA. Effective physician-patient
communication and health outcomes: a
review. CMAJ 1995;152(9):1423-33.
4. Clark NM, Gong M, Schork MA, Kaciroti N,
Evans D, Roloff D, et al. Long-term effects of
asthma education for physicians on patient
satisfaction and use of health services. Eur
Respir J 2000;16(1):15-21.
5. Global Initiative for Asthma. Global Strategy
for Asthma Management and prevention.
2007 update
6. Philippine Consensus on Recognition,
Diagnosis and Management of Asthma 1996
7. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie
PJ, King DR. Development and validation of
a questionnaire to measure asthma control.
Eur Respir J 1999;14:902-7
8. Nathan, RA, Sorkness CA, Kosinski M,
Schatz M, Li JT, Marcus P, et al.
Development of the asthma control test: a
survey for assessing asthma control. J
Allergy Clin Immunol 2004;113(1):59-65.
52
Chapter 5
Identify and
Reduce
Exposure to Risk
Factors
54
KEY POINTS:
• Measures to prevent the development of
asthma, asthma symptoms, and asthma
exacerbations by avoidance or reducing
exposure to asthma risk factors should be
implemented whenever possible.
• Presently, few measures for asthma prevention
can be recommended because asthma in itself
is a variable disease and its development
complex and incompletely understood.
• Asthma exacerbations are usually caused by a
variety of risk factors or "triggers" such as
allergens and pollutants (both indoor and
outdoor), viral infections and drugs.
• Reduction of an asthmatic's exposure to some
categories of risk factors improves the control of
asthma. Complete avoidance of these risk
factors, however, is often impractical and
extremely limiting for the patient.
INTRODUCTION
The pharmacologic intervention that has evolved
through the years in treating asthma has
effectively controlled symptoms, reduced
exacerbations, lowered mortality rate, and has
significantly improved the quality of life of an
asthmatic individual. Just as important, however,
in the management is the implementation of
measures aimed at preventing the development
of asthma and asthma symptoms by avoiding
and reducing exposure to risk factors.1
The
former is currently a focus of intensive research
and hence, until such time that measures to
prevent the development of asthma has been
successful, present efforts should primarily focus
on prevention of asthma symptoms and attacks.2
ASTHMA PREVENTION
Few measures can be recommended for asthma
prevention because the disease is a very
variable one, and its development is complex
and incompletely understood. Other than
preventing tobacco exposure both in-utero and
after birth, during which time the lungs are still
developing, there are no proven and accepted
interventions that can prevent the development
of asthma. Interventional modalities aimed at
preventing allergic sensitization or the
development of atopy3
, (and hence prevent
asthma development in sensitized individuals)
most relevant prenatally3.4
and perinatally, are
still in the realm of research. At present, there is
no sufficient evidence on the critical timing and
appropriate doses of allergen exposure that
would permit intervention in this process. Thus,
no strategy can be recommended in this area.
Dietary intervention (e.g. prescribing an antigen-
avoidance diet likely to be low in proteins) to a
high risk woman during pregnancy has not been
proven to decrease the risk of giving birth to an
atopic child5
. More importantly, such a diet could
have an adverse effect on maternal and fetal
nutrition.
The role of breast-feeding in relation to the
development of asthma has been studied more
extensively. It is an accepted fact that infants fed
on formulas of cow’s milk or soy protein have a
higher incidence of wheezing compared to
infants who are breast-fed6
. Likewise, exclusive
breast-feeding during the first months after birth
is correlated with lower rates of childhood
asthma7
.
A focal point in any discussion of asthma
prevention is the concept of "hygiene
hypothesis" which states that little or no
exposure to bacteria and viruses during a critical
period of infancy can lead to an imbalance in the
immune system and result in diseases such as
asthma, especially in high risk groups like
55
children who have parents with asthma. Though
still largely controversial, the hypothesis has led
to the suggestion that in order to prevent allergic
sensitization, strategies should be made to
redirect a predisposed child’s immune response
toward a Th1 (non-allergic) response or
modulate T regulator cells8
. Again, such
strategies at present are in the realm of theories
and research and require further investigation.
The hygiene hypothesis has also led to the
concept of the role of probiotics in the prevention
of allergy and asthma. Though this concept is
still unclear, it has gained more attention in the
last few years9
. A probiotic supplement like
Lactobacillus GG apparently can stimulate the
immune system and, in the end, prevent or at
least delay the appearance of early signs of
asthma such as wheezing and frequent rhinitis.
More definite evidence-based data on this
matter is presently still lacking.
Exposure to tobacco smoke both prenatally and
postnatally is associated with measurable and
well-documented harmful effects, including
effects on lung development10
and a greater risk
of developing wheezing illnesses in childhood11
.
Although there is little evidence that maternal
smoking during pregnancy has an effect on
allergic sensitization12
, passive smoking
increases the risk of allergic sensitization in
children12,13
. It is highly recommended, therefore,
that pregnant women and parents of young
children should not smoke.
Once allergic sensitization has occurred, there
are still options and opportunities to prevent the
actual development of asthma. The role of H1-
antagonists and antihistamines14,15
as well as
allergen-specific immunotherapy16,17
in the
prevention of development of asthma in highly-
atopic children remain to be an area of
continued investigation. As such, no clear-cut
recommendation on this matter can be made
and definite interventions cannot be
recommended for wide scale adoption as part of
management strategies in clinical practice2
.
PREVENTION OF ASTHMA
SYMPTOMS AND EXACERBATIONS
Asthma exacerbations may be caused by a
variety of factors, referred to as "triggers",
including allergens, viral infections, pollutants,
and drugs. Central to the prevention or reduction
of the occurrence and severity of asthmatic
exacerbations is a decrease in, and preferably
the removal of, the offending environmental
allergen(s). Since many asthma patients react to
multiple factors that are ubiquitous in the
environment, avoiding these factors completely
is usually impractical and very limiting to the
patient. Thus, medications to maintain asthma
control have an important role in preventing
symptoms and exacerbations because patients
are often less sensitive to these triggers when
their asthma is under good control.2
Climate changes and Global warming
Asthma is an etiologically complex disease, with
numerous contributing factors and interactive
effects modified by climate18,19
. Severe weather
and atmospheric conditions favor the
development of asthma exacerbations by a
variety of mechanisms, including exposure to
dust and pollution, increases in respirable
allergens, and changes in temperature/humidity.
The climate change hypothesis proposes that
the global rise of asthma is an early impact of
anthropogenic climate change20
. Increasing
temperatures (global warming) stimulates the
growth of fungus, molds, pollens and other
allergens. Global warming itself extends the
growing season of such airborne allergens and
hence, CO2
increases and the plants’ pollen-
producing capacity increases. It is feasible that
both pollen quantity and allergenicity have
already had an impact on asthma reflected in
56
the global rise in asthma prevalence and
increased severity of asthma episodes.
Thunderstorm asthma is a little understood
entity where rain water has been implicated to
cause an "osmotic shock" on pollen grains21
.
The
air becomes filled with allergenic proteins
produced by starch granules from grass pollen
grains which are spread by the strong winds of a
thunderstorm22
. These tiny particles are smaller
than pollen and therefore more deeply inhaled,
precipitating attacks in those who are sensitive.
Indoor Allergens
There is conflicting evidence on whether
measures to create a low-allergen environment
in patients' homes and reduce exposure to
indoor allergens are effective at reducing
asthma symptoms54,55
. It is likely that no single
intervention aimed at reducing allergen load will
achieve sufficient benefits to be cost effective24-
26
.
Domestic mites. No single measure is likely to
reduce exposure to mite allergens, and single
chemical and physical methods aimed at
reducing mite allergens are not effective in
reducing asthma symptoms in adults24,27,28
(Evidence A). One study showed some efficacy
of mattress encasing at reducing airway
hyperresponsiveness in children29
(Evidence B).
An integrated approach including barrier
methods, dust removal, and reduction of
microhabitats favorable to mites has been
suggested, although its efficacy at reducing
symptoms has only been confirmed in deprived
populations with a specific environmental
exposure30
(Evidence B) and a
recommendation for its widespread use cannot
be made.
Furred animals. Complete avoidance of pet
allergens is impossible, as the allergens are
ubiquitous and can be found in many
environments outside the home31
, including
schools32
, public transportation, and cat-free
buildings33
. Although removal of such animals
from the home is encouraged, even after
permanent removal of the animal it can be many
months before allergen levels decrease34
and
the clinical effectiveness of this and other
interventions remains unproven.
Cockroaches. Allergens found in cockroach
dried body parts, feces and saliva can cause
allergic symptoms or trigger asthma symptoms
in some individuals. Cockroaches are commonly
found in crowded cities and likely play a
significant role in asthma in urban areas.
Although avoidance measures are only partially
effective in removing residual allergens35
(Evidence C), pest management
measures/advice include the following:
Do not leave food or garbage out.
Store food in airtight containers.
Clean all food crumbs or spilled liquids
right away.
Wash dishes as soon as you are done
using them.
Keep counters, sinks, tables and floors
clean and clear of clutter.
Fix plumbing leaks and other moisture
problems.
Seat cracks or openings around or
inside cabinets.
Remove piles of boxes, newspapers
and other hiding places for pests from
your home.
Make sure trash is stored in containers
with lid that close securely, and remove
trash daily.
Try using poison baits, boric acid or
traps first before using pesticide sprays.
Fungi. Fungal exposure has been associated
with exacerbations from asthma and the number
of fungal spores can best be reduced by
removing or cleaning mold-laden objects36
.
In tropical and subtropical climates, fungi may
grow on the walls of the house due to water
57
seepage and humidity. To avoid this, the walls
could be tiled or cleaned as necessary. Air
conditioners and dehumidifiers may be used to
reduce humidity to levels less than 50% and to
filter large fungal spores. However, air
conditioning and sealing of windows have also
been associated with increases in fungal and
house dust mite allergens37
.
HEPA devices, Ionizers and Dehumidifiers.
Mechanical and electrical devices reduce indoor
allergen load, however their clinical benefit in
reducing asthma symptoms in predisposed
individuals remains inconclusive.
Mechanical filters such as fan-driven HEPA
filters force air through a special mesh that traps
particles including allergens like pollen, pet
dander and dust mites. They also capture irritant
particles like tobacco smoke. Electronic filters
such as ionizers use electrical charges to attract
and deposit allergens and irritants; however,
ionizers do not work any better than high-
efficiency particulate air (HEPA) filters or
electrostatic filters in removing allergens from
the air and may generate unwanted ozone.
Dehumidifiers are more appropriate than
ionizers and HEPA filters in reducing house dust
mites that thrive in humid environments.
Outdoor Allergens
Outdoor allergens such as pollens and molds
are impossible to avoid completely. Exposure
may be reduced by closing windows and doors,
remaining indoors when pollen and mold counts
are highest and using air conditioning if possible.
Some countries use radio, television, and the
Internet to provide information on outdoor
allergen levels. The impact of these measures is
difficult to assess.
Indoor Air Pollutants
The most important indoor pollutant is tobacco
smoke. Avoidance of passive and active
smoking is the most important measure in
controlling indoor air pollutants. Secondhand
smoke increases the frequency and severity of
symptoms in children with asthma.
Parents/caregivers of children with asthma
should be advised not to smoke and not to allow
smoking in rooms their children use. In addition
to increasing asthma symptoms and causing
long term impairments in lung function, active
cigarette smoking reduces the efficacy of
inhaled and systemic glucocorticosteroids38,39
(Evidence B), and smoking cessation needs to
be vigorously encouraged for all patients with
asthma who smoke.
Indoor particulate concentrations in rural areas
of developing countries, where acute respiratory
infection (ARI) morbidity and mortality are
highest,
range from a few hundred to more than 10,000
g/m3
.
Domestic cooking is a significant source of
indoor air pollution. The average Filipino woman
spends a large amount of her time at home
cooking and related work and is thus exposed to
emissions from cooking fuels which may take
any one of the following types: biomass,
liquefied petroleum gas, kerosene or a
combination of two or all three.
Biomass consists of organic material from trees,
agricultural crops and other living plant material.
It excludes organic material which has been
transformed by geological processes into
substances such as coal or petroleum. It stores
solar energy in organic matter and is, therefore,
a renewable energy source which when burned,
releases chemical energy as heat. It can be
used as fuel or for industrial production. There
may be a significant association between
symptoms of asthma and chronic bronchitis and
biomass fuel usage in females living in a rural
area40
.
58
Outdoor Air Pollutants
Outbreaks of asthma exacerbations have been
shown to occur in relationship to increased
levels of air pollution, and this may be related to
a general increase in pollutant levels or to an
increase in specific allergens to which
individuals are sensitized41-43
. Most
epidemiological studies show a significant
association between air pollutants—such as
ozone, nitrogen oxides, acidic aerosols, and
particulate matter—and symptoms or
exacerbations of asthma. As the prevalence of
asthma, particularly among urban residents, has
escalated over the past three decades, ambient
air pollutants, especially ozone and particulate
matter (PM), have come under scrutiny as
stimuli of asthma exacerbations.
It appears possible that there is subclinical
airway inflammation or preexisting airway
remodeling that is "unmasked" by exposure to
higher air pollutant levels, resulting in greater
pollution-related effects on lung function among
asthmatics on corticosteroids.
Volcanic ash. In June 1991, Mt. Pinatubo in
Pampanga spawned 20 million tons of gas and
ash as high as 12-18 miles into the stratosphere
and as far as the Indian Ocean and with
satellites tracking ash clouds several times
around the globe44
. Although the eruption did not
permanently increase stratospheric chlorine
concentrations, it did produce large amounts of
tiny particles which increased chlorine's
effectiveness at destroying ozone and thus
destroying ozone faster than would have
otherwise occurred.
The potential respiratory symptoms from the
inhalation of volcanic ash are short term and are
not considered harmful for people without
existing respiratory conditions. Individuals with
chronic bronchitis, emphysema, and asthma,
however, should take special precaution to avoid
exposure to ash particles and be aware that the
use of any respirator other than single-use
(disposable) respirators may cause additional
cardio-pulmonary stress.
Diesel Exhaust. Diesel exhaust (DE) is a
complex mixture containing carbonaceous
particles, oxides of nitrogen, carbon monoxide,
aldehydes and other volatile organic carbon
species. In addition DE particles may act as
vectors for the delivery to the lung of toxic
materials, including heavy metal ions,
hydrocarbons and allergens45,46
.
The observation that a two hour walk along a
busy thoroughfare with high density of diesel
exhaust can increase asthmatic symptoms,
reduce lung capacity, and inflammation in the
lungs offers support for the hypothesis that
diesel exhaust may play a role in causing
asthma.
Researchers believe that DE causes problems
for people with asthma through minute particles
of dust, dirt, soot and smoke - which are
released into the air. Respirable particulates of
less than 2.5 microns, are easily inhaled into the
lungs and may interfere with respiration47,48,49
.
Occupational Exposures
The early identification of occupational
sensitizers and the removal of sensitized
patients from any further exposure are important
aspects of the management of occupational
asthma (Evidence B). Once a patient has
become sensitized to an occupational allergen,
the level of exposure necessary to induce
symptoms may be extremely low, and resulting
exacerbations become increasingly severe.
Attempts to reduce occupational exposure have
been successful especially in industrial settings,
and some potent sensitizers, such as soy castor
bean, have been replaced by less allergenic
substances50
(Evidence B).
59
Food and Food Additives
Food allergy as an exacerbating factor for
asthma is uncommon and occurs primarily in
young children. Food avoidance should not be
recommended until an allergy has been clearly
demonstrated (usually by oral challenges)51
.
When food allergy is demonstrated, food
allergen avoidance can reduce asthma
exacerbations52
(Evidence D).
Sulfites (common food and drug preservatives
found in such foods as processed potatoes,
shrimp, dried fruits, beer, and wine) have often
been implicated in causing severe asthma
exacerbations but the likelihood of a reaction is
dependent on the nature of the food, the level of
residual sulfite, the sensitivity of the patient, the
form of residual sulfite and the mechanism of the
sulfite-induced reaction53
. The role of other
dietary substances—including the yellow dye
tartrazine, benzoate, and monosodium
glutamate—in exacerbating asthma is probably
minimal, confirmation of their relevance requires
double-blind challenge before making specific
dietary restrictions.
Drugs
Some medications can exacerbate asthma.
Aspirin and other nonsteroidal anti-inflammatory
drugs can cause severe exacerbations and
should be avoided in patients with a history of
reacting to these agents54,55
. Beta-blocker drugs
administered orally or intraocularly may
exacerbate bronchospasm (Evidence A) and
close medical supervision is essential when
these are used by patients with asthma56
.
Influenza Vaccination
Patients with moderate-to-severe asthma should
be advised to receive an influenza vaccination
every year57
or at least when vaccination of the
general population is advised. However, routine
influenza vaccination of children58
and adults59
with asthma does not appear to protect them
from asthma exacerbations or improve asthma
control. Inactivated influenza vaccines are
associated with few side effects and are safe to
administer to asthmatic adults and children over
the age of 3 years, including those with difficult-
to-treat asthma60
.
Infections
Respiratory viral infections are major causes of
morbidity and mortality in asthma. However,
there is lack of specific antiviral strategies in the
prevention or reduction of viral-triggered asthma
exacerbations.
Rhinitis, sinusitis, and polyposis. Rhinovirus
is the most common respiratory virus present in
most patients hospitalized for life-threatening
asthma and acute nonlife-threatening asthma.
Patients with asthma are not more susceptible to
upper respiratory tract rhinovirus infections than
healthy people but suffer from more severe
consequences of the lower respiratory tract
infection. Recent epidemiologic studies suggest
that viruses provoke asthma attacks by additive
or synergistic interactions with allergen exposure
or with air pollution. An impaired antiviral
immunity to rhinovirus may lead to impaired viral
clearance and hence prolonged symptoms.
Studies have shown the association of air
pollutants and virally induced exacerbations.
Tarlo et al. reported that asthma exacerbations
with colds were associated with higher levels of
sulfur dioxide and nitrogen oxides compared
with exacerbations without colds61
. Chauhan et
al, found that participants exposed to high levels
of NO2 in the week before the onset of virally
induced exacerbation had worse symptom
scores and lower peak flows than did
participants exposed to low levels of NO2 before
their virally induced exacerbations62
.
60
Bacterial Infections. Infection or colonization of
the airways with mycoplasma pneumonia and
chlamydia pneumonia may potentiate asthma in
some individuals. In addition, a constituent of the
Gram-negative bacteria [outer membrane
(lipopolysaccharide [LPS], also known as
endotoxin) is present in high concentrations in
organic dusts, air pollution, and household
dusts. Inhaled LPS can exacerbate airway
inflammation and airflow obstruction in allergic
asthmatics. Allergic subjects are more sensitive
than nonallergic subjects to the
bronchoconstrictive properties of inhaled LPS.
Previous studies have shown that adults already
suffering from asthma have a 200 percent higher
chance of developing pneumonia due to
bacterial infections than those exposed to the
pathogen, but without pre-existing conditions.
There is very limited evidence to support the
routine use of pneumococcal vaccine in people
with asthma. A randomised trial of vaccine
efficacy in children and adults with asthma is
needed.
Intestinal Parasites. The lower incidence of
asthma in rural subsistence societies has led to
the postulate that high degrees of parasite
infection might prevent asthma symptoms in
atopic individuals. A systematic review and
meta-analysis of asthma and intestinal parasite
infection found that current infection with Ascaris
lumbricoides was associated with a significant
increase in the risk of asthma. Results of studies
are conflicting and any relation between
intestinal parasite infection and asthma risk is
likely to be species specific. Parasite infections
do not in general protect against asthma63
.
Other Factors That May Exacerbate
Asthma
Obesity. Increases in body mass index (BMI)
have been associated with increased prevalence
of asthma, although the mechanisms behind this
association are unclear64
. Weight reduction in
obese patients with asthma has been
demonstrated to improve lung function,
symptoms, morbidity, and health status65
(Evidence B).
Exercise. Asthmatics should not avoid
exercising. A lack of exercise, results in less
time being devoted to mechanical stretching of
the airways and to promotion of good airway
muscle tone through enhancement of an
efficient smooth-muscle contractile process.
Emotional Stress. Emotional stress may lead to
asthma exacerbations, primarily because
extreme emotional expressions (laughing,
crying, anger, or fear) can lead to
hyperventilation and hypocapnia, which can
cause airway narrowing66,67
. Panic attacks,
which are rare but not exceptional in some
patients with asthma, have a similar effect68,69
.
However, it is important to note that asthma is
not primarily a psychosomatic disorder.
Gastroesophageal reflux can exacerbate
asthma, especially in children, and asthma
sometimes improves when the reflux is
corrected.70,71
Menstruation and Pregnancy. Many women
complain that their asthma is worse at the time
of menstruation, and premenstrual
exacerbations have been documented72
.
Similarly, asthma may improve, worsen, or
remain unchanged during pregnancy73
.
RECOMMENDATION:
Something related to diesel exhaust
and LPG use
Biomass fuel in rural areas
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37. Hiirsch T, Hering M, Burkner K, Hirsch D,
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38. Cahudhuri R, Livingston E, McMahon AD,
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2003;168(11):1308-11.
39. Chalmers GW, Macleod KJ, Little SA,
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Influence of cigarette smoking on inhaled
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Morell F, Roca J, et al. Long term outcome
of soybean epidemic asthma after an
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42. Chen LL, Tager IB, Peden DB, Christian DL,
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43. Marks GB, Colquhoun JR, Girgis ST, Koski
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PS, Boyle C. Evidence based guidelines for
the prevention, identification, and
management of occupational asthma. Occup
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Mini-Primer):S470-5.
52. Roberts G, Patel N, Levi-Schaffer F, Habibi
P, Lack G. Food allergy as a risk factor for
life-threatening asthma in childhood: a case-
controlled study. J Allergy Clin Immunol
2003;112(1):168-74.
53. Taylor SL, Bush RK, Selner JC, Nordlee JA,
Weiner MB, Holden K, et al. Sensitivity to
sulfited foods among sulfite-sensitive
subjects with asthma. J Allergy Clin Immunol
1988;81(6):1159-67.
54. Szczeklik A, Nizankowska E, Bochenek G,
Nagraba K, Mejza F, Swiercrzynska M.
Safety of a specific COX-2 inhibitor in
aspirin-induced asthma. Clin Exp Allergy
2001;31(2):219-25.
55. Jenkins C, Costelo J, Hodge L. Systematic
review of prevalence of aspirin induced
asthma and its implications for clinical
practice. BMJ 2004;328:434-41
56. Covar RA, Macomber BA, Szefler SJ.
Medications as asthma triggers. Immunol
Allergy Clin North Am 2005;25(1):169-90.
57. Nicholson KG, Nguyen-Van-Tam JS, Ahmed
AH, Wiselka MJ, Leese J, Ayres J, et al.
Randomised placebo-controlled crossover
trial on effect of inactivated influenza vaccine
on pulmonary function in asthma. Lancet
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58. Beuving HJ, Bernsen RM, de Jongste JC,
van Suijlekorn-Smit LW, Rimmelzwaan GF,
Osterhaus AD, et al. Influenza vaccination in
children with asthma: randomized double-
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59. Cates CJ, Jefferson TO, Bara AI, Rowe BH.
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60. The safety of inactivated influenza vaccine in
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61. Tarlo S, Broder I, Corey P, Chan-Yeung M,
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Manfreda J. The role of symptomatic colds in
asthma exacerbations: influence of outdoor
allergens and air pollutants. J Allergy Clin
Immunol 2001;108:52-8.
62. Chauhan AJ, Inskip HM, Linaker CH, Smith
S, Schreiber J, Johnston SL, Holgate ST.
Personal exposure to nitrogen dioxide (NO2)
and the severity of virus-induced asthma in
children. Lancet. 2003;361:1939-44.
63. Jo Leonardi- Bee, David Pritchard, John
Britton, and the Parasites in Asthma
Collaboration. Asthma and current Intestinal
Parasite Infection. Systematic review and
meta- Analysis. Am J Respir Crit Care Med
2006;174: 514-23.
64. Tantisira KJ, Litonjua AA, Weiss ST,
Fuhlbrigge AL. association of body mass
with pulmonary function in the Childhood
Asthma Management Program (CAMP).
Thorax 2003;58(12):1036-41.
65. Stenius-Aarniala B, Poussa T, Kvamstrom J,
Gronlund EL, Ylikahri M, Mustajoki P.
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reduction in obese people with asthma:
randomized controlled study. BMJ
2000;320(7238):827-32.
66. Rietveld S, van Beest I, Everaerd W. Stress-
induced breathlessness in asthma. Psychol
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role of acute and chronic stress in asthma
attacks in children. Lancet
2000;356(9234):982-7.
68. Lehrer PM, Isenberg S, Hochron SM.
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1993;30(1):5-21.
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LP. Psychological factors associated with
emergency room visits among asthmatic
patients. Behav Modif 1999;23(2):217-33.
70. Harding SM, Guzzo MR, Richter JE. The
prevalence of gastroesophageal reflux in
asthma patients without reflux symptoms.
64
Am J Respir Crit Care Med 2000;162(1):34-
9.
71. Patterson PE, Harding SM.
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asthma. Curr Opin Pulm Med 1999;5(1):63-
7.
72. Chien S, Mintz S. Pregnancy and menses.
In: Weiss EB, Stein M, eds. Bronchial
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Boston: Little Brown; 1993:1085-98.
73. Barron WM, Leff AR. Asthma in Pregnancy.
Am Rev Respir Dis 1993;147(3):510-1.
Chapter 6
Assess, Treat
and Monitor
Asthma
66
KEY POINTS:
The goal of asthma treatment, to achieve
and maintain clinical control, can be reached
in a majority of patients with a
pharmacologic intervention strategy
developed in partnership between the
patient/family and the doctor.
The GINA ‚5-step‛ treatment strategy to
assessing, treating to achieve and
monitoring to maintain control should be
adopted.
The PCRDMA 2004 recommends the use of
the severity classification of asthma at the
initial medical consultation and for patients
who are not on any controller medication
(‛controller-naïve‛ patients) or are non-
adherent to previously prescribed controller
medications. Subsequently, patients should
be assessed according to their level of
control.
For patients already on controller
medications, treatment adjustment should
also follow the level of control.
Treatment should be adjusted in a
continuous cycle. If asthma is not controlled
on the current regimen, drug therapy should
be stepped up until control is achieved.
When control is maintained for at least three
months, treatment can be stepped down. At
each step, reliever medication should be
provided for quick relief of symptoms as
needed.
Ongoing monitoring is essential to maintain
control and to establish the lowest step and
dose of treatment to minimize cost and
maximize safety.
Inhaled steroids are the recommended first
line controllers. In the Philippines, low-
doses of a fixed-dose combination steroid-
LABA inhaler may be started as initial
treatment for symptomatic patients.
INTRODUCTION
International guidelines agree that the goal of
asthma treatment is to achieve and maintain
clinical control. The US National Heart, Lung,
and Blood institute’s 2007 National Asthma
Education Program Expert Panel Report 3
further expands the therapeutic targets to aim at
reducing impairment and reducing risk of
recurrent exacerbations, loss of lung function
and drug-related adverse events.1
GINA 2008
states that this goal can be achieved with a
pharmacologic intervention strategy developed
in partnership between the patient/family and the
doctor.
Aiming at achieving this goal cannot be
overemphasized in the local population. A local
survey, the National Asthma Epidemiology study
(NAES), showed that while a majority of self-
reported Filipino asthmatics living in urban areas
had consulted a physician for the disorder, only
about 10% of adult respondents had an action
plan and about half of the patients still used
maintenance oral bronchodilators. Seventy-five
percent (75%) admitted to discontinuing their
asthma medications when their symptoms had
resolved for a week.2
A different survey, the
Asthma Insights and Reality in Asia-Pacific
study, reported that only less than 10% of
Filipino asthmatics admitted to current use of
inhaled steroids, even if about 40% had
persistent symptoms.3
Out-of-pocket settlement is by far the prevalent
mode of health care payment in the country, with
patients directly paying for their medical
consultations, hospitalization and medications.
As the above studies have shown, the majority
of asthmatics consult only when symptoms
become bothersome. Local practice also reveals
that there is demand for rapid improvement for
every peso paid. When this is not achieved,
patients will usually seek consultation with a
different doctor who can prescribe quick-relief
medications. Thus, adherence to drug therapies
that take time to manifest symptomatic
improvement is low. Indeed, the NAES survey2
reported that the use of inhaled steroids alone
as controllers among definite asthmatics is
rather unpopular (1%), probably because days
to weeks are needed for asthma control to be
felt.
67
In the development of the current consensus
guidelines, the expert panel thoughtfully
considered the aforementioned insights and
‘realities’ of the Filipino patients’ attitude and
practices when dealing with their asthma. The
panel is thus recommending the adaptation of a
more aggressive approach in initiating chronic
maintenance therapy, addressing the patients’
need for early perception of relief, hopefully as a
means of enhancing long term compliance. (See
Figure 6.1.)
The GINA ‚5-treatment steps‛ cyclic strategy to
assessing, treating to achieve and monitoring to
maintain control should still be adopted, but with
local modifications. (See Table 2.2 and Figure
6.2.) At each consultation, a patient is assigned
an appropriate step, depending on his current
level of control. Treatment is then modified
continuously as the asthma control status
changes.
ASSESSING ASTHMA CONTROL
The PCRDMA 2004 severity classification of
asthma (Table 2.1) is recommended at the initial
medical consultation and for patients who are
not on any controller medication (‛controller-
naïve‛ patients) or are non-adherent to
previously prescribed maintenance medications.
Subsequently, all patients should be assessed
according to their level of asthma control (i.e.,
whether their asthma is controlled, partly
controlled or uncontrolled). This involves a
detailed accounting of their current treatment
regimen and adherence to it and appraisal of
daytime and nighttime symptoms, limitation of
activities due to asthma, the need for rescue
medication use and level of lung function. (See
Table 2.2.) Any adverse event related to drugs
taken must also be elicited.
Uncontrolled asthma may lead to an
exacerbation. Its recognition and prompt
treatment is mandatory, in order to regain
asthma control. Management recommendation
for exacerbations can be found in Chapter 7.
TREATING TO ACHIEVE CONTROL
The GINA long-term management approach
based on asthma control, as shown in Figure
6.2, is recommended for local adaptation. The
treatment action plan that will be prescribed
during each consultation will be determined by a
patient’s assessed current level of control and
his or her current medications.
If asthma is not controlled on the current
treatment regimen, drug therapy should be
stepped up until control is achieved. If control
has been maintained for at least three months,
treatment can be stepped down with the aim of
establishing the lowest step and dose of
treatment that maintains control (see Monitoring
to Maintain Control below).
If asthma is partly controlled, an increase in
treatment should be considered, subject to
whether more effective options are available
(e.g., increased dose or an additional treatment),
safety and cost of possible treatment options,
and the patient’s satisfaction with the level of
control achieved.
The Five-Step Treatment Strategy for
Achieving Control
Most of the medications available for asthma
patients, when compared with medications used
for other chronic diseases, have extremely
favorable therapeutic ratios. Each step
represents treatment options that, although not
of identical efficacy, are alternatives for
controlling asthma.
Steps 1 to 5 provide options of increasing
efficacy, except for Step 5 where issues of
availability and safety influence the selection of
treatment.
At each treatment step, a reliever medication
(rapid-onset bronchodilator, either short-
acting or long-acting) should be provided for
quick relief of symptoms. However, the regular
use of reliever medication is one of the elements
defining uncontrolled asthma and is an indicator
of the need to increase controller treatment.
Thus, reducing or eliminating the need for
reliever treatment is both an important goal and
a measure of the success of therapy.
68
In addition to stepping up of treatment with
maintenance controller medications, a trial of a
5-to-10 day course of an oral steroid given at 0.5
” 1 mg/kg/day may be considered in very
symptomatic patients, to prevent worsening and
to achieve more rapid resolution of the
uncontrolled asthma.
Symptomatic patients who are controller-naive
or were non-adherent to previously prescribed
therapy and have mild-to-moderate persistent
asthma can start their treatment at Step 3.
Once control is achieved, treatment can be
brought down to step 2.
Step 1: As-needed reliever medication.
Step 1 treatment with an as-needed reliever
medication is reserved for patients who are
assessed to have asthma of intermittent severity
or untreated patients with occasional daytime
symptoms (cough, wheeze, dyspnea occurring
twice or less per week) of short duration.
Between episodes, the patient is asymptomatic
with normal lung function and has no nocturnal
awakening.
For the majority of patients in Step 1, a rapid-
acting inhaled ß2-agonist is the recommended
reliever treatment (Evidence A). An inhaled
anticholinergic, short-acting oral 2-agonist, or
short-acting theophylline may be considered as
alternatives, although they have a slower onset
of action and higher risk of side effects
(Evidence A).
When symptoms are more frequent, and/or
worsen periodically, patients should be
prescribed regular controller treatment (see
Steps 2 or higher) in addition to as-needed
reliever medication (Evidence B).
Exercise-induced bronchoconstriction. Physical
activity is an important cause of asthma
symptoms for most asthma patients, and for
some it is the only cause. However, exercise-
induced bronchoconstriction often indicates that
the patient's asthma is not well controlled, and
stepping up controller therapy generally results
in the reduction of exercise-related symptoms.
For those patients who still experience exercise-
induced bronchoconstriction despite otherwise
well-controlled asthma, and for those in whom
exercise-induced bronchoconstriction is the only
manifestation of asthma, a rapid-acting inhaled
ß2-agonist (short- or long-acting), taken prior to
exercise or to relieve symptoms that develop
after exercise, is recommended. A leukotriene
modifier is an alternative (Evidence A). Training
and sufficient warm-up also reduce the
incidence and severity of exercise-induced
bronchoconstriction (Evidence B).
Step 2: Single controller plus a reliever
medication.
All patients with persistent asthma should be
assessed within treatment steps 2 through 5.
These patients must receive at least one regular
controller and an as-needed reliever medication
to achieve and maintain control.
At Step 2, a low-dose inhaled
glucocorticosteroid is recommended as the
initial controller treatment for asthma patients of
all ages (Evidence A).
However, in the local setting, for the majority of
symptomatic patients, the consensus is to start
at step 3, with low doses of a fixed-dose steroid-
LABA combination inhaler. This will ensure not
only rapid relief of symptoms but also control of
the underlying inflammation. This may also
promote adherence to maintenance therapy
(Evidence D).
Alternative controller medications include
leukotriene modifiers (Evidence A),
appropriate particularly for patients who are
unable or unwilling to use inhaled
glucocorticosteroids, or who experience
intolerable side effects such as persistent
hoarseness from inhaled glucocorticosteroid
treatment and those with concomitant allergic
rhinitis (Evidence C).
In the local setting where cost and availability
are main considerations, cheaper oral controller
medications may also be alternative options,
such as sustained-release theophylline, which at
low daily doses (to achieve a plasma
concentration of ~5mg/ml) has been found to
exert anti-inflammatory action with fewer side
effects compared to higher doses.4
69
Maintenance low dose oral steroids have been
used in developing countries as replacement for
inhaled steroids or in addition to low dose
inhaled steroid to control asthma and limit costs.
Few studies have looked at the efficacy and
safety of such strategies. A meta-analysis by
Mash et. al. compared inhaled versus low dose
oral steroids in asthmatics over the age of 15
years and found that such trials were small and
no data could be pooled.5
Nevertheless, the
authors concluded that in developing countries
where inhaled steroids are not widely available
and there is no alternative to oral steroids, the
lowest effective dose (prednisolone 7.5-12
mg/day, which appears to be as effective as
300-2000 g/day ICS), may be prescribed.
However, physicians and patients should be
aware that side effects may be present over
time, even at a daily low dose of 5 mg/day.
The use of inhaled long acting 2-agonists as the
single first-line controller in asthma is strongly
discouraged. Studies and meta-analyses have
reported increased risk for asthma-related
complications with the use of LABAs, prompting
a US FDA review.6-12
All current guidelines
recommend that inhaled LABAs should only be
used in combination with inhaled steroids. 13
Step 3: Two controllers plus a reliever
medication.
At Step 3, the recommended option for
adolescents and adults is to use a low-dose
inhaled steroid with an inhaled long-acting
2-agonist, either in a combination inhaler
device or as separate components (Evidence
A). Because of the additive effect of this
combination, the low-dose steroid is usually
sufficient, and need only be increased if control
is not achieved with this regimen (Evidence A).
Low doses of fixed-dose steroid-LABA
combination inhalers are recommended as first-
line controller in symptomatic patients with
persistent asthma. As noted previously, this
approach may encourage the increased use of
inhaled steroids in the country (Evidence D). A
study which sought to compare the adherence
and effectiveness of LABAs and ICS
administered either concurrently or in
combination demonstrated that those patients
using the medications in combination were 17%
less likely to stop their medication and were also
17% less likely to have a moderate-to-severe
asthma exacerbation than the latter. The authors
concluded that combination therapy might be
preferable for patients with low adherence to
controller therapy.14
If a combination inhaler containing formoterol
and budesonide is selected, it may be used for
both rescue and maintenance. This approach
has been shown to result in reductions in
exacerbations and improvements in asthma
control in adults and adolescents at relatively
low doses of treatment (Evidence A). Whether
this approach can be employed with other
combinations of controller and reliever requires
further study.
For patients on medium- or high-dose of inhaled
glucocorticosteroid delivered by a pressurized
metered-dose inhaler, use of a spacer device is
recommended to improve delivery to the
airways, reduce oropharyngeal side effects, and
reduce systemic absorption (Evidence A).
Another option at Step 3 is to combine a low-
dose ICS with leukotriene modifiers (Evidence
A) or low-dose sustained-release theophylline
(Evidence B).
Step 4: More than two controllers plus
reliever medication.
The selection of treatment at Step 4 depends on
prior selections at Steps 2 and 3. However, the
order in which additional medications should be
added is based, as far as possible, upon
evidence of their relative efficacy in clinical trials.
Where possible, patients who are not controlled
on Step 3 treatments should be referred to a
pulmonary specialist with expertise in the
management of asthma for investigation of
alternative diagnoses and/or causes of difficult-
to-treat asthma.
The preferred treatment at Step 4 is to combine
a medium- or high-dose ICS with LABA.
However, in most patients, the increase from a
medium- to a high-dose of ICS provides
relatively little additional benefit (Evidence A).
The high dose is recommended only on a trial
70
basis for 3 to 6 months when control cannot be
achieved with medium dose ICS”LABA and/or
a third controller (e.g., leukotriene modifiers or
sustained-release theophylline) (Evidence B).
Prolonged use of high-dose ICS is also
associated with increased potential for adverse
effects. At medium- and high-doses, twice-daily
dosing is necessary for most but not all inhaled
glucocorticosteroids (Evidence A). With
budesonide, efficacy may be improved with
more frequent dosing (four times daily)
(Evidence B).
Leukotriene modifiers as add-on treatment to
medium-to high-dose ICS have been shown to
provide benefit (Evidence A), but usually less
than that achieved with the addition of a LABA
(Evidence A). The addition of a low-dose of
sustained release Theophylline to medium- or
high-dose ICS-LABA may also provide benefit
(Evidence B).
Step 5: Reliever medication plus
additional controller options.
The addition of oral glucocorticosteroids to
other controller medications may be effective
(Evidence D) but is associated with severe side
effects (Evidence A) and should only be
considered if the patient’s asthma remains
severely uncontrolled on Step 4 medications
with daily limitation of activities and frequent
exacerbations. Patients should be counseled
about potential side effects and all other
alternative treatments must be considered.
The addition of anti-IgE treatment to other
controller medications has been shown to be
effective in allergic asthma, when control has not
been achieved on combinations of other drugs
including high-doses of inhaled or oral
glucocorticosteroids (Evidence A). Its major
drawback is its cost.
MONITORING TO MAINTAIN
CONTROL
When asthma control has been achieved,
ongoing monitoring is essential to maintain
control and to establish the lowest step and
dose of treatment necessary, which minimizes
the cost and maximizes the safety of treatment.
On the other hand, asthma is a variable disease,
and treatment has to be adjusted periodically in
response to loss of control as indicated by
worsening symptoms or the development of an
exacerbation. Asthma control should be
monitored by the health care professional and
preferably also by the patient at regular
intervals, using either a simplified scheme as
presented in Table 2.2 or a validated composite
measure of control.
The frequency of health care visits and
assessments depends upon the patient’s initial
clinical severity, and the patient’s training and
confidence in playing a role in the ongoing
control of his or her asthma. Typically, patients
are seen one to three months after the initial
visit, and every three months thereafter. After an
exacerbation, follow-up should be offered within
two weeks to one month (Evidence D).
Duration and Adjustments to Treatment
For most classes of controller medications,
improvement begins within days of initiating
treatment, but the full benefit may only be
evident after 3 or 4 months. In severe and
chronically undertreated disease, this can take
even longer. The reduced need for medication
once control is achieved is not fully understood,
but may reflect the reversal of some of the
consequences of long-term inflammation of the
airways. Higher doses of anti-inflammatory
medication may be required to achieve this
benefit than to maintain it.
Alternatively, the reduced need for medication
might simply represent spontaneous
improvement as part of the cyclical natural
history of asthma. Rarely, asthma may go into
remission particularly in children aged 5 years
and younger and during puberty. Whatever the
explanation, in all patients the minimum
controlling dose of treatment must be sought
through a process of regular follow-up and
staged dose reductions.
71
Stepping Down Treatment When Asthma
Is Controlled
There is little experimental data on the optimal
timing, sequence, and magnitude of treatment
reductions in asthma, and the approach will
differ from patient to patient depending on the
combination of medications and the doses that
were needed to achieve control. These changes
should ideally be made by agreement between
patient and health care professional, with full
discussion of potential consequences including
reappearance of symptoms and increased risk
of exacerbations.
Although further research on stepping down
asthma treatment is needed, some
recommendations can be made based on the
current evidence:
“ When inhaled glucocorticosteroids alone in
medium to high-doses are being used, a 50%
reduction in dose should be attempted at 3-
month intervals (Evidence B).
“ Where control is achieved at a low-dose of
inhaled glucocorticosteroids alone, in most
patients’ treatment may be switched to once-
daily dosing (Evidence A).
“ When asthma is controlled with a combination
of inhaled glucocorticosteroid and long-
acting 2-agonist, the preferred approach is to
begin by reducing the dose of inhaled steroid by
approximately 50% while continuing the inhaled
LABA (Evidence B).
If control is maintained, further reductions in the
inhaled steroid should be attempted until a low-
dose is reached, at which time, the LABA may
be stopped (Evidence D).
An alternative is to switch the combination
treatment to once-daily dosing. A second
alternative is to discontinue the long-acting 2-
agonist at an earlier stage and substitute the
combination treatment with inhaled
glucocorticosteroid monotherapy at the same
dose contained in the combination inhaler.
However, for some patients these alternative
approaches lead to loss of asthma control
(Evidence B).
“ When asthma is controlled with inhaled
glucocorticosteroids in combination with
controllers other than long-acting 2-
agonists, the dose of inhaled steroid should be
reduced by 50% until a low-dose is reached,
then the combination treatment can be stopped,
as described above (Evidence D).
Controller treatment may be stopped if the
patient’s asthma remains controlled on the
lowest dose of controller and no recurrence of
symptoms occurs for one year (Evidence D).
Stepping Up Treatment in Response to
Loss of Control
Treatment has to be adjusted periodically in
response to worsening control, which may be
recognized by the minor recurrence or
worsening of symptoms.
Treatment options are as follows:
“ Rapid-onset, short-acting or long-acting 2-
agonist bronchodilators. Repeated dosing
with bronchodilators in this class provides
temporary relief until the cause of the worsening
symptoms passes. The need for repeated doses
over more than one or two days signals the
need for review and possible increase of
controller therapy.
“ Inhaled glucocorticosteroids. Temporarily
doubling the dose of inhaled
glucocorticosteroids has not been demonstrated
to be effective, and is no longer recommended
(Evidence A).
A four-fold or greater increase has been
demonstrated to be equivalent to a short course
of oral glucocorticosteroids in adult patients with
an acute deterioration (Evidence A).
The higher dose should be maintained for seven
to fourteen days but more research is needed in
both adults and children to standardize the
approach.
Combination of inhaled glucocorticosteroids
and rapid and long-acting 2-agonist
bronchodilator (e.g. formoterol) for
combined relief and control.
72
Figure 6.1 Algorithmic Approach to Asthma Assessment and Management
The use of the combination of a rapid and long-
acting 2-agonist (formoterol) and an inhaled
glucocorticosteroid (budesonide) in a single
inhaler both as a controller and reliever is
effective in maintaining a high level of asthma
control and reduces exacerbations requiring
systemic glucocorticosteroids and hospitalization
(Evidence A). The benefit in preventing
exacerbations appears to be the consequence
of early intervention at a very early stage of a
threatened exacerbation since studies involving
doubling or quadrupling doses of combination
treatment once deterioration is established (for 2
or more days) show some benefit but results are
inconsistent. Because there are no studies using
this approach with other combinations of
controller and relievers, other than
budesonide/formoterol, the alternative
approaches described in this section should be
used for patients on other controller therapies.
The usual treatment for an acute exacerbation is
a high-dose of 2-agonist and a burst of
systemic glucocorticosteroids administered
orally or intravenously. (Refer to Chapter 7 for
more information.)
Following treatment for an exacerbation of
asthma, maintenance treatment can generally
be resumed at previous levels unless the
exacerbation was associated with a gradual loss
of control suggesting chronic undertreatment. In
this case, provided inhaler technique has been
checked, a step-wise increase in treatment
(either in dose or number of controllers) is
indicated.
Difficult-to-Treat Asthma
Although the majority of asthma patients can
obtain the targeted level of control, some
patients will not do so even with the best
therapy. Patients who do not reach an
acceptable level of control at Step 4 can be
73
Figure 6.2. Management Approach Based on Level of Control, adapted from GINA 2008
Alternative reliever treatments include inhaled anticholinergics, short-acting oral β2-agonists, some long-acting β
2-agonists, and short-
acting theophylline.
Regular dosing with short and long-acting β2-agonist is not advised unless accompanied by regular use of an inhaled glucocorticosteroid.
considered to have difficult-to-treat asthma.
These patients may have an element of poor
glucocorticosteroid responsiveness, and require
higher doses of inhaled glucocorticosteroids
than are routinely used in patients whose
asthma is easy to control. However, there is
currently no evidence to support continuing
these high doses of inhaled glucocorticosteroids
beyond 6 months in the hope of achieving better
control. Instead, dose optimization should be
pursued by stepping down to a dose that
maintains the maximal level of control achieved
on the higher dose. Because very few patients
are completely resistant to glucocorticosteroids,
these medications remain a mainstay of therapy
for difficult-to-treat asthma, while additional
diagnostic and generalized therapeutic options
can and should also be considered:
Confirm the diagnosis of asthma. In
particular, the presence of COPD must be
excluded. Vocal cord dysfunction must be
considered.
Investigate and confirm compliance with
treatment. Incorrect or inadequate use of
medications remains the most common
reason for failure to achieve control.
74
Consider smoking, current or past, and
encourage complete cessation. A history of
past tobacco smoking is associated with a
reduced likelihood of complete asthma
control, and this is only partly attributable to
the presence of fixed airflow obstruction. In
addition, current smoking reduces the
effectiveness of inhaled and oral
glucocorticosteroids. Counseling and
smoking cessation programs should be
offered to all asthma patients who smoke.
Investigate the presence of co-morbidities
that may aggravate asthma. Chronic
sinusitis, gastroesophageal reflux, and
obesity/obstructive sleep apnea have been
reported in higher percentages in patients
with difficult-to-treat asthma. Psychological
and psychiatric disorders should also be
considered. If found, these comorbidities
should be addressed and treated as
appropriate; nevertheless, the ability to
improve asthma control by doing so remains
unconfirmed. When these reasons for lack
of treatment response have been
considered and addressed, a compromise
level of control may need to be accepted
and discussed with the patient to avoid futile
over-treatment (with its attendant cost and
potential for adverse effects). The objective
is then to minimize exacerbations and need
for emergency medical interventions while
achieving as high a level of clinical control
with as little disruption of activities and as
few daily symptoms as possible. For these
difficult-to-treat patients, frequent use of
rescue medication is accepted, as is a
degree of chronic lung function impairment.
Although lower levels of control are generally
associated with an increased risk of
exacerbations, not all patients with chronically
impaired lung function, reduced activity levels,
and daily symptoms have frequent
exacerbations. In such patients, the lowest level
of treatment that retains the benefits achieved at
the higher doses of treatment should be
employed. Reductions should be made
cautiously and slowly at intervals not more
frequent than 3 to 6 months, as carryover of the
effects of the higher dose may last for several
months and make itdifficult to assess the impact
of the dose reduction (Evidence D). Referral to
a physician with an interest in and/or special
focus on asthma may be helpful and patients
may benefit from phenotyping into categories
such as allergic, aspirin sensitive, and/or
eosinophilic asthma. Patients categorized as
allergic might benefit from anti-IgE therapy, and
leukotriene modifiers can be helpful for patients
determined to be aspirin sensitive (who are often
eosinophilic as well).
References
1. http://www.nhlbi.nih.gov/guidelines/asthma/a
sthgdln.htm
2. Roa CC, David-Wang AS, Diaz DV, et al.
National Asthma Epidemiology Study.
Prevalence survey of asthma in Filipino
adults living in urban communities (Metro
Manila, Cebu, Davao). Report submitted to
the Department of Health and World Health
Organization , January 2004.
3. Lai CK, de Guia TS, Kim YY et al. Asthma
control in the Asia-Pacific region: the Asthma
Insights and Reality in Asia-Pacific Study. J
Allergy Clin Immunol 2003;11(2)263-8.
4. Barnes PJ. Theophylline: New perspectives
for an old drug. Am J Respir Crit Care Med
2003;167:813-8.
5. Mash BRK, Bheekie A, Jones P. Inhaled
versus oral steroids for adults with chronic
asthma. Cochrane Database Syst Rev
2001;1:CD002160.
6. Anderson HR, Ayres JG, Sturdy PM, et al.
Bronchodilator treatment and deaths from
asthma: case-control study. BMJ
2005;330:117-23.
7. Nelson HS, Weiss ST, Bleecker ER et al.
The Salmeterol Multicenter Asthma
Research Trial: a comparison of usual
pharmacotherapy for asthma or usual
pharmacotherapy plus salmeterol. Chest
2006;129:15-26.
8. Ni Chroinin M, Greenstone IR, Danish A, et
al. Long acting 2-agonists versus placebo in
addition to inhaled corticosteroids in children
75
and adults with chronic asthma. Cochrane
Database Syst Rev 2005;4:CD005535.
9. Salpeter SR, Buckley NS, Ornistorn TM,
Salpeter EE. Meta-analysis: effect of long-
acting -agonists on severe asthma
exacerbations and asthma-related deaths.
Ann Intern Med 2006;144:904-12.
10. Sears MR, Ottosson A, Radner F, Suissa S.
Long-acting b-agonists: a review of
formoterol safety data from asthma clinical
trials. Eur Respir J 2009;33:21-32.
11. Wijesinghe M, Perrin K, Harwood M, et. al.
The risk of asthma mortality with long-acting
inhaled beta-agonists. Postgrad Med J
2008;84:467-72.
12. USFDA.
http://www.medpagetoday.com/Pulmonary/A
sthma/12117
13. Beasley R, Martinez FD, Hackshaw A, et al.
Safety of long-acting b-agonists: urgent need
to clear the air remains. Eur Respir J
2008;33:3-5.
14. Marceau C, Lemiere C, Berbiche D, et al.
Persistence, adherence, and effectiveness of
combination therapy among adult patients
with asthma. J Allergy Clin Immunol
2006;118:574-81.
76
Chapter 7
Acute
Exacerbations
78
KEY POINTS:
Asthma exacerbations (“asthma
attacks”) are acute or subacute
episodes of progressive worsening of
shortness of breath, cough, wheezing or
chest tightness or some combination of
these symptoms.1
Severity of exacerbations should be
evaluated using clinical as well as
objective measurements of lung function
(PEF or FEV1).
1
The primary therapies for exacerbations
include repetitive administration of
inhaled 2-agonists, early introduction of
systemic steroids, and oxygen
supplementation.1
Aims of treatment are to restore lung
function to normal, relieve airway
obstruction and hypoxemia as soon as
possible and prevent future relapses.1
Severe exacerbations are potentially life
threatening and their treatment requires
close supervision. Most patients with
severe asthma exacerbations should be
treated in an acute care facility setting
(clinic or hospital emergency room).
Patients at high risk of asthma-related
death also require closer attention.1
Patients with milder exacerbations
characterized by a reduction in peak
flow of less than 20% nocturnal
awakening, and increasing use of
reliever medications can be managed at
home or in a community setting. 1
Early treatment of asthma exacerbations
is the best strategy for management.
Important elements of early treatment at
the patient’s home include (EPR-2
199726
):
o Patient education, including a
written asthma action plan to
guide patient self-management
of exacerbations at home,
especially for patients who have
moderate or severe persistent
asthma and any patient who
has a history of severe
exacerbations (Evidence B). A
peak flow-based plan may be
particularly useful for patients
who have difficulty perceiving
airflow obstruction and
worsening asthma (Evidence
D).
o Recognition of early signs of
worsening asthma and taking
prompt action (Evidence A).
o Removal or withdrawal of the
environmental factor
contributing to the exacerbation.
INTRODUCTION
Exacerbations of asthma (“asthma attacks”) are
episodes of progressive worsening of shortness
of breath, cough, wheezing, or chest tightness
or some combination of these symptoms.
Respiratory distress is common. Exacerbations
are characterized by significant decreases in
PEF or FEV1 which are more reliable indicators
of severity of airflow obstruction than degree of
symptoms.1, 3
Severity of exacerbations may range from mild
to life-threatening deterioration usually
progresses over hours or days, but may
occasionally happen precipitously over some
minutes. Morbidity and mortality are most often
associated with underassessment of
exacerbation’s severity, inadequate action at
the onset of exacerbation and under-treatment
of the exacerbation.
Treatment of exacerbations depends on the
patient and the physician’s experience with what
79
therapies are most effective for the particular
patient. The primary therapy in the ideal
situation includes the repetitive administration of
inhaledβ2-agonist and an early introduction of
systemic steroids and oxygen
supplementation.1,3
The aims of treatment are to126
:
Relieve airway obstruction as quickly as
possible
Relieve hypoxemia
Restore lung function to normal as early
as possible
Plan and avoidance of future relapses
Develop a written action plan in cases of
future exacerbations.
Patients at high risk of asthma-related deaths
require intensive patient education, close
monitoring and prompt care. These include
patients with a history of any of the following1,126
:
Current use of or recent withdrawal from
systemic corticosteroids
Emergency care visit for asthma in the
past year
History of near-fatal asthma requiring
intubation or mechanical intubation4
Not currently using inhaled
glucocorticoids5
Overdependence on rapid acting
inhaled b2 agonists, especially those
with more than one canister monthly6
Psychiatric disease or psychosocial
problems, including the use of sedatives
Noncompliance with asthma medication
plan
Full recovery from asthma exacerbations is
usually gradual. It may take many days for lung
function to return to normal and weeks for
airway hyperresponsiveness to decrease. In
addition to symptoms and physical signs which
are not accurate indicators of airflow obstruction,
PEF monitoring should be performed. Likewise,
response to treatment should be assessed
clinically as well as objectively by lung function
(PEF or FEV1). Treatment should continue until
measurements of lung function return to normal
or to the patient’s previous personal best.
Decision to admit or discharge can be
recommended based on these lung function
values.1
ASSESSMENT OF SEVERITY
The severity of exacerbation determines the
treatment required. Tables 7.1 and 7.21,2
provide
a guide to the severity of an exacerbation of
asthma at the time the examination is made.
The presence of several parameters, but not
necessarily all, indicates the general
classification of the exacerbation. A more
severe grading should be given if the patient has
no or minimal response to initial treatment, if the
attack progressed quickly, or if the patient is at
high risk from asthma-related death historically.
Indices of severity, particularly PEFR, pulse rate,
and respiratory rate, and pulse oximetry should
be monitored during treatment. Any deterioration
requires prompt intervention.1
*Serial measurements of lung function.
FEV1 or PEF appears to be more useful in
adults for categorizing the severity of the
exacerbation and the response to treatment and
in predicting the need for hospitalization.
Repeated FEV1 or PEF measures to the
Emergency room (ER) and 1 hour after
treatment were the strongest single predictor of
hospitalization among adults who present to the
ER with an asthma exacerbation (Karass et al
2000; Kelly et al 2004; McCarren et al 2000;
Rodrigo et al 2004 Weber et al 2002).7,8,9,10,11
Pulse oximetry is indicated for patients who are
in severe distress, have FEV1 or PEF <40% of
predicted, or are unable to perform lung function
measures.2
*Signs and symptoms scores
Some multifaceted prediction models have been
tested and shown to improve slightly on the
accuracy of the FEV1 or PEF alone
10,12,13,14
.
Kelly and colleagues 7
used multiple signs and
symptoms to determine the level of the severity
of the exacerbation at 1 hour after the first ER
Table 7-1. Classifying Severity of Asthma Exacerbations in the urgent or Emergency Care Setting
80
treatment as well as the duration of symptoms
(either <6 hours or ≥6 hours) before the patient’s
arrival at the ER (Kelly et al. 2002b)13
and found
the additional measures improved the prediction
rate by 5–10 percent.
For EDs that have limited resources, the
presence of drowsiness in a patient is a useful
predictor of impending respiratory failure and
reason to consider immediate transfer of the
patient to a facility equipped to deal with
ventilatory support (Cham et al 2002)15
.
HOME MANAGEMENT OF ACUTE
EXACERBATION
Milder exacerbations, defined by a reduction in
peak flow of less than 20%, nocturnal
awakening, and increased use of short acting
β2-agonists can usually be treated in a
community setting.1
Beginning treatment at
home avoids treatment delays, prevents
exacerbations from becoming severe, and also
adds to patients’ sense of control over their
asthma. The degree of care provided in the
home depends on the patients’ abilities and
experience and on the availability of emergency
care. General guidelines for managing
exacerbations at home are presented in Figure
7-12
.
It is recommended2
that the preparation of
patients for home management of asthma
exacerbations should include the following:
Teach all patients how to monitor signs
and symptoms so they can recognize
early signs of deterioration and take
appropriate action (Evidence A)
particularly since many
Table 7-1. Classifying Severity of Asthma Exacerbations in the Urgent or Emergency Care Setting
81
Table 7-2. Formal Evaluation of Asthma Exacerbation Severity in the Urgent or Emergency Care
Setting
82
fatal asthma exacerbations occur out of
hospital16
. Patients should be taught how to
adjust their medications early in an
exacerbation13
and when to call for further
help or seek medical care. Patients should
seek medical help earlier if the exacerbation
is severe, treatment does not give rapid,
sustained improvement or there is further
deterioration.
Teach all patients how to monitor lung
function by using PEF to facilitate early
and accurate assessment of
exacerbations and response to treatment
(Evidence B). Signs and symptoms
imperfectly mirror airflow obstruction;
therefore, other tools may be required,
especially in the group of people who are
“poor perceivers” and have failed to
recognize previous exacerbations or
symptom deteriorations early17,18
.
Exacerbations recognized and treated within
6 hours of onset may be less likely to result
in hospitalizations13
. When using PEF
expressed only as a percent of personal
best, the impact of any irreversible airflow
obstruction must be considered. For
example, in a person whose personal best is
only 160 L/min, a drop to 60 percent of
personal best represents life-threatening
airflow obstruction.
Provide all patients with a written asthma
action plan that includes daily
management and recognizing and
handling worsening asthma, including
self-adjustment of medications in
response to acute symptoms or changes
in PEF measures in the event of an
exacerbation. A written asthma action
plan should state when to seek medical
help.
Advise patients who have moderate or
severe persistent asthma or a history of
severe exacerbations to have the
medication (e.g., corticosteroid tablets or
liquid) and equipment (e.g., peak flow
meter) for treating exacerbations at home
(Evidence A).
Recommendations for pharmacologic therapy
for home management of exacerbations:
Increase the frequency of SABA
treatment (Evidence A). For mild to
moderate exacerbations, repeated
administration of rapid-acting inhaled β2-
agonists (2 to 4 puffs every 20 minutes for
the first hour) is usually the best and most
cost-effective method of achieving rapid
reversal of airflow limitation. After the first
hour, the dose of β2-agonist required will
depend on the severity of the exacerbation.
Mild exacerbations respond to 2 to 4 puffs
every 3 to 4 hours; if there is a lack of
response, the patient should be referred to
an acute care facility. No additional
medication is necessary if the rapid-acting
inhaled β2-agonist produces a complete
response (PEF returns to greater than 80%
of predicted or personal best) and the
response lasts for 3 to 4 hours.1
Initiate oral systemic corticosteroid
treatment under certain circumstances
(Evidence A). Short courses or “bursts” of
oral corticosteroids reduce the duration and
may prevent hospitalizations and relapse
following an acute exacerbation 14, 19, 20
. Oral
glucocorticosteroids (0.5 to 1 mg of
prednisolone/kg or equivalent during a 24-
hour period) should be used to treat
exacerbations especially if they develop
after instituting the other short-term
treatment options recommended for loss of
control.
83
Figure 7.1. Management of Asthma Exacerbations: Home Treatment
Merely doubling the dose of an ICS in those
patients already receiving ICS therapy has
not been effective at reducing the severity or
preventing progression of
exacerbations21,22,23,24
(Evidence B).
Preliminary evidence indicates that
quadrupling the dose of an ICS for 7 days,
starting at the first appearance of worsening
symptoms, may prevent exacerbations
requiring oral systemic corticosteroids25
. For
patients who experience substantial adverse
effects with oral systemic corticosteroids
(e.g., mood changes, worsening diabetes),
high-dose ICS (beclomethasone >1000-
84
2000 ug/day or its equivalent)source: GINA Figure 3-1
may be an effective alternative for mild to
moderate exacerbations.
Continue more intensive treatment
for several days26
. Recovery from an
exacerbation varies, with symptom relief
in 1–2 days for moderate
exacerbations but in 3 or more days for
severe exacerbations (See figure 7–1.).
For many persons, the improvement is
quite gradual. Even when symptoms
have resolved, evidence of inflammation
in the airways may continue for up to
2–3 weeks27
. In managing an
exacerbation at home, patients’ greater
use of SABA should be continued until
symptoms and PEF are stable. Hence,
patients should seek medical care rather
than rely on bronchodilator therapy in
excessive doses or for prolonged
periods (e.g., >12 puffs/day for more
than 24 hours).
The following home management techniques
are not recommended26
:
Drinking large volumes of liquid or
breathing warm, moist air (e.g., the mist
from a hot shower)
Using over-the-counter products such
as antihistaminics or cold remedies.
Over-the-counter bronchodilators may
provide transient bronchodilation, but
their use should not delay seeking
medical care
Although pursed-lip and other forms of
controlled breathing may help to
maintain calm during respiratory
distress, these methods do not bring
about improvement in lung function.
MANAGEMENT: ACUTE CARE SETTING
Management of asthma exacerbations requiring
urgent medical care (e.g., in the urgent care
setting or emergency room (ER) includes:
Oxygen to relieve hypoxemia in
moderate or severe exacerbations26
.
SABA to relieve airflow obstruction, with
addition of inhaled ipratropium bromide in
severe exacerbations (Evidence A).
Systemic corticosteroids to decrease
airway inflammation in moderate or
severe exacerbations or for patients who
fail to respond promptly and completely
to a SABA (Evidence A).
Consideration of adjunct treatments,
such as intravenous magnesium sulfate
or heliox, in severe exacerbations
unresponsive to the initial treatments
listed above (Evidence B).
Preventing relapse of the exacerbation
or recurrence of another exacerbation by
providing: referral to follow up asthma
care within 1–4 weeks; an ER asthma
discharge plan with instructions for
medications prescribed at discharge and
for increasing medications or seeking
medical care if asthma worsens; review
of inhaler techniques whenever possible;
and consideration of initiating inhaled
corticosteroids (ICSs)
Emergency Room and Hospital
Management of Asthma Exacerbations
Severe exacerbations of asthma are potentially
life threatening. Care must be prompt. Effective
initial therapies (i.e., SABA and the means of
giving it by aerosol and a source of
supplemental oxygen) should be readily
available in a doctor’s clinic. Serious
exacerbations, however, require close
observation for deterioration, frequent treatment,
and repetitive measurement of lung function.
Therefore, most severe exacerbations of asthma
require prompt transfer to an ER for more
complete therapy 14, 20
. Despite appropriate
therapy, approximately 10–25 percent of ER
patients
85
86
Figure 7-2. Management of Acute Exacerbation: ER Department and Hospital Based Care
who have acute asthma will require
hospitalization37,
38
. In the hospital,
multidisciplinary (e.g., nursing and respiratory
care) clinical pathways for asthma appear to be
effective in reducing hospital length-of-stay and
inpatient costs, but they have less clear impact
on clinical outcomes39
. An overview of the
treatment strategies in ERs and hospitals is
presented in Figure 7–2.
87
Figure 7-3. Dosages of Drugs for Acute Exacerbation
ASSESSMENT
All clinicians treating patients who have asthma
should be prepared to treat an asthma
exacerbation, be familiar with the symptoms and
signs of severe and life-threatening
exacerbations and have procedures for
facilitating immediate patient transfer to an
emergency care facility26
.
Initial assessment should include a brief history,
brief physical examination, and, for most
patients, objective measures of lung function.
Initial laboratory studies may be helpful, but they
are not required for most patients, and they
should not delay initiation of asthma treatment26
.
88
In the ER, all patients presenting with a reported
asthma exacerbation must be evaluated and
triaged immediately, based on at least vital signs
and an overall physical assessment (e.g., ability
to breathe well enough to talk). Treatment
should begin immediately following recognition
of a moderate, severe, or life-threatening
exacerbation by assessment of symptoms,
signs, or, when possible, lung function26
.
While treatment is given, obtain a brief, focused
history and physical examination pertinent to the
exacerbation (See figure 5–2.). Take a more
detailed history and complete physical
examination and perform laboratory studies only
after initial therapy has been completed
(Evidence D).
Obtain objective lung function
measurements.
FEV1 or PEF values provide important
information about the level of airflow obstruction
both initially and in response to treatment.
Because low PEF values cannot distinguish
between poor effort, restrictive ventilatory
disorders (e.g., neuromuscular weakness,
pneumonia), and obstructive ventilatory
disorders (e.g., asthma), FEV1 measurements
are preferable if they are readily available
(Evidence D). In the initial assessment of a life-
threatening asthma exacerbation, FEV1 or PEF
are not indicated (Evidence D). Very severe
exacerbations may preclude performance of a
maximal expiratory maneuver and, in such
cases, the clinical presentation should suffice for
clinical assessment and prompt initiation of
therapy (Evidence D).
In less severe exacerbations, in the clinic or ER,
FEV1 or PEF should be obtained on arrival and
30–60 minutes after initial treatment (Evidence
B). In the hospital, FEV1 or PEF should be
measured on admission and 15–20 minutes
after bronchodilator therapy during the acute
phase and at least daily thereafter until
discharge (Evidence C).
Any FEV1 or PEF value <25 percent of predicted
that improves by <10 percent after treatment or
values that fluctuate widely are potential
indications for ICU admission and close
monitoring for respiratory failure (Evidence C).
Monitor oxygen saturation.
Pulse oximetry is indicated for any patient who is
in severe distress or has an FEV1 or PEF <40
percent of predicted to assess the adequacy of
arterial oxygen saturation
(SaO2)40,41,42,43
(Evidence C).
Serial pulse oximetry measurements can be
useful to assess both the severity of the
exacerbation and improvement with treatment
(Evidence B). By contrast, a single pulse
oximetry value on admission is of relatively little
value for predicting hospital admission 44,45,43
.
Obtain a brief history to determine26
:
1. Time of onset and any potential causes
of current exacerbations.
2. Severity of symptoms especially
compared with previous exacerbations,
and response to any treatment given
before admission to ER.
3. All current medications and time of last
dose, especially of asthma medications.
4. Estimate of number of previous
unscheduled clinic visits, ER visits, and
hospitalizations for asthma, particularly
within the past year.
5. Any prior episodes of respiratory
insufficiency due to asthma (loss of
consciousness or intubation and
mechanical ventilation).
6. Other potentially complicating illnesses,
especially other pulmonary or cardiac
disease or diseases that may be
aggravated by systemic corticosteroid
therapy (such as diabetes, peptic ulcer,
hypertension, and psychosis).
89
Perform Initial brief physical examination
to26
:
1. Assess the severity of the exacerbation,
as indicated by the findings listed in
Table 7-2.
2. Assess overall patient status, including
level of alertness, fluid status, and
presence of cyanosis, respiratory
distress, and wheezing. Wheezing can
be an unreliable indicator of
obstruction; in rare cases, extremely
severe obstruction may be
accompanied by a “silent chest”46
.
3. Identify possible complications (e.g.,
pneumonia, pneumothorax, or
pneumomediastinum); although rare,
these will influence management of the
asthma exacerbation.
4. Rule out upper airway obstruction. Both
intrathoracic and extrathoracic central
airway obstruction can cause severe
dyspnea and may be diagnosed as
asthma. Causes include upper airway
foreign bodies, epiglottitis, organic
diseases of the larynx, vocal cord
dysfunction, and extrinsic and intrinsic
tracheal narrowing.
Clues to the presence of alternative
reasons for dyspnea include dysphonia,
inspiratory stridor, monophonic
wheezing loudest over the central
airway, normal values for PO2, and
unexpectedly complete resolution of
airflow obstruction with intubation.
When upper airway obstruction is
suspected, further evaluation is
indicated by flow-volume curves and by
referral for laryngoscopy
LABORATORY STUDIES
Most patients who have an asthma exacerbation
do not require any initial laboratory studies. If
laboratory studies are ordered, they must not
delay initiation of asthma treatment26
. The most
important objective of laboratory studies is
detection of actual or impending respiratory
failure. Other objectives include detection of
theophylline toxicity or conditions that
complicate the treatment of asthma
exacerbations (such as cardiovascular disease,
pneumonia, or diabetes).
Consider arterial blood gas (ABG)
measurement for evaluating arterial carbon
dioxide tension (PCO2) in patients who have
suspected hypoventilation, severe distress, or
FEV1 or PEF ≤25 percent of predicted after initial
treatment. (Note: Respiratory drive is typically
increased in asthma exacerbations, so a
“normal” PCO2 of 40 mmHg indicates severe
airflow obstruction and a heightened risk of
respiratory failure.)
Complete blood count (CBC) is not required
routinely but may be appropriate in patients who
have fever or purulent sputum. It must be noted
that modest leukocytosis is common in asthma
exacerbations and that corticosteroid treatment
causes a further outpouring of
polymorphonuclear leukocytes within 1–2 hours
of administration.
It may be prudent to measure serum
electrolytes in patients who have been taking
diuretics regularly and in patients who have
coexistent cardiovascular disease because
frequent SABA administration can cause
transient decreases in serum potassium,
magnesium, and phosphate.
Chest radiography is not recommended for
routine assessment but should be obtained for
patients suspected of a complicating
cardiopulmonary process, such as congestive
heart failure, or another pulmonary process such
as pneumothorax, pneumomediastinum,
pneumonia, or lobar atelectasis.
Electrocardiograms are not required routinely,
but a baseline electrocardiogram and continual
monitoring of cardiac rhythm are appropriate in
patients older than 50 years of age and in those
who have coexistent heart disease or chronic
90
obstructive pulmonary disease.
TREATMENT
Recommended initial treatments in acute care
settings include: oxygen for most patients; SABA
for all patients; adding multiple doses of
ipratropium bromide for ER patients who have
severe exacerbations (but ipratropium bromide
is not recommended during hospitalization1
);
and systemic corticosteroids for most patients.
(For recommended doses, see Figure 5–3.).
For severe exacerbations unresponsive to the
initial treatments, adjunct treatments
(magnesium sulfate or heliox) merit
consideration to decrease the likelihood of
intubation.
The following are not recommended26
:
methylxanthines, antibiotics (except as needed
for comorbid conditions), aggressive hydration,
chest physical therapy, mucolytics, or sedation.
For patients who have mild exacerbations give
SABA therapy and assess the patient’s
response before deciding whether additional
therapy is necessary.
Oxygen
Administer supplemental oxygen (by nasal
cannulae or mask, whichever is best tolerated)
to maintain an SaO2 >90 percent (>95 percent in
pregnant women and in patients who have
coexistent heart disease). Monitor SaO2 until a
clear response to bronchodilator therapy has
occurred. When SaO2 monitoring is not
available, give supplemental oxygen to patients
who have significant hypoxemia and to patients
who have FEV1 or PEF <40 percent of
predicted.
Inhaled SABA.
SABA treatment is recommended for all patients
(Evidence A)
The repetitive or continuous administration of
SABA is the most effective means of reversing
airflow obstruction48,49,50,51
. In the ER, three
treatments of SABA spaced every 20–30
minutes can be given safely as initial therapy.
Thereafter, the frequency of administration
varies according to the improvement in airflow
obstruction and associated symptoms and the
occurrence of side effects. Continuous
administration of SABA may be more effective in
more severely obstructed patients48, 52
.
In mild or moderate exacerbations, equivalent
bronchodilation can be achieved either by high
doses (4–12 puffs) of a SABA by MDI with a
valved holding chamber (VHC e.g., VolumaticTM
)
in infants, children, and adults under the
supervision of trained personnel or by nebulizer
therapy53, 54
. However, nebulizer therapy may be
preferred for patients who are unable to
cooperate effectively in using an MDI because of
their age, agitation, or severity of the
exacerbation.
The onset of action for SABA is less than 5
minutes; repetitive administration produces
incremental bronchodilation. In about 60–70
percent of patients, response to the initial three
doses in the ER will be sufficient to discharge
them, and most patients will have a significant
response after the first dose 55,56,57
.
Duration of action of bronchodilation from SABA
in severe asthma exacerbations is not precisely
known, but duration can be significantly shorter
than that observed in stable asthma.
A recent meta-analysis of six trials suggests that
the use of nebulized magnesium sulfate in
combination with SABA may result in further
improvements in pulmonary function58
, but
further research is needed.
Inhaled ipratropium bromide.
In the ER, adding multiple high doses of
ipratropium bromide (0.5 mg nebulizer solution
or 8 puffs by MDI in adults; 0.25–0.5 mg
91
nebulizer solution or 4–8 puffs by MDI in
children) to a selective SABA produces
additional bronchodilation, resulting in fewer
hospital admissions, particularly in patients who
have severe airflow obstruction59,60
. (Evidence A)
Two controlled clinical trials in children failed to
detect a significant benefit from the addition of
ipratropium to treatment after hospitalization for
severe acute asthma61,62
. Studies among
hospitalized adults are not available.
Systemic corticosteroids.
In the ER: Give systemic corticosteroids to
patients who have moderate or severe
exacerbations and patients who do not respond
completely to initial SABA therapy (Evidence A).
These medications speed the resolution of
airflow obstruction and reduce the rate of
relapse and may reduce hospitalizations63,64,65
.
Oral administration of prednisone has been
shown to have effects equivalent to those of
intravenous methylprednisolone (Evidence A)
66,67
and is usually preferred because it is less
invasive. Give a 5- to 10-day course following
ER discharge to prevent early relapse26
.
Give supplemental doses of oral corticosteroids
to patients who take them regularly, even if the
exacerbation is mild (Evidence D).
High doses of an ICS may be considered in the
ER, although current evidence is insufficient to
permit conclusions about using ICS rather than
oral systemic corticosteroids in the ER
(Evidence B).
In the hospital: Give systemic corticosteroids to
patients who are admitted to the hospital
(Evidence A) because oral systemic
corticosteroids speed the resolution of asthma
exacerbations70,71
.
Adjunct Treatments
For severe exacerbations unresponsive to the
initial treatments listed above, whether given
before arrival at the acute care setting or in the
ER, adjunct treatments may be considered to
decrease the likelihood of intubation:
intravenous magnesium or heliox may be useful
(Evidence B). (Refer to Chapter 3)
The following treatments are NOT
recommended:
Methylxanthines.
Theophylline/aminophylline is not recommended
for acute exacerbations because it appears to
provide no additional benefit to optimal SABA
therapy and increases the frequency of adverse
effects. (Evidence A). Therapy with oral or
intravenous methylxanthines does not improve
lung function or other outcomes in hospitalized
adults72
. Most studies show no benefit, but
increased toxicity, with theophylline in children
who are hospitalized with severe asthma73
. A
meta-analysis reported that those patients
receiving intravenous aminophylline had a small
(8–9 percent) increase in percent predicted
FEV1 but did not result in significant differences
in length of stay, ICU admission or stay, or
symptoms. There were significantly greater
numbers of patients in the theophylline group
who discontinued therapy due to adverse
effects.74
Antibiotics
Antibiotics are not generally recommended
for the treatment of acute asthma
exacerbations except as needed for
comorbid conditions (Evidence B). Bacterial,
Chlamydia, or Mycoplasma infections
infrequently contribute to exacerbations of
asthma; therefore, the use of antibiotics is
generally reserved for patients who have fever
and purulent sputum and for patients who have
evidence of pneumonia3
. When the presence of
bacterial sinusitis is strongly suspected, treat
with antibiotics.
Chest physical therapy
92
For most exacerbations, chest physiotherapy is
not beneficial and is unnecessarily stressful for
the breathless asthma patient. Because mucus
plugging is a major contributing cause of fatal
asthma73
, further studies are needed on the role
of improved airway clearance in near-fatal
exacerbations. (Evidence D).
Mucolytics
Avoid mucolytic agents (e.g., acetylcysteine,
potassium iodide) because they may worsen
cough or airflow obstruction. (Evidence C)
Leukotriene modifiers
There is little data to suggest a role for
leukotriene modifiers in acute exacerbations of
asthma1
Sedation
Sedation should be strictly avoided during
asthma exacerbations (Evidence D). Anxiolytic
and hypnotic drugs are contraindicated because
of their respiratory depressant effect. In
asthmatic patients who have severe emotional
impact, and possible comorbid anxiety disorder,
therapy should stay focused on the asthma
exacerbation. The benefit of short-acting
sedatives is not known.
REPEAT ASSESSMENT
Repeat assessment of patients who have severe
exacerbations should be made after the initial
dose of a SABA and after three doses of a
SABA (60–90 minutes after initiating treatment)
(Evidence A).26
The response to initial treatment in the ER is a
better predictor of the need for hospitalization
than is the severity of an exacerbation on
presentation.7,8,11-13,15
The elements to be
evaluated include the patient’s subjective
response, physical findings, FEV1 or PEF, and
measurement of pulse oximetry or ABG (if the
patient meets the criteria described in the earlier
discussion of laboratory studies).
HOSPITALIZATION
The decision to hospitalize a patient should be
based on the duration and severity of symptoms,
severity of airflow obstruction, response to ER
treatment, course and severity of prior
exacerbations, medication use at the time of the
exacerbation, access to medical care and
medications, adequacy of support and home
conditions, and presence of psychiatric illness
(Evidence C)76,77
.
In general, the principles of care in the hospital
and recommendation for treatment resemble
those for care in the ER and involve both
treatment (with oxygen, aerosolized SABA, and
systemic corticosteroids and, perhaps, adjunct
therapies) and frequent assessment, including
clinical assessment of respiratory distress and
fatigue as well as objective measurement of
airflow (PEF or FEV1) and oxygen saturation
26
.
IMPENDING RESPIRATORY FAILURE
Intubation must not be delayed once it is
deemed necessary. Exactly when to intubate is
based on clinical judgment (Evidence D). Most
patients respond well to therapy. However, a
small minority will show signs of worsening
ventilation, whether from worsening airflow
obstruction, worsening respiratory muscle
fatigue, or a combination of the two. Signs of
impending respiratory failure include inability to
speak, altered mental status, intercostal
retraction, worsening fatigue, and a PCO2 of
≥42 mmHg78
. Because respiratory failure can
progress rapidly and can be difficult to reverse,
early recognition and treatment are critically
important.
Adjunct treatments such as magnesium sulfate
or heliox may be considered to avoid intubation,
but intubation should not be delayed once it is
deemed necessary (Evidence B).26
Because
intubation of a severely ill asthma patient is
93
difficult and associated with complications,
additional treatments are sometimes attempted.
Intravenous Magnesium Sulfate.
Consider intravenous magnesium sulfate in
patients who have life-threatening exacerbations
and in those whose exacerbations remain in the
severe category after 1 hour of intensive
conventional therapy (Evidence B). Meta-
analyses of studies of both children and
adults79,80
show that intravenous magnesium
sulfate (2 grams in adults and 25–75 mg/kg up
to 2 grams in children) added to conventional
therapy reduces hospitalization rates in ER
patients who present with severe asthma
exacerbations (PEF <40 percent). However, not
all individual studies have found positive
results81,82,83
. The treatment has no apparent
value in patients who have exacerbations of
lesser severity, and one study84
found that
intravenous magnesium sulfate improved
pulmonary function only in patients whose initial
FEV1 was <25 percent predicted, and the
treatment did not improve hospital admission
rates.
Heliox
Consider heliox-driven albuterol nebulization for
patients who have life-threatening exacerbations
and for those patients whose exacerbations
remain in the severe category after 1 hour of
intensive conventional therapy (Evidence B).
Because of helium’s low density, a mixture of
helium and oxygen (heliox) could improve gas
exchange in patients who have airway
obstruction85
. However, a meta-analysis of six
studies (four in adults, two in pediatric patients)
performed between 1996 and 2002 did not find a
statistically significant improvement in
pulmonary function or other measured outcomes
in patients receiving heliox compared to oxygen
or air86
. Other investigators recently described
two randomized controlled trials (RCTs) of
adults that demonstrated more rapid and greater
improvements in peak flow and dyspnea scores
in patients who presented with severe
exacerbations and received initial treatment with
heliox versus oxygen-driven albuterol therapy
(Lee et al. 2005)89
. The discrepancy in findings
may result from small sample sizes. More
importantly, however, some studies have
neglected to account for the different effect of
heliox versus oxygen (or room air) on respirable
mass90
.
Other adjunct therapies to avoid intubation
include intravenous β2-agonists, intravenous
leukotriene receptor antagonists (LTRAs), and
noninvasive ventilation; however, insufficient
data are available to make recommendations
regarding these possible adjunct therapies
(Evidence D).
Intravenous β2-agonists remain a largely
unproven treatment. Current evidence does not
suggest an improved benefit from intravenous
β2-agonists compared to aerosol
administration91
, but data are sparse92
on the
benefit of adding an intravenous βeta2-agonist to
high-dose nebulized therapy.
Noninvasive ventilation is another experimental
approach for treatment of respiratory failure due
to severe asthma exacerbation, but data are
very limited96
.
Intubation
Patients who present with apnea or coma should
be intubated immediately26
. There are no other
absolute indications for endotracheal intubation,
but persistent or increasing hypercapnia,
exhaustion, and depression of mental status
strongly suggest the need for ventilatory support
(Evidence D).
Intubate semielectively, before the crisis of
respiratory arrest, because intubation is difficult
in patients who have asthma26
. Because
intubation should not be delayed once it is
deemed necessary, it is often performed in the
94
ER or inpatient ward, and the patient is
subsequently transferred to an ICU appropriate
to the patient’s age.
Even without intubation, patients who have
severe exacerbations and are slow to respond to
therapy may benefit from admission to an ICU,
where they can be monitored closely and
intubated if it is indicated.
Although many issues require consideration at
the time of intubation, clinicians should pay
close attention to maintaining or replacing
intravascular volume, because hypotension
commonly accompanies the initiation of positive
pressure ventilation.26
“Permissive hypercapnia” or “controlled
hypoventilation”.
Permissive hypercapnia provides adequate
oxygenation and ventilation while minimizing
high airway pressures and barotrauma99,100,101,102
.
(Evidence C) It involves administration of as
high a fraction of inspired oxygen as is
necessary to maintain adequate arterial
oxygenation, acceptance of hypercapnia, and
treatment of respiratory acidosis with
intravenous sodium bicarbonate. Adjustments
are made to the tidal volume, ventilator rate, and
inspiration-to-expiration ratio to minimize airway
pressures. Consultation with or co--management
by physicians who have expertise in ventilator
management is appropriate, because
mechanical ventilation of patients who have
severe refractory asthma is complicated and
fraught with risk. Continuation of a SABA in
ventilated patients is recommended, although no
RCTs provide evidence for or against this
practice103,104
. This ventilator strategy is not
uniformly successful in critically ill asthma
patients, and additional therapies are being
evaluated.
PATIENT DISCHARGE
Clinicians, before patients’ discharge from the
ER or hospital, should provide patients with
necessary medications and education on how to
use them, a referral for a follow-up appointment,
and instruction in an ER asthma discharge plan
for recognizing and managing relapse of the
exacerbation or recurrence of airflow obstruction
(Evidence B).
The following actions are recommended
for discharging patients from the ER:
In general, discharge is appropriate if FEV1 or
PEF has returned to ≥70 percent of predicted or
personal best and symptoms are minimal or
absent. Patients who have an incomplete
response to therapy (FEV1 or PEF 50–69
percent of predicted or personal best) and with
mild symptoms should be assessed individually
for their suitability for discharge home, with
consideration given to factors listed in Figure
7–2 (Evidence C).
Criteria for Hospital Admission:
Criteria for ICU Admission:
95
Patients who have a rapid response should be
observed for 30–60 minutes after the most
recent dose of bronchodilator to ensure their
stability of response before discharge to home.
Extended treatment and observation in a holding
area, clinical decision unit, or overnight unit to
determine the need for hospitalization may be
appropriate, provided there is sufficient
monitoring and nursing care105
.
Prescribe sufficient medications for the
patient to continue treatment after discharge.
Patients given systemic corticosteroids should
continue oral systemic corticosteroids for 3–10
days (Evidence A). The need for further
corticosteroid therapy should be assessed at a
follow-up visit. For corticosteroid courses of less
than 1 week, there is no need to taper the dose.
For 10-day courses, there remains no need to
taper if patients are concurrently taking ICS 106
.
Consider initiating an ICS at discharge, in
addition to oral systemic corticosteroids
(Evidence B). A retrospective review of a large
patient database found a significant reduction in
the risk of subsequent ER visits among patients
Figure 7-4. Emergency Department – Asthma Discharge Plan
96
using ICS therapy after ER discharge107
. A
clinical RCT comparing ER patients discharged
with and without ICS demonstrated that ICS
added to oral systemic corticosteroids halved
patients’ risk of relapse events108
. A Cochrane
review 109
noted that two other relapse trials did
not report similar benefit, but the review found
that the combined estimate of the three available
trials had borderline statistical significance (odds
ratio 0.68; 95 percent CI 0.46 to 1.02). Initiating
ICS therapy (e.g., providing a 1–2 month
supply) at discharge from ER should be
considered, given the potential for ICS is to
reduce subsequent ER visits, the strong
evidence that long-term-control ICS therapy
reduces exacerbations in patients who have
persistent asthma, and that the initiation (and
continuation) of ICS therapy at ER discharge
can be an important effort to bridge the gap
between emergency and primary care for
asthma.
Patients already taking ICS therapy should
continue it following discharge.
Emphasize the need for continual, regular care
in an outpatient setting, and refer the patient for
a follow-up asthma care appointment within 1–
4 weeks (Evidence B). If appropriate, consider
referral to an asthma self-management
education program (Evidence B). A visit to the
ER is often an indication of inadequate long-
term management of asthma or inadequate
plans for handling exacerbations. Having fewer
general practice contacts in the previous year
has been independently associated with an
increased risk of fatal asthma110
, and an
observational study found that having follow-up
appointments within 30 days of an asthma-
related ER visit was associated with a reduced
90-day readmission rate107
. Likewise, referral of
patients in the ER to an asthma specialist for
consultation was associated with a reduced rate
of subsequent ER visits111
.
At the follow-up appointment, the health care
provider should try to ascertain the cause of the
exacerbation and institute appropriate, specific,
preventative therapy if possible. The follow-up
visit should also include a detailed review of the
patient’s medications, inhaler and peak flow
meter technique, and development of a
comprehensive written asthma action plan that
will help prevent subsequent exacerbations and
urgent or emergency care visits.26
Review discharge medications with the patient
and provide patient education on correct use of
an inhaler (Evidence B)
Give the patient an ER asthma discharge plan
with instruction for medications prescribed at
discharge and for increasing medications or
seeking medical care if asthma should worsen
(Evidence B).
Although evidence from RCTs is limited, for
many patients, a thoughtful, asthma-oriented ER
discharge plan will suffice. If local staff and
resources permit, however, the provision of a
more detailed plan may be appropriate,
especially for patients who had severe
exacerbations or who do not have regular
asthma care. Refer to Chapter 4 (Patient
Education).
Consider issuing a peak flow meter and
giving appropriate education on how to
measure and record PEF to patients who
have difficulty perceiving airflow obstruction
or symptoms of worsening asthma (Evidence
D).
97
Studies document that some patients are unable
to perceive signs of deterioration that would
indicate a need to increase medication116, 117
.
These “poor perceivers” may particularly benefit
from action plans based on peak flow
monitoring, because this tool may prevent
delays in treating exacerbations.
The following actions are recommended for
discharging patients from the hospital:
Prior to discharge, adjust the patient’s
medication to an outpatient regimen26
During the first 24 hours after this
medication adjustment, observe the
patient for possible deterioration.
Discharge medications should include a
SABA and sufficient oral systemic
corticosteroids to complete the course of
therapy (Evidence A) and instructions
to continue long-term control therapy
until the follow-up appointment
(Evidence B).
Consider initiating ICS therapy for
patients who did not use an ICS prior to
the hospital admission (Evidence B). If
the decision is made to start the patient
on an ICS, the ICS should be started
before the course of oral corticosteroids
is completed, because their onset of
action is gradual118
. Starting the ICS
therapy before discharge gives the
patient additional time to learn and
demonstrate appropriate technique.
Provide patient education:
o Review patient understanding of
the causes of asthma
exacerbations, the purposes and
correct uses of treatment
(including inhaler )
An exacerbation severe enough to require
hospitalization may reflect a failure of the
patient’s self-management, particularly in
patients who have low levels of health literacy119
.
Some studies report that 35 percent of adult
patients presenting to the ER are current
smokers120
. It would be appropriate to query
patients hospitalized for asthma about their
smoking status and encourage smoking
cessation along with their asthma discharge
plan. Hospitalized patients may be particularly
receptive to information and advice about their
illness
— Educate patients about their discharge
medications and the importance of taking
medications as prescribed and attending their
followup visit (Evidence B). Low levels of
adherence to asthma medications are common,
even in patients recently hospitalized for severe
asthma exacerbations121
.
— Referral to an asthma specialist should be
considered for patients who have a history of
life-threatening exacerbations or multiple
hospitalizations (Evidence B)122,123,124,125
.
Figure 7-8. Checklist for Hospital Discharge of
Patients who have Asthma
98
— Recommend peak flow monitoring to patients
who have a history of severe exacerbations or
who have moderate or severe persistent asthma
(Evidence B) and those who poorly perceive
airflow obstruction or worsening asthma
(Evidence D).
Review or develop a written plan for managing
either relapse of the exacerbation of recurrent
symptoms or exacerbations (Evidence B). The
plan should describe the signs, symptoms,
and/or peak flow values that should prompt
increases in self-medication, contact with a
health care provider, or return for emergency
care. The plan given at discharge from the ER
may be quite simple (e.g., instructions for
discharge medications and returning for care if
asthma worsens; see Figure 7–7). The
preparation for discharge from the hospital
should be more complete (See Figure 7–8.). A
detailed written asthma action plan for
comprehensive long-term management and
handling of exacerbations should be developed
by the regular provider at a follow-up visit.
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perception of dyspnea in patients with a history of
near‐fatal asthma. N Engl J Med
1994;330(19):1329– 34.
118. Kraan J, Koeter GH, van der Mark TW, Boorsma
M, Kukler J, Sluiter HJ, De Vries K. Dosage and
time effects of inhaled budesonide on bronchial
103
hyperreactivity. Am Rev Respir Dis
1988;137(1):44–8.
119. Paasche‐Orlow MK, Riekert KA, Bilderback A,
Chanmugam A, Hill P, Rand CS, Brancati FL,
Krishnan JA. Tailored education may reduce
health literacy disparities in asthma
self‐management. Am J Respir Crit Care Med
2005;172(8):980–6. Epub August 2005.
120. Silverman RA, Boudreaux ER, Woodruff PG,
Clark S, Camargo CA Jr. Cigarette smoking
among asthmatic adults presenting to 64
emergency rooms. Chest 2003;123(5):1472–9.
121. Krishnan V, Diette GB, Rand CS, Bilderback AL,
Merriman B, Hansel NN, Krishnan JA. Mortality in
patients hospitalized for asthma exacerbations in
the United States. Am J Respir Crit Care Med
2006;174(6):633–8.
122. Harish Z, Bregante AC, Morgan C, Fann CS,
Callaghan CM, Witt MA, Levinson KA, Caspe
WB. A comprehensive inner‐city asthma program
reduces hospital and emergency room utilization.
Ann Allergy Asthma Immunol 2001;86(2):185–9.
123. Mahr TA, Evans R III. Allergist influence on
asthma care. Ann Allergy 1993;71(2):115–20.
124. Mayo PH, Richman J, Harris HW. Results of a
program to reduce admissions for adult asthma.
Ann Intern Med 1990;112(11):864–71.
125. Sperber K, Ibrahim H, Hoffman B, Eisenmesser
B, Hsu H, Corn B. Effectiveness of a specialized
asthma clinic in reducing asthma morbidity in an
inner‐city minority population. J Asthma
1995;32(5):335–43.
126. Philippine Consensus Report on Asthma 2004
104
Chapter 8
Special
Consideration
106
KEY POINTS:
It is safer for pregnant women with
asthma to be treated
pharmacologically than to continue
to have asthma symptoms and
exacerbations. 1
Modest reductions in peak flow rate
at the time of menstruation for
affected women compared to
unaffected women were noted, but
these were not usually associated
with clinical deterioration.
A diagnosis of gastroesophageal
reflux in patients with asthma can
best be made by simultaneously
monitoring esophageal pH and lung
function. Medical management
should be given for the relief of
reflux symptoms as it is often
effective.
The likelihood of intraoperative and
postoperative respiratory
complications depends on the
severity of asthma at the time of
surgery, the type of surgery, and
type of anesthesia. The use of peri-
operative steroids to control asthma
does not put the asthmatic at
greater risk for peri-operative
complications.
Upper airway diseases like rhinitis,
sinusitis and nasal polyps can
influence lower airway function in
some patients with asthma.
Although the mechanisms behind
this relationship have not been
established, inflammation likely
plays a similarly critical role in the
pathogenesis..
Pharmacologic therapy for
occupational asthma is identical to
therapy for other forms of asthma,
but it is not a substitute for adequate
avoidance.
Respiratory infections have an
important relationship to asthma as
they provoke wheezing and
increased symptoms in many
patients.
The mechanism involved in
exercise-induced asthma (EIA) may
be due to the humidification and
heating function of the nose being
by-passed and cold air reaching the
airways, which in turn produces
bronchial spasm. Cold air may
likewise produce a humoral effect or
a nerve reaction in the small airways
that leads to airway narrowing.
Anaphylaxis is a potentially life-
threatening condition that can both
mimic and complicate severe
asthma. Effective treatment of
anaphylaxis demands early
recognition of the event.
INTRODUCTION
Special considerations are required in
managing asthma in relation to pregnancy;
menstrual cycle; surgery; rhinitis, sinusitis,
and nasal polyps; occupation; respiratory
infections; gastroesophageal reflux;
exercise; aspirin intake; and anaphylaxis.
PREGNANCY
During pregnancy the severity of asthma
often changes, and patients may require
close follow-up and adjustment of
medications. In approximately one-third of
women asthma becomes worse; in one-third
asthma becomes less severe; and in the
remaining one third it remains unchanged
during pregnancy.2,3,4
Although concern
exists with the use of medications in
pregnancy, poorly controlled asthma can
have an adverse effect on the fetus,
resulting in complications which include
increased risk of perinatal mortality,
intrauterine growth retardation, preterm
birth, low birth weight,5,6,7
and neonatal
hypoxia. The overall perinatal prognosis for
children born to women with asthma that is
107
well managed during pregnancy is
comparable to that for children born to
women without asthma.8
For this reason,
using medications to obtain optimal control
of asthma is justified even when their safety
in pregnancy has not been unequivocally
proven. For most medications used to treat
asthma, there is little evidence to suggest an
increased risk to the fetus.
Appropriately monitored use of theophylline,
inhaled glucocorticosteroids, β2-agonists,
and leukotriene modifiers (specifically
montelukast) are not associated with an
increased incidence of fetal abnormalities.
Inhaled glucocorticosteroids have been
shown to prevent exacerbations of asthma
during pregnancy. According to the Asthma
and Pregnancy Working Group (APWG) of
the National Asthma Education and
Prevention Program, optimal treatment of
asthma during pregnancy includes treatment
of comorbid allergic rhinitis (AR) which can
trigger or aggravate asthma symptoms.
Intranasal corticosteroids are recommended
for treatment of allergic rhinitis as a
comorbid condition because they have a low
risk of systemic effect.7,9,10
LTRAs can also
be used, but minimal data are available on
their use during pregnancy.11,12,13,14
The
current second-generation antihistamines of
choice are loratadine or cetirizine. Table 1
shows the common allergic rhinitis
medications and their FDA pregnancy risk
categories.1
.
As in other situations, the focus of asthma
treatment must remain on control of
symptoms and maintenance of normal lung
function. Acute exacerbations should be
treated aggressively in order to avoid fetal
hypoxia. Treatment should include
nebulized rapid-acting β2-agonists and
oxygen and systemic glucocorticosteroids
should be instituted when necessary.15,16
As
a rule, women with more severe asthma
prior to pregnancy are likely to deteriorate
during pregnancy. The factors most likely
contributing to worsening asthma during
pregnancy include upper respiratory tract
infections and patient non-compliance with
medical regimen. The peak of
exacerbations appears between the 24th-
36th weeks of age of gestation (AOG).
Asthma generally remains quiescent during
labor and delivery in about 90% of pregnant
women. Whatever the course of asthma
Note: ARIA* advises that due to the risk of rhinitis
medicamentosa, intranasal decongestants should not be used
(even by nonpregnant patient) for more than 9 days.
*ARIA – Allergic Rhinitis and its Impact on Asthma
Table 8.1. Common Allergic Rhinitis
Medications in Pregnant Asthmatics
108
may be during pregnancy, changes
generally revert to pre-pregnancy level of
severity within 3 months post-partum.
Severe persistent asthma has been related
to the development of maternal
complications like pre-eclampsia, maternal
hypertension, hyperemesis gravidarium,
uterine vaginal hemorrhage, toxemia,
placenta previa, and induced and
complicated labors.17
It is safer for pregnant
women with asthma to be treated
pharmacologically than to continue to have
asthma symptoms and exacerbations.
While all patients should have adequate
opportunity to discuss the safety of their
medications, pregnant patients with asthma
should be advised that the greater risk to
their baby lies with poorly controlled asthma,
and the safety of most modern asthma
treatments should be stressed.18,19,20
Table 2
shows US FDA pregnancy risk categories
for asthma medications.1,8
Asthma and the Menstrual Cycle
Premenstrual asthma (PMA) is a
phenomenon first described by Frank in
1931, as a symptom of “premenstrual
tension”.21
Large scale longitudinal studies
have not yet been undertaken to adequately
address just how prevalent the condition is.
Several small studies, however, seem to
suggest that 30-40% of female asthmatics
experience a premenstrual worsening of
symptoms but these were retrospective and
based on patient-recorded recollections of
subjective data without any objective finding
of increased asthma in severity.22,23,24
Modest reductions in peak flow rate at the
time of menstruation for affected women
compared to unaffected women were noted,
but these were not usually associated with
clinical deterioration.25
Progesterone levels fall in the days before
menstruation and it has a relaxant effect on
airway smooth muscle contractility. Thus,
this may lead to cyclic changes in airway
responsiveness in women prone to
perimenstrual exacerbation of asthma. 26,27
Progesterone-induced hyperventilation may
further influence asthma leading to
symptomatic deterioration and dyspnea.
Although an increase in asthma symptoms
and a decrease in peak expiratory flow rates
have been demonstrated in the luteal phase
of menstrual cycle, there seems to be no
deterioration in airway reactivity. 28
It must
be emphasized, however, that there is no
real relationship between airway function
and absolute levels of progesterone.
Prostaglandins have previously been
reported to have bronchoconstrictive effects;
endogenous prostaglandin synthesis,
however, has not been shown to correlate
with occurrence of premenstrual asthma.29,30
Table 8.2. US FDA Pregnancy Risk
Categories for Asthma Medications
109
Surgery
Airway hyperresponsiveness, airflow
limitation, and mucus hypersecretion
predispose patients with asthma to
intraoperative and postoperative respiratory
complications.31
The likelihood of these
complications depends on the severity of
asthma at the time of surgery, the type of
surgery (thoracic and upper abdominal
surgeries pose the greatest risks), and type
of anesthesia (general anesthesia with
endotracheal intubation carries the greatest
risk).32,33,34
These variables need to be
assessed prior to surgery and pulmonary
function should be measured. If possible,
this evaluation should be undertaken
several days before surgery to allow time for
additional treatment. In particular, if the
patient’s FEV1 is less than 80% of personal
best, a brief course of oral
glucocorticosteroids should be considered to
reduce airflow limitation.35
Furthermore,
patients who have received systemic
glucocorticosteroids within the past 6
months should have systemic coverage
during the surgical period (100 mg
hydrocortisone every 8 hours intravenously).
This should be rapidly reduced 24 hours
following surgery, as prolonged systemic
glucocorticosteroid therapy may inhibit
wound healing.
The use of peri-operative steroids to control
asthma does not put the asthmatic at
greater risk for peri-operative
complications.36
Prior to surgery, patients
should be free of wheezing, with a peak flow
greater than 80 percent of the predicted
personal best value.37,38,39
To achieve this
goal, the patient may need oral
corticosteroids (1mg /kbw. of prednisone
daily or the equivalent).
Rhinitis, Sinusitis, and Nasal Polyps
Upper airway diseases can influence lower
airway function in some patients with
asthma. Although the mechanisms behind
this relationship have not been established,
inflammation likely plays a similarly critical
role in the pathogenesis of rhinitis, sinusitis,
and nasal polyps as in asthma.40,41,42
Rhinitis
The majority of patients with asthma have a
history or evidence of rhinitis and up to 30%
of patients with persistent rhinitis have or
develop asthma.43,43
Rhinitis frequently
precedes asthma, and is both a risk factor
for the development of asthma45
and is
associated with increased severity and
health resource use in asthma.46
Rhinitis
and asthma share several risk factors:
common indoor and outdoor allergens such
as house dust mites, animal dander, and,
less commonly, pollen affecting both the
nose and bronchi,47,48
occupational
sensitizers,49
and non-specific factors like
aspirin. For these reasons, the Allergic
Rhinitis and its Impact on Asthma (ARIA)
initiative recommends that the presence of
asthma must be considered in all patients
with rhinitis, and that in planning treatment,
both should be considered together.50
Both
asthma and rhinitis are considered to be
inflammatory disorders of the airway, but
there are some differences between the two
conditions in mechanisms, clinical features,
and treatment approach. Although the
inflammation of the nasal and bronchial
mucosa may be similar, nasal obstruction is
largely due to hyperemia in rhinitis, while
airway smooth muscle contraction plays a
dominant role in asthma. 51
Treatment of rhinitis may improve asthma
symptoms.52,53
Anti-inflammatory agents
including glucocorticosteroids and cromones
as well as leukotriene modifiers and
anticholinergics can be effective in both
conditions. However, some medications are
selectively effective against rhinitis (e.g., H1-
antagonists) and others against asthma
(e.g., β2-agonists).
54
Use of intra-nasal
110
glucocorticosteroids for concurrent rhinitis
has been found to have a limited benefit in
improving asthma and reducing asthma
morbidity in some but not all studies.55,56,57
Leukotriene modifiers,58
allergen-specific
immunotherapy,50,59
and anti-IgE therapy60,61
are effective in both conditions .
Sinusitis
Sinusitis is a complication of upper
respiratory infections, allergic rhinitis, nasal
polyps, and other forms of nasal obstruction.
Both acute and chronic sinusitis can worsen
asthma. Clinical features of sinusitis lack
diagnostic precision,62
and CT Scan
confirmation is recommended when
available. Treatment should also include
medications to reduce nasal congestion,
such as topical nasal decongestants or
topical nasal or even systemic
glucocorticosteroids. These agents remain
secondary to primary asthma therapies.45,54
Approximately 40-60% of asthmatic patients
will show radiographic evidence of sinusitis.
Some patients with recurrent sinusitis will
develop chronic tissue inflammation with
mucosal thickening and formation of nasal
polyps, also called chronic hyperplastic
sinusitis and nasal polyp formation
(CHS/NP).
Nasal polyps
Nasal polyps associated with asthma and
rhinitis, and sometimes with aspirin
hypersensitivity,64
are seen primarily in
patients over 40 years old. Between 36%
and 96% of aspirin-intolerant patients have
polyps, and 29% to 70% of patients with
nasal polyps may have asthma.64,65
Nasal
polyps are quite responsive to topical
glucocorticosteroids. A limited number of
patients with glucocorticosteroid-refractory
polyps may benefit from surgery.
Occupational Asthma
Occupational exposures have been
estimated to cause 5-15% of adult-onset
asthma. The prevalence of occupational
asthma (OA) due to agents with high
molecular weight is generally less than 5%
while prevalence due to low molecular
weight agents is 5-10%.66,67
The list of
agents can be viewed at
http://www.asmanet.com. In a recent report
on “Occupational Risk Factors and Asthma
among Health Care Professionals” by
George L. Delcos, et.al, (American Journal
of Critical Care Med Vol 175. pp 667-675,
2007), he reported an approximate twofold
increase in the likelihood of asthma after
entry into a health care profession for tasks
involving instrument cleaning and
disinfection, general cleaning products used
on indoor building surfaces, use of
powdered latex gloves, and the
administration of aerosolized medications.68
In every adult whose asthma begins or
worsens while working, the possibility of
Work-Related Asthma (WRA) should be
considered and evaluated. Physicians
should consider the possibility of OA in all
adults with asthma. Therefore, an
occupational history should be the first step
in the initial evaluation of the patient. The
diagnosis should be confirmed as soon as
possible to prevent worsening of
symptoms69
and should be investigated
when workers are at the workplace, because
a prolonged avoidance of exposure may
influence the reliability of diagnostic
procedures.
Once a diagnosis of occupational asthma is
established, complete avoidance of the
relevant exposure ,70-72
is ideally an
important component of management.69,70
Occupational asthma may persist even
several years after removal from exposure
to the causative agent, especially when the
patient has had symptoms for a long time
111
before cessation of exposure.73,74
Continued
exposure may lead to increasingly severe
and lower probability of subsequent
remission,75
and, ultimately, permanently
impaired lung function.76-79
Pharmacologic
therapy for occupational asthma is identical
to therapy for other forms of asthma, but it is
not a substitute for adequate avoidance.80
Consultation with a specialist in asthma
management or occupational medicine is
advisable. The British Occupational Health
Research Foundation Guidelines for the
prevention, identification, and management
of occupational asthma are available at
http://www.bohrf.org.uk/downloads/asthevre.
pdf.
The Diagnosis and Management of Work-
Related Asthma: ACCP Consensus
Statement has a detailed discussion of the
diagnosis and management of work-related
asthma. 81
Repiratory Infections
Respiratory infections have an important
relationship to asthma as they provoke
wheezing and increased symptoms in many
patients.82
Epidemiological studies have
found that infectious microorganisms
associated with increased asthma
symptoms are often respiratory viruses,83
but seldom bacteria.84
Respiratory syncytial
virus is the most common cause of
wheezing in infancy, while rhinoviruses
(which cause the common cold), are the
principal triggers of wheezing and worsening
of asthma in older children and adults.85
Other respiratory viruses, such as
parainfluenza, influenza, adenovirus, and
coronavirus, are also associated with
increased wheezing and asthma
symptoms.86
A number of mechanisms have
been identified that explain why respiratory
infections trigger wheezing and increased
airway responsiveness, including damage to
airway epithelium, stimulation of virus-
specific IgE antibody, enhanced mediator
release, and the appearance of a late
asthmatic response to inhaled antigen.87
Thus, there is evidence that viral infections
are an “adjuvant” to the inflammatory
response and promote the development of
airway injury by enhancing airway
inflammation.88
Treatment of an infectious
exacerbation follows the same principles as
treatment of other asthma exacerbations—
that is, rapid-acting inhaled β2-agonists and
early introduction of oral glucocorticosteroids
or increases in inhaled glucocorticosteroids
by at least four-fold are recommended.
Because increased asthma symptoms can
often persist for weeks after the infection is
cleared, anti-inflammatory treatment should
be continued for this full period to ensure
adequate control.
The role of chronic infection with Chlamydia
pneumoniae and Mycoplasma pneumoniae
in the pathogenesis or worsening of asthma
is currently uncertain.89
The benefit from
macrolide antibiotics remains unclear. 90-96
Parasitic Infections
Parasite infections are very common,
particularly in the developing world, and
systematic eradication programs are being
introduced in many areas. Although
eradication is undoubtedly beneficial to
many aspects of individual and public
health, the hypothesis that parasite
infections may protect against allergic
disease raises the possibility that
eradication may increase asthma and other
manifestations of allergy.
Results of studies are conflicting. A
systematic review and meta-analysis
suggest that any relation between intestinal
parasite infection and asthma risk is likely to
be species specific. Parasite infections do
not in general protect against asthma97
112
Gastroesophageal Reflux
The relationship of increased asthma
symptoms, particularly at night, to
gastroesophageal reflux disease (GERD)
remains uncertain, although this condition is
nearly three times as prevalent in patients
with asthma compared to the general
population.98,99
Some of these patients also
have a hiatal hernia; furthermore,
theophylline and oral β2-agonists may
increase the likelihood of symptoms by
relaxing the lower esophageal ring. A
relationship between GERD and asthma
was first documented in the late 1960s when
asthma patients were reported to be “cured”
of asthma following surgery for hiatal hernia
and/or GERD.100
Additional research has
continued to show that reflux may cause or
trigger asthma symptoms.
There are two accepted mechanisms for the
role of GERD in asthma. The first hypothesis
states that stimulation of esophageal
mucosal receptors produces vagally
mediated bronchospasm. Prolonged reflux
clearance time often causes symptomatic
esophageal disease and esophagitis,
consequently increasing the sensitivity of
esophageal receptors to refluxed material.
Once stimulated, the receptors transmit a
signal that results in constriction of the
bronchioles. The second hypothesis is the
micro-or macro-aspiration of gastric contents
into the lungs, especially in the supine
position of sleep, causing a chemical
pneumonitis. More recent research,
however, has suggested that although
aspiration does occur on rare occasions, it is
unlikely to be the primary reason for reflux-
triggered asthma.101-105
More recently, a third mechanism being
proposed is heightened bronchial reactivity
secondary to esophageal reflux.
Furthermore, nocturnal esophageal acid
events are associated with lower respiratory
resistance.106
A diagnosis of gastroesophageal reflux in
patients with asthma can best be made by
simultaneously monitoring esophageal pH
and lung function. Medical management
should be given for the relief of reflux
symptoms as it is often effective. Patients
may be advised to eat smaller, more
frequent meals; avoid food or drink between
meals and especially at bedtime; avoid fatty
meals, alcohol, theophylline, and oral H2-
agonists; use proton pump inhibitors or H2-
antagonists; and elevate the head of the
bed. However, the role of anti-reflux
treatment in asthma control is unclear, as it
does not consistently improve lung function,
asthma symptoms, nocturnal asthma, or the
use of asthma medications in subjects with
asthma but without clear reflux-associated
respiratory symptoms. Subgroups of
patients may benefit, but it appears difficult
to predict which patients will respond to this
therapy. 107
Surgery for gastroesophageal reflux is
reserved for the severely symptomatic
patient with well-documented esophagitis
and failure of medical management. In
patients with asthma, it should be
demonstrated that the reflux causes asthma
symptoms before surgery is advised.100,108-113
Aspirin-Induced Asthma (AIA)
Up to 28% of adults with asthma, but rarely
children with asthma, suffer from asthma
exacerbations in response to aspirin and
other nonsteroidal anti-inflammatory drugs
(NSAIDs). This syndrome is more common
in severe asthma. 114
The clinical picture and course of aspirin-
induced asthma (AIA) are characteristic.115
The majority of patients first experience
symptoms, which may include vasomotor
rhinitis and profuse rhinorrhea, during the
third to fourth decade of life. Chronic nasal
congestion evolves, and physical
examination often reveals nasal polyps.
113
Asthma and hypersensitivity to aspirin often
develop subsequently. The hypersensitivity
to aspirin presents a unique picture: within
minutes to one or two hours following
ingestion of aspirin, an acute, often severe,
asthma attack develops, and is usually
accompanied by rhinorrhea, nasal
obstruction, conjunctival irritation, and
scarlet flush of the head and neck. This may
be provoked by a single aspirin or other
cyclooxygnease-1 (COX-1) inhibitor and
include violent bronchospasm, shock, loss of
consciousness, and even respiratory arrest.
116,117
Persistent marked eosinophilic inflammation,
epithelial disruption, cytokine production,
and upregulation of adhesion molecules are
found in the airways of patients with
AIA.118,119
Airway expression of interleukin-5
(IL-5), which is involved in recruitment and
survival of eosinophils, is also increased.120
AIA is further characterized by increased
activation of cysteinyl leukotriene
pathways,which may be partly explained by
a genetic polymorphism of the LTC4
synthase gene found in about 70% percent
of patients.121
However, the exact
mechanism by which aspirin triggers
bronchoconstriction remains unknown.122
The ability of a cyclooxygenase inhibitor to
trigger reactions depends on the drug's
cyclooxygenase inhibitory potency, as well
as on the individual sensitivity of the patient.
123,124
A characteristic history of reaction can only
be confirmed by aspirin challenge, as there
are no suitable in vitro tests for diagnosis.
The aspirin challenge test is not
recommended for routine practice as it is
associated with a high risk of potentially fatal
consequences and must only be conducted
in a facility with cardiopulmonary
resuscitation capabilities. 123
Once aspirin or NSAID hypersensitivity
develops, it is present for life. Patients with
AIA should avoid aspirin, products
containing it, other analgesics that inhibit
COX-1, and often also hydrocortisone
hemisuccinate.124
Avoidance does not
prevent progression of the inflammatory
disease of the respiratory tract. Where an
NSAID is indicated, a cyclooxygenase-2
(COX-2) inhibitor125
may be considered with
appropriate physician supervision and
observation for at least one hour after
administration.126
For NSAID-sensitive
patients with asthma who require NSAIDs
for other medical conditions, desensitization
may be conducted in the hospital under the
care of a specialist. 127,128
Generally, asthma patients, especially those
with adult onset asthma and associated
upper airway disease (nasal polyposis),
should be counselled to avoid NSAIDs,
taking acetaminophen/paracetamol instead.
Exercise-Induced Asthma
During exercise, the humidification and
heating function of the nose by bypassed
and cold air reaches the airways,129,130,131
which in turn produces bronchial spasm.132
This theory also suggests that the cold air
may produce a humoral effect or a nerve
reaction in the small airways that leads to
bronchospasm. 133,134
Neurohumoral
transmitters like leukotrienes have also been
implicated in mediating a portion of the
airway narrowing.135
Leukotrienes have been found to play a role
in airway refractoriness with repeated bouts
of exercise. They may act through release
of inhibitory prostaglandins or by inhibiting
other mediator release. 136
Non-pharmacologic treatment entails
avoiding inclement atmospheres and
choosing a sport that is less likely to induce
an asthmatic attack. A third strategy would
be by inducing the known refractory period a
few times earlier in the day of competition so
114
that at the time of exercise competition, the
neurohumoral transmitters are exhausted.137
Anaphylaxis and Asthma
Anaphylaxis is a potentially life-threatening
condition that can both mimic and
complicate severe asthma. Effective
treatment of anaphylaxis demands early
recognition of the event. The possibility of
anaphylaxis should be considered in any
setting where medication or biological
substances are given, especially by
injection. Examples of documented causes
of anaphylaxis include the administration of
allergenic extracts in immunotherapy, food
intolerance (nuts, fish, shellfish, eggs, milk),
avian-based vaccines, insect stings and
bites, latex hypersensitivity, drugs (β-lactam
antibiotics, aspirin and NSAIDs, and
angiotensin converting enzyme (ACE)
inhibitors), and exercise.
Symptoms of anaphylaxis include flushing,
pruritis, urticaria, and angioedema; upper
and lower airway involvement such as
stridor, dyspnea, wheezing, or apnea;
dizziness or syncope with or without
hypotension; and gastrointestinal symptoms
such as nausea, vomiting, cramping, and
diarrhea. Exercise-induced anaphylaxis,
often associated with medication or food
allergy, is a unique physical allergy and
should be differentiated from exercise-
induced bronchoconstriction. 138
Airway anaphylaxis could account for the
sudden onset of asthma attacks in severe
asthma and the relative resistance of these
attacks to increased doses of β2-agonists. If
there is a possibility that anaphylaxis is
involved in an asthma attack, epinephrine
should be the bronchodilator of choice.
Prompt treatment for anaphylaxis is crucial
and includes oxygen, intramuscular
epinephrine, injectable antihistamine,
intravenous hydrocortisone, oropharyngeal
airway, and intravenous fluid. Preventing a
recurrence of anaphylaxis depends on
identifying the cause and instructing the
patient on avoidance measures and self-
administered emergency treatment with pre-
loaded epinephrine syringes.139
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