Professional Documents
Culture Documents
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Federal University of Bahia
School of Medicine Cape Town, South Africa
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Salvador, Brazil
Allan Becker, MD
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Tari Haahtela, MD University of Manitoba
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Helsinki University Central Hospital Winnipeg, Manitoba, Canada
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Helsinki, Finland
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Elisabeth Bel, MD
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Mark L. Levy, MD University of Amsterdam
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University of Edinburgh Amsterdam, The Netherlands
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London, England, UK
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Jeffrey M. Drazen, MD
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Paul O’Byrne, MD
Boston, Massachusetts, USA
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McMaster University
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Tokyo, Japan
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Pisa, Italy
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Kolding, Denmark
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Paul O’Byrne, MD
McMaster University
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Helen Reddel, MD
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Sally E. Wenzel, MD
University of Pittsburgh
Pittsburgh, Pennsylvania, USA
*Disclosures for members of GINA Board of Directors and Science Committees can be
found at http://www.ginasthma.org i
PREFACE
Asthma is a serious global health problem. People of all In spite of these dissemination efforts, international
ages in countries throughout the world are affected by surveys provide direct evidence for suboptimal asthma
this chronic airway disorder that, when uncontrolled, can control in many countries, despite the availability of
place severe limits on daily life and is sometimes fatal. effective therapies. It is clear that if recommendations
The prevalence of asthma is increasing in most countries, contained within this report are to improve care of people
especially among children. Asthma is a significant burden, with asthma, every effort must be made to encourage
not only in terms of health care costs but also of lost health care leaders to assure availability of and access to
productivity and reduced participation in family life. medications, and develop means to implement effective
asthma management programs including the use of
During the past two decades, we have witnessed many appropriate tools to measure success.
scientific advances that have improved our understanding
of asthma and our ability to manage and control it In 2002, the GINA Report stated that “It is reasonable
effectively. However, the diversity of national health to expect that in most patients with asthma, control
care service systems and variations in the availability of the disease can, and should be achieved and
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of asthma therapies require that recommendations for maintained.” To meet this challenge, in 2005, Executive
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asthma care be adapted to local conditions throughout Committee recommended preparation of a new report
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the global community. In addition, public health officials not only to incorporate updated scientific information
require information about the costs of asthma care, how but to implement an approach to asthma management
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to effectively manage this chronic disorder, and education based on asthma control, rather than asthma severity.
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methods to develop asthma care services and programs Recommendations to assess, treat and maintain asthma
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responsive to the particular needs and circumstances control are provided in this document. The methods used
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within their countries. to prepare this document are described in the Introduction.
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In 1993, the National Heart, Lung, and Blood Institute It is a privilege for me to acknowledge the work of the
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collaborated with the World Health Organization to many people who participated in this update project, as
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convene a workshop that led to a Workshop Report: well as to acknowledge the superlative work of all who
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Global Strategy for Asthma Management and Prevention. have contributed to the success of the GINA program.
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with the goal of reducing chronic disability and premature The GINA program has been conducted through
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deaths while allowing patients with asthma to lead unrestricted educational grants from Almirall, AstraZeneca,
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At the same time, the Global Initiative for Asthma (GINA) generous contributions of these companies assured that
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was implemented to develop a network of individuals, Committee members could meet together to discuss
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organizations, and public health officials to disseminate issues and reach consensus in a constructive and timely
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information about the care of patients with asthma while manner. The members of the GINA Committees are,
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at the same time assuring a mechanism to incorporate however, solely responsible for the statements and
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the results of scientific investigations into asthma conclusions presented in this publication.
care. Publications based on the GINA Report were
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prepared and have been translated into languages to GINA publications are available through the Internet
promote international collaboration and dissemination of (http://www.ginasthma.org).
information. To disseminate information about asthma
care, a GINA Assembly was initiated, comprised of asthma
care experts from many countries to conduct workshops
with local doctors and national opinion leaders and to
hold seminars at national and international meetings. In Mark FitzGerald, MD
addition, GINA initiated an annual World Asthma Day (in Professor of Medicine
2001) which has gained increasing attention each year Head, UBC and VGH Divisions of Respiratory Medicine
to raise awareness about the burden of asthma, and to Director, Centre for Lung Health
initiate activities at the local/national level to educate Co-Director Institute for Heart and Lung Health
families and health care professionals about effective The Lung Centre, 7th Floor
methods to manage and control asthma. Gordon and Leslie Diamond Health Care Centre,
2775 Laurel Street
Vancouver, B.C. V5Z 1M9 Canada
ii
GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION
Table of Contents
PREFACE ii Medical History 16
Symptoms 16
METHODOLOGY AND SUMMARY OF NEW Cough variant asthma 16
RECOMMENDATION, 2011 UPDATE vi Exercise-Induced bronchospasm 17
Physical Examination 17
INTRODUCTION x Tests for Diagnosis and Monitoring 17
Measurements of lung function 17
CHAPTER 1. DEFINITION AND OVERVIEW 1 Spirometry 18
Peak expiratory flow 18
KEY POINTS 2 Measurement of airway responsiveness 19
Non-Invasive markers of airway inflammation 19
DEFINITION 2 Measurements of allergic status 19
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Prevalence, Morbidity and Mortality 3 DIFFERENTIAL DIAGNOSIS 20
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Social and Economic Burden 3 Children 5 Years and Younger 20
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Older Children and Adults 20
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FACTORS INFLUENCING THE DEVELOPMENT AND The Elderly 21
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EXPRESSION OF ASTHMA 4 Occupational Asthma 21
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Host Factors 4 Distinguishing Asthma from COPD 21
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Genetic 4
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Obesity 5 CLASSIFICATION OF ASTHMA
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Sex 5 Etiology 21
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Occupational sensitizers 6
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Reliever Medications 36 ASTHMA PREVENTION 61
Rapid-acting inhaled β2-agonists 36 PREVENTION OF ASTHMA SYMPTOMS AND
Systemic glucocorticosteroids 37 EXACERBATIONS 62
Anticholinergics 37 Indoor Allergens 62
Theophylline 37 Domestic mites 62
Short-acting oral β2-agonists 37 Furred animals 62
Cockroaches 63
Complementary and Alternative Medicine 37 Fungi 63
Outdoor Allergens 63
ASTHMA TREATMENT: CHILDREN 38 Indoor Air Pollutants 63
Route of Administration 38 Outdoor Air Pollutants 63
Controller Medications 39 Occupational Exposures 63
Inhaled glucocorticosteroids 39 Food and Drug Additives 64
Leukotriene modifiers 41 Drugs 64
Long-acting inhaled β2-agonists 41 Influenza Vaccination 64
Theophylline 42 Obesity 64
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Anti-IgE 42 Emotional Stress 64
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Cromones: sodium cromoglycate and Other Factors That May Exacerbate Asthma 64
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nedocromil sodium 43
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Systemic glucocorticosteroids 43 COMPONENT 3: ASSESS,TREAT AND MONITOR
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Reliever Medications 43 ASTHMA 65
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Rapid-acting inhaled β2-agonists and short-acting
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oral β2-agonists 43 KEY POINTS 65
Anticholinergics 43 PY
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INTRODUCTION 65
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REFERENCES 43
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controllers 68
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controllers 68
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controller options 69
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ASTHMA EDUCATION 57
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INTRODUCTION 73 GINA DISSEMINATION/IMPLEMENTATION
ASSESSMENT OF SEVERITY 74 RESOURCES 108
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Inhaled glucocorticosteroids 78
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Magnesium 78
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Helium oxygen therapy 78
Leukotriene modifiers 78
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Sedatives 78
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Criteria for Discharge from the Emergency
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Department vs. Hospitalization 78
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COMPONENT 5: SPECIAL CONSIDERATIONS 80
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Pregnancy 80
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Obesity 80
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Surgery 80
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Rhinitis 81
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Sinusitis 81
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Nasal polyps 81
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Occupational Asthma 81
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Respiratory Infections 81
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Gastroesophageal Reflux 82
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Aspirin-Induced Asthma 82
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REFERENCES 83
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INTRODUCTION 105
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Methodology and Summary of New Recommendations
Global Strategy for Asthma Management and Prevention:
2012 Update1
Background: When the Global Initiative for Asthma Science Committee, providing an abstract and the full
(GINA) program was initiated in 1993, the primary goal paper are submitted in (or translated into) English.
was to produce recommendations for the management of
asthma based on the best scientific information available. All members of the Committee receive a summary of
Its first report, NHLBI/WHO Workshop Report: Global citations and all abstracts. Each abstract is assigned to
Strategy for Asthma Management and Prevention was at least two Committee members, although all members
issued in 1995 and revised in 2002 and 2006. In 2002 are offered the opportunity to provide an opinion on
and in 2006 revised documents were prepared based on all abstracts. Members evaluate the abstract or, up to
published research. her/his judgment, the full publication, and answer four
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specific written questions from a short questionnaire, and
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The GINA Science Committee2 was established in 2002 to indicate if the scientific data presented impacts on
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to review published research on asthma management recommendations in the GINA report. If so, the member
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and prevention, to evaluate the impact of this research is asked to specifically identify modifications that should
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on recommendations in the GINA documents related to be made.
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management and prevention, and to post yearly updates
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on the GINA website. Its members are recognized The entire GINA Science Committee meets twice yearly
leaders in asthma research and clinical practice with
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to discuss each publication that was considered by at
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the scientific credentials to contribute to the task of the least 1 member of the Committee to potentially have
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Committee, and are invited to serve for a limited period an impact on the management of asthma. The full
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and in a voluntary capacity. The Committee is broadly Committee then reaches a consensus on whether to
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representative of adult and pediatric disciplines as well include it in the report, either as a reference supporting
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from diverse geographic regions. current recommendations, or to change the report. In the
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Updates of the 2006 report have been issued in an open vote of the full Committee. Recommendations
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December of each year with each update based on the by the Committee for use of any medication are based
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impact of publications from July 1 of the previous year on the best evidence available from the literature and
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through June 30 of the year the update was completed. not on labeling directives from government regulators.
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Posted on the website along with the updated The Committee does not make recommendations for
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documents is a list of all the publications reviewed by the therapies that have not been approved by at least one
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Process: To produce the updated documents a Pub For the 2012 update, between July 1, 2011 and June 30,
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Med search is done using search fields established by 2012, 386 articles met the search criteria. Of the 386,
the Committee: 1) asthma, All Fields, All ages, only items 19 papers were identified to have an impact on the GINA
with abstracts, Clinical Trial, Human, sorted by Authors; report. The changes prompted by these publications
and 2) asthma AND systematic, All fields, ALL ages, only were posted on the website in December 2012. These
items with abstracts, Human, sorted by author. The first were either: A) modifying, that is, changing the text or
search includes publications for July 1-December 30 for introducing a concept requiring a new recommendation
review by the Committee during the ATS meeting. The to the report; or B) confirming, that is, adding to or
second search includes publications for January 1 – June replacing an existing reference.
30 for review by the Committee during the ERS meeting.
(Publications that appear after June 30 are considered
in the first phase of the following year.) To ensure
publications in peer review journals not captured by
this search methodology are not missed, the respiratory
community is invited to submit papers to the Chair, GINA
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1
The Global Strategy for Asthma Management and Prevention (updated 2012), the updated Pocket Guides and the complete list of references examined by the Committee are available on the GINA website
www.ginasthma.org.
2
Members (2011-2012): H. Reddel, Chair; P. Barnes, N. Barnes, E. Bateman, A. Becker, E. Bel, J. DeJongste, J. Drazen, M. FitzGerald, R. Lemanske, P. O’Byrne, K. Ohta, S. Pedersen, E. Pizzichini, S. Wenzel.
SUMMARY OF RECOMMENDATIONS IN THE 2013 Page 38, right column, last paragraph, add statement
UPDATE and reference: although spacer devices or face masks
differ in their drug delivery, and therefore may not be
A. Additions to the text: interchangeable237.
Reference 237. Lavorini F, Fontana GA. Targeting drugs
Page 33, right column, insert new paragraph: Tiotropium, to the airways: The role of spacer devices. Expert Opin
a long-acting inhaled anticholinergic bronchodilator, Drug Deliv 2009;6:91-102.
has been studied in adults with uncontrolled asthma
and compared with salmeterol, doubling the dose of Page 40, left column, first paragraph replace with: The
inhaled glucocorticosteroid and as add-on to inhaled clinical benefits of intermittent systemic or inhaled
glucocorticosteroids and salmeterol231,233. One study glucocorticosteroids for children with intermittent, viral-
showed comparable bronchodilator effects with no induced wheeze remain controversial. A one-year study
significant changes on asthma control232. Another study of intermittent treatment with inhaled glucocorticosteroids
showed that adding tiotropium to patients not controlled was equally effective as daily treatment, and reduced
on inhaled glucocorticosteroids and long-acting ß2- the total glucocorticosteroid dose threefold in preschool
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agonists improved lung function but not symptoms233. children with frequent wheezing and a high asthma
The studies have been relatively short-term and no effect predictive index238. Some studies in older children found
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on exacerbations has so far been reported. There are no small benefits while another study in young children
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data about these medications in children. found no effects on wheezing symptoms139. There is no
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Reference 231: Peters SP, Kunselman SJ, Icitovic N, evidence to support the use of maintenance low-dose
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Moore WC, Pascual R, Ameredes BT et al. National inhaled glucocorticosteroids for preventing early transient
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Heart, Lung, and Blood Institute Asthma Clinical wheezing136, 139, 199.
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Research Network. Tiotropium bromide step-up therapy Reference 238: Zeiger RS, Mauger D, Bacharier LB,
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for adults with uncontrolled asthma. N Engl J Med Guilbert TW, Martinez FD, Lemanske RF Jr, et al; CARE
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Reference 232: Kerstjens HA, Disse B, Schroder-Babo Daily or intermittent budesonide in preschool children
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W, Bantje TA, Gahlemann M, Sigmund R, Engel M, with recurrent wheezing. N Engl J Med. 2011 Nov
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controlled trial. J Allergy Clin Immunol. 2011 Page 40, Figure 3-5, bullet 6: Modify age range to 2-10
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Reference 233: Bateman ED, Kornmann O, Schmidt Reference 239: Guilbert TW, Mauger DT, Allen DB,
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P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is Zeiger RS, Lemanske RF Jr, Szefler SJ, et al; Childhood
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noninferior to salmeterol in maintaining improved lung Asthma Research and Education Network of the
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function in B16-Arg/Arg patients with asthma. J Allergy National Heart, Lung, and Blood Institute. Growth of
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Clin Immunol. 2011 Aug;128(2):315-22. preschool children at high risk for asthma 2 years after
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Page 34, right column, insert line 15: …. although this 2011 Nov;128(5):956-63.
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Reference 235: Hanania NA, Alpan O, Hamilos DL, et Page 71, right column, replace second bullet and add
al. Omalizumab in severe allergic asthma inadequately reference: Investigate and confirm adherence with
controlled with standard therapy: a randomized trial. Ann treatment. Incorrect or inadequate use of medications
Internal Med 2011;154:573-82. and inhalers405 remains the most common reason for
failure to achieve good control. In patients with difficult-
Page 38, left column, first paragraph, add sentence and to-treat asthma, improved adherence and improved
reference: A systematic review of yoga interventions health outcomes can be achieved with a comprehensive
for asthma found no convincing evidence of benefit; the concordance intervention416.
quality of studies was generally poor236. Reference 416: Gamble J, Stevenson M, Heaney LG.
Reference 236. Posadzki P, Ernst E. Yoga for asthma? A A study of a multi-level intervention to improve non-
systematic review of randomized clinical trials. J Asthma. adherence in difficult to control asthma. Respir Med.
2011 Aug;48(6):632-9. 2011 Sep;105(9):1308-15.
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Page 72, left column insert in last paragraph: Extended poorly controlled asthma: a randomized controlled trial.
follow-up on a small number of patients has provided JAMA. 2012 Jan 25;307(4):373-81.
some additional support for long-term safety of bronchial
thermoplasty417. However, longer-term follow-up of B. References that provided confirmation or update of
larger number of control and active patients is needed previous recommendations.
to assess effectiveness and caution should be used in
selecting patients for this procedure. Page 6, right column, first sentence in paragraph four,
Reference 417: Castro M, Rubin A, Laviolette M, add reference 136.
Hanania NA, Armstrong B, Cox G; AIR2 Trial Study Reference 136: Burke H, Leonardi-Bee J, Hashim A,
Group. Persistence of effectiveness of bronchial Pine-Abata H, Chen Y, Cook DG, Britton JR, McKeever
thermoplasty in patients with severe asthma. Ann TM. Prenatal and passive smoke exposure and incidence
Allergy Asthma Immunol. 2011 Jul;107(1):65-70. of asthma and wheeze: systematic review and meta-
analysis. Pediatrics. 2012 Apr;129(4):735-44.
Page 77, left column replace paragraph on oxygen:
To achieve arterial oxygen saturation of 90% (95% Page 33, right column, insert reference 234 after
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in children), oxygen should be administered by nasal reference 215.
cannulae, by mask, or rarely by head box in some Reference 234: Kemp J, Armstrong L, Wan Y,
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infants. For severe asthma exacerbations, controlled Alagappan VK, Ohlssen D, Pascoe S. Safety of
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oxygen therapy using pulse oximetry to maintain formoterol in adults and children with asthma: a
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oxygen saturation at 90 – 93% is associated with better meta-analysis. Ann Allergy Asthma Immunol. 2011
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physiological outcomes, compared to high flow 100% Jul;107(1):71-8.
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oxygen therapy218, 419. Oxygen therapy should be titrated
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against pulse oximetry to maintain a satisfactory oxygen Page 41, right column, line 10, insert reference 234 after
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saturation219. However, oxygen should not be withheld if reference 75, and in line 17, after reference 169.
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Reference 419. Perrin K, Wijesinghe M, Healy B, Alagappan VK, Ohlssen D, Pascoe S. Safety of
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Wadsworth K, Bowditch R, Bibby S, Baker T, Weatherall formoterol in adults and children with asthma: a
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M, Beasley R. Randomised controlled trial of high meta-analysis. Ann Allergy Asthma Immunol. 2011
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Page 78, left column, end of first paragraph, insert text Reference 414: Shah S, Sawyer SM, Toelle BG, Mellis
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and reference: Two days of oral dexamethasone can CM, Peat JK, Lagleva M, Usherwood TP, Jenkins CR.
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also be used to treat asthma exacerbations, but there are Improving paediatric asthma outcomes in primary health
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concerns about metabolic side-effects if dexamethasone care: a randomised controlled trial. Med J Aust. 2011 Oct
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glucocorticosteroids, either in the short-term245 or over Page 61, right column, paragraph 2 insert reference:
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several weeks, as long as the patient is on maintenance Reference 415: Gehring U, de Jongste JC, Kerkhof M,
inhaled glucocorticosteroids246 (Evidence B). Oldewening M, Postma D, van Strien RT, et al. The 8-year
Reference 420: Kravitz J, Dominici P, Ufberg J, Fisher J, follow-up of the PIAMA intervention study assessing the
Giraldo P. Two days of dexamethasone versus 5 days of effect of mite-impermeable mattress covers. Allergy. 2012
prednisone in the treatment of acute asthma: a Feb;67(2):248-56
randomized controlled trial. Ann Emerg Med. 2011
Aug;58(2):200-4. Page 73, right column end of first paragraph insert
reference 418 after reference 349.
Page 82, right column, paragraph 2, insert in line 4: …in Reference 418: Ortega H, Miller DP, Li H.
adults392-394 or in children422. Characterization of asthma exacerbations in primary care
Reference 422. Holbrook JT, Wise RA, Gold BD, using cluster analysis. J Asthma. 2012 Mar;49(2):158-69.
Blake K, Brown ED, Castro M, Dozor AJ, et al. Writing
Committee for the American Lung Association Asthma Page 81, right column, last sentence under section on
Clinical Research Centers. Lansoprazole for children with Occupational Asthma, insert insert (See also reference 421).
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Reference 421: Fishwick D, Barber CM, Bradshaw LM,
Ayres JG, Barraclough R, Burge S, et al. Standards of
care for occupational asthma: an update. Thorax. 2012
Mar;67(3):278-80.
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INTRODUCTION
Asthma is a serious public health problem throughout the health officials in various countries to design, implement,
world, affecting people of all ages. When uncontrolled, and evaluate asthma care programs to meet local needs.
asthma can place severe limits on daily life, and is The GINA Board of Directors recognizes that this is a
sometimes fatal. difficult task and, to aid in this work, has formed several
groups of global experts, including: a Dissemination and
In 1993, the Global Initiative for Asthma (GINA) was Implementation Committee; the GINA Assembly, a network
formed. Its goals and objectives were described in a 1995 of individuals who care for asthma patients in many
NHLBI/WHO Workshop Report, Global Strategy for Asthma different health care settings; and two regional programs,
Management and Prevention. This Report (revised in 2002 GINA Mesoamerica and GINA Mediterranean. These efforts
and 2006), and its companion documents, have been aim to enhance communication with asthma specialists,
widely distributed and translated into many languages. primary-care health professionals, other health care
A network of individuals and organizations interested in workers, and patient support organizations. The Board of
asthma care has been created and several country-specific Directors continues to examine barriers to implementation
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asthma management programs have been initiated. of the asthma management recommendations, especially
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Yet much work is still required to reduce morbidity and the challenges that arise in primary-care settings and in
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mortality from this chronic disease. developing countries.
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In 2006, the Global Strategy for Asthma Management and While early diagnosis of asthma and implementation of
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Prevention was revised to emphasize asthma management appropriate therapy significantly reduce the socioeconomic
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based on clinical control, rather than classification of burdens of asthma and enhance patients’ quality of life,
the patient by severity. This important paradigm shift for PY
medications continue to be the major component of the
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asthma care reflected the progress made in pharmacologic cost of asthma treatment. For this reason, the pricing of
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care of patients. Many asthma patients are receiving, or asthma medications continues to be a topic for urgent
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have received, some asthma medications. The role of need and a growing area of research interest, as this has
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the health care professional is to establish each patient’s important implications for the overall costs of asthma
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current level of treatment and control, then adjust management. Moreover, a large segment of the world’s
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treatment to gain and maintain control. Asthma patients population lives in areas with inadequate medical facilities
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should experience no or minimal symptoms (including and meager financial resources. The GINA Board of
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at night), have no limitations on their activities (including Directors recognizes that “fixed” international guidelines
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physical exercise), have no (or minimal) requirement for and “rigid” scientific protocols will not work in many
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rescue medications, have near normal lung function, and locations. Thus, the recommendations found in this Report
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experience only very infrequent exacerbations. must be adapted to fit local practices and the availability of
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clinical control described in the 2006 report have been As the GINA Board of Directors expand their work, every
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updated annually. This 2011 update reflects a number of effort will be made to interact with patient and physician
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modifications, described in “Methodology and Summary of groups at national, district, and local levels, and in multiple
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New Recommendations.” As with all previous GINA reports, health care settings, to continuously examine new and
levels of evidence (Table A) are assigned to management innovative approaches that will ensure the delivery of the
recommendations where appropriate in Chapter 4, the Five best asthma care possible. GINA is a partner organization
Components of Asthma Management. Evidence levels are in a program launched in March 2006 by the World
indicated in boldface type enclosed in parentheses after the Health Organization, the Global Alliance Against Chronic
relevant statement—e.g., (Evidence A). Respiratory Diseases (GARD). Through the work of the
GINA Board of Directors, and in cooperation with GARD,
FUTURE CHALLENGES progress toward better care for all patients with asthma
should be substantial in the next decade.
In spite of laudable efforts to improve asthma care over the
past decade, a majority of patients have not benefited from
advances in asthma treatment and many lack even the
rudiments of care. A challenge for the next several years
is to work with primary health care providers and public
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Table A. Description of Levels of Evidence
Evidence Sources of Evidence Definition
Category
A Randomized controlled Evidence is from endpoints of well designed RCTs that provide a consistent
trials (RCTs). Rich body pattern of findings in the population for which the recommendation is made.
of data. Category A requires substantial numbers of studies involving substantial numbers
of participants.
B Randomized controlled Evidence is from endpoints of intervention studies that include only a limited
trials (RCTs). Limited number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of
body of data. RCTs. In general, Category B pertains when few randomized trials exist, they are
small in size, they were under-taken in a population that differs from the target
population of the recommendation, or the results are somewhat inconsistent.
C Nonrandomized trials. Evidence is from outcomes of uncontrolled or non-randomized trials or from
Observational studies. observational studies.
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D Panel consensus judg- This category is used only in cases where the provision of some guidance was
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ment. deemed valuable but the clinical literature addressing the subject was insufficient
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to justify placement in one of the other categories. The Panel Consensus is
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based on clinical experience or knowledge that does not meet the above listed
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criteria.
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AND
CHAPTER
OVERVIEW
DEFINITION
Wheezing appreciated on auscultation of the chest is the
KEY POINTS: most common physical finding.
• Asthma is a chronic inflammatory disorder of the The main physiological feature of asthma is episodic airway
airways in which many cells and cellular elements obstruction characterized by expiratory airflow limitation.
play a role. The chronic inflammation is associated The dominant pathological feature is airway inflammation,
with airway hyperresponsiveness that leads to sometimes associated with airway structural changes.
recurrent episodes of wheezing, breathlessness,
chest tightness, and coughing, particularly at night Asthma has significant genetic and environmental
or in the early morning. These episodes are usually components, but since its pathogenesis is not clear, much
associated with widespread, but variable, airflow of its definition is descriptive. Based on the functional
obstruction within the lung that is often reversible consequences of airway inflammation, an operational
either spontaneously or with treatment. description of asthma is:
• Clinical manifestations of asthma can be controlled Asthma is a chronic inflammatory disorder of the airways
with appropriate treatment. When asthma is in which many cells and cellular elements play a role.
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controlled, there should be no more than occasional The chronic inflammation is associated with airway
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flare-ups and severe exacerbations should be rare. hyperresponsiveness that leads to recurrent episodes of
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wheezing, breathlessness, chest tightness, and coughing,
• Asthma is a problem worldwide, with an estimated
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particularly at night or in the early morning. These
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300 million affected individuals. episodes are usually associated with widespread, but
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variable, airflow obstruction within the lung that is often
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• Although from the perspective of both the patient and reversible either spontaneously or with treatment.
society the cost to control asthma seems high, the PY
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cost of not treating asthma correctly is even higher. Because there is no clear definition of the asthma
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• A number of factors that influence a person’s risk of this complex disease turn to characteristics that can
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developing asthma have been identified. These can be measured objectively, such as atopy (manifested as
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be divided into host factors (primarily genetic) and the presence of positive skin-prick tests or the clinical
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• The clinical spectrum of asthma is highly variable, excessively in response to triggers that have little or
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and different cellular patterns have been observed, no effect in normal individuals), and other measures of
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but the presence of airway inflammation remains a allergic sensitization. Although the association between
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consistent feature. asthma and atopy is well established, the precise links
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influence the risk of developing asthma, and mechanisms. There is now good evidence that the clinical manifestations
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these topics, but rather a brief overview of the background of daily activity, impairment of lung function, and use of
that informs the approach to diagnosis and management rescue medications—can be controlled with appropriate
detailed in subsequent chapters. Further details are found treatment. When asthma is controlled, there should be no
in the reviews and other references cited at the end of the more than occasional recurrence of symptoms and severe
chapter. exacerbations should be rare1.
DEFINITION
Asthma is a disorder defined by its clinical, physiological,
and pathological characteristics. The predominant feature
of the clinical history is episodic shortness of breath,
particularly at night, often accompanied by cough.
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that international differences in asthma symptom work, premature death)17. For example, asthma is a major
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prevalence have been reduced, particularly in the 13-14 cause of absence from work in many countries4-6, including
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year age group, with decreases in prevalence in North Australia, Sweden, the United Kingdom, and the United
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America and Western Europe and increases in prevalence States2,3,18,19. Comparisons of the cost of asthma in different
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in regions where prevalence was previously low. Although regions lead to a clear set of conclusions:
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there was little change in the overall prevalence of current
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wheeze, the percentage of children reported to have had • The costs of asthma depend on the individual patient’s
asthma increased significantly, possibly reflecting greater PY
level of control and the extent to which exacerbations
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awareness of this condition and/or changes in diagnostic are avoided.
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World Health Organization has estimated that 15 million • Non-medical economic costs of asthma are substantial.
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to asthma, representing 1% of the total global disease effective.Families can suffer from the financial burden
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to correlate well with prevalence (Figure 1-1)2,3. There Although from the perspective of both the patient and
society the cost to control asthma seems high, the cost
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described variations in prevalence within and between of not treating asthma correctly is even higher119. Proper
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Figure 1-1. Asthma Prevalence and Mortality2, 3 substantial global burden of asthma can be dramatically
reduced through efforts by individuals, their health care
providers, health care organizations, and local and national
governments to improve asthma control.
Permission for use of this figure obtained from J. Bousquet. DEFINITION AND OVERVIEW 3
*(http://www.ginasthma.org/ReportItem.asp?I1=2&I2=2&intld=94
asthma in developed than in developing nations, in poor
FACTORS INFLUENCING THE
compared totoaffluent
compared affluentpopulations
populationsin in developed
developed nations,
nations,
DEVELOPMENT AND EXPRESSION
FACTORS INFLUENCING THE and in affluent compared to poor populations in developing
and in affluent compared to poor populations in developing
OF ASTHMA
DEVELOPMENT AND EXPRESSION nations—likely reflect lifestyle differences such as
nations—likely reflect lifestyle differences such as exposure
OF ASTHMA toexposure
allergens, toaccess
allergens, accesscare,
to health to health
etc. care, etc.
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immunesusceptibility
asthma response and the
22,23
. Intiming of infectious
addition, exposures
developmental sensiti
are ation) are
themselves themselves
products products
of complex of complex
gene-environment
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during the first years
aspects—such as theofmaturation
life—are emerging as important
of the immune response gene-environment
interactions and areinteractions andfeatures
therefore both are therefore both and
of asthma
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features
risk factorsoffor
asthma and risk factors
the development fordisease.
of the the development
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factors
and themodifying the risk of exposures
timing of infectious asthma in the genetically
during the first years
susceptible
of person. as important factors modifying the risk
life—are emerging of the disease.
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Host Factors
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of asthma in the genetically susceptible person.
Host Factors
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Figure 1-2.
Figure 1-2. Factors
Factors Influencing
Influencing the
the Development
Development Genetic. Asthma has a heritable component, but it is not
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and Expression
and Expression ofof Asthma
Asthma Genetic.
simple.
O Asthma
Current datahas showa heritable
that multiplecomponent,
genes may but itbe is not
simple. in
involved Current data show that
the pathogenesis multiple24,25
of asthma gene
, ands may be
different
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HOST FACTORS
HOST FACTORS involved
genes mayinbe theinvolved
pathogenesisin differentof asthma
ethnic , and different
groups.
24,25 The
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Genetic, e.g.,
Genetic, e.g., search
genesfor may genes linked to
be involved in the development
different of asthma
ethnic groups. The
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Genes pre-disposing
Genes pre-disposing to
to atopy
atopy has focused
search on four
for genes major
linked toareas: production of
the development of asthma
allergen- has
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Genes pre-disposing
Genes pre-disposing to
to airway
airway hyperresponsiveness
hyperresponsiveness specific
focusedIgE onantibodies
four major (atopy); expressionofofallergen-
areas: production airway
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Obesity hyperresponsiveness;
specific IgE antibodiesgeneration of inflammatory
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Sex
Sex mediators, such as cytokines,
hyperresponsiveness; generation chemokines, and growth
of inflammatory
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factors;
mediators, such as cytokines, chemokines, andTh1
and determination of the ratio between growth
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ENVIRONMENTAL FACTORS
ENVIRONMENTAL FACTORS factors; and determination the ratio between Th1 and
hypothesis of asthma)26. Family studies and case-
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Allergens
Allergens Th2 immune responses (as relevant to the hygiene
control association analyses have identified a number
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Indoor: Domestic
Indoor: Domestic mites,
mites, furred
furred animals
animals (dogs,
(dogs, cats,
cats, hypothesis of asthma)26.
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mice), cockroach
mice), cockroach allergen,
allergen, fungi,
fungi, molds,
molds, yeasts
yeasts of chromosomal regions associated with asthma
susceptibility. For example, a tendency to produce an
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Outdoor: Pollens,
Pollens, fungi,
fungi, molds,
molds, yeasts Family studies
level ofand totalcase-control association analyses have
Outdoor: yeasts
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Occupational sensiti
Occupational ers
sensitizers with asthma susceptibility. For example, a tendency to
airway hyperresponsiveness is located near a major locus
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Tobacco smoke
Tobacco smoke produce an elevated level of total
that regulates serum IgE levels on chromosome 5q . serum IgE is co-inherited
27
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Passive smoking
Passive smoking with airway
However, thehyperresponsiveness,
search for a specific gene and a(or gene (or genes)
genes) involved
Active smoking
Active smoking governing airway hyperresponsiveness
in susceptibility to atopy or asthma continues, as results is located near ato
Outdoor/Indoor Air
Outdoor/Indoor Air Pollution
Pollution major
date locus
have beenthatinconsistent
regulates serum 24,25
. IgE levels on
Diet
Diet chromosome 5q 27. However, the search for a specific
Ingene (or genes)
addition to genes involved in susceptibility
that predispose to atopy
to asthma thereor are
Additionally, some characteristics have been linked to an asthma continues, as results to
genes that are associated with the response to asthmadate have been
increased risk
Additionally, for asthma,
some but are not
characteristics havethemselves
been linkedtrue
to an inconsistentFor
treatments.
24,25
.example, variations in the gene encoding
causal factors.
increased The
risk for apparent
asthma, butracial and
are not ethnic differences
themselves true the beta-adrenoreceptor have been linked to differences
in the prevalence
causal factors. Theof apparent
asthma reflect
racialunderlying
and ethnicgenetic
differences inInsubjects’
addition responses
to genes that to βpredispose
2
-agonists28to asthma
. Other thereofare
genes
variances
in with a significant
the prevalence of asthmaoverlay
reflect of socioeconomic
underlying geneticand genes that are associated with the response
interest modify the responsiveness to glucocorticosteroids to asthma 29
environmental
variances with factors. In turn,
a significant the links
overlay between asthma
of socioeconomic and treatments. For example, 30 variations in the gene encoding
and leukotriene modifiers . These genetic markers will
and socioeconomic
environmental status—with
factors. In turn, thea higher prevalence
links between of
asthma the beta-adrenoreceptor
likely become important not haveonly been linked
as risk to differences
factors in the in
and socioeconomic status—with a higher prevalence of pathogenesis of asthma but also as determinants of
asthma in developed than in developing nations, in poor responsiveness to treatment28,30-33.
4 DEFINITION AND OVERVIEW
4 DEFINITION AND OVERVIEW
Obesity. Asthma is more frequently observed in obese children is not straightforward. It depends on the allergen,
subjects (Body Mass Index > 30 kg/m2) and is more difficult the dose, the time of exposure, the child’s age, and
to control124-127,134. Obese people with asthma have lower probably genetics as well.
lung function and more co-morbidities compared with
normal weight people with asthma131. The use of systemic For some allergens, such as those derived from house dust
glucocorticosteroids and a sedentary lifestyle may promote mites and cockroaches, the prevalence of sensitization
obesity in severe asthma patients, but in most instances, appears to be directly correlated with exposure38,41.
obesity precedes the development of asthma. However, although some data suggest that exposure to
house dust mite allergens may be a causal factor in the
How obesity promotes the development of asthma is development of asthma42, other studies have questioned
still uncertain but it may result from the combined effects this interpretation43,44. Cockroach infestation has been
of various factors. It has been proposed that obesity shown to be an important cause of allergic sensitization,
could influence airway function due to its effect on lung particularly in inner-city homes45.
mechanics, development of a pro-inflammatory state, in
addition to genetic, developmental, hormonal or neurogenic In the case of dogs and cats, some epidemiologic
influences35,129,130. In this regard, obese patients have a studies have found that early exposure to these animals
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reduced expiratory reserve volume, a pattern of breathing may protect a child against allergic sensitization or
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that may possibly alter airway smooth muscle plasticity and the development of asthma46-48, but others suggest
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airway function34. Furthermore, the release by adipocytes that such exposure may increase the risk of allergic
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of various pro-inflammatory cytokines and mediators such sensitization47,49-51. This issue remains unresolved.
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as interleukin-6, tumor necrosis factor (TNF)-α, eotaxin,
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and leptin, combined with a lower level of anti-inflammatory The prevalence of asthma is reduced in children raised
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adipokines in obese subjects can favor a systemic in a rural setting, which may be linked to the presence of
inflammatory state although it is unknown how this could PY
endotoxin in these environments52.
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influence airway function131,132.
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Sex. Male sex is a risk factor for asthma in children. Prior associated with the inception of the asthmatic phenotype.
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to the age of 14, the prevalence of asthma is nearly twice Respiratory syncytial virus (RSV) and parainfluenzavirus
D
as great in boys as in girls36. As children get older the produce a pattern of symptoms including bronchiolitis that
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difference between the sexes narrows, and by adulthood parallel many features of childhood asthma53,54. A number
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the prevalence of asthma is greater in women than in men. of long-term prospective studies of children admitted
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The reasons for this sex-related difference are not clear. to the hospital with documented RSV have shown that
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However, lung size is smaller in males than in females at approximately 40% will continue to wheeze or have asthma
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birth37 but larger in adulthood. into later childhood53. On the other hand, evidence also
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Environmental Factors including measles and sometimes even RSV, may protect
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There is some overlap between environmental factors allow specific conclusions to be drawn. Parasite infections
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that influence the risk of developing asthma, and factors do not in general protect against asthma, but infection with
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that cause asthma symptoms—for example, occupational hookworm may reduce the risk120.
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However, the factors that cause some people but not
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others to develop occupational asthma in response to
others to develop occupational asthma in response to the
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Figure 1-3. Examples of Agents Causing Asthma in the same exposures are not well identified. Very high
Selected Occupations* same exposures are not well identified. Very high
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exposures to inhaled irritants may cause “irritant induced
exposures to inhaled irritants may cause “irritant induced
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asthma” (formerly called the reactive airways dysfunctional
asthma” (formerly called the reactive airways dysfunctional
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Occupation/occupational field Agent
syndrome) even in non-atopic persons. Atopy and
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Animal and Plant Proteins syndrome) even in non-atopic persons. Atopy and
tobacco smoking may increase the risk of occupational
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Bakers Flour, amylase tobacco smoking may increase the risk of occupational
sensitization, but screening individuals for atopy is of
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Dairy farmers Storage mites sensiti ation, but screening individuals for atopy is of
limited value in preventing occupational asthma73.73The
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Detergent manufacturing Bacillus subtilis en
enzymes
ymes limited value in preventing occupational asthma . The
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Electrical soldering Colophony (pine resin) most important method of preventing occupational asthma
most important method of preventing occupational asthma
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Health care workers Psyllium, latex asthma133, increases asthma severity, may render patients
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Poultry farmers Poultry mites, droppings, feathers systemic glucocorticosteroids, and reduces the likelihood
74
glucocorticosteroids, and75reduces the likelihood of asthma
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Research workers, veterinarians Locusts, dander, urine proteins of asthma being controlled .
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Sawmill workers, carpenters Wood dust (western red cedar, oak, mahogany, being controlled76.
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maple, eastern white cedar) Exposure to tobacco smoke both prenatally135,136 and
Exposure to tobacco smoke both prenatally and after birth
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Shipping workers Grain dust (molds, insects, grain) after birth is associated with measurable harmful
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MECHANISMS OF ASTHMA B lymphocytes95. An increase in Th2 cell activity may be due in
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part to a reduction in regulatory T cells that normally inhibit Th2
Diet. The role of diet, particularly breast-feeding, in relation
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cells. There may also be an increase in inKT cells, which release
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to the development
Asthma of asthma
is an inflammatory has of
disorder been
the extensively studied
airways, which large amounts of T helper 1 (Th1) and Th2 cytokines96.
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involves several inflammatory cells and multiple mediators of
and, in general, the data reveal that infants fed formulas
Dendritic cells sample allergens from the airway surface and
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intact
that cow’s
result milk or soy protein
in characteristic have a higherchanges
pathophysiological incidence
21,90 of
. migrate to regional lymph nodes, where they interact with
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In ways that are87still not well understood, this pattern ofthose
wheezing illnesses in early childhood compared with
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regulatory T cells and ultimately stimulate production of Th2
fed breast milk .
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inflammation is strongly associated with airway hyper- cells from na ve T cells97.
responsiveness and asthma symptoms.
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Macrophages are increased in number in the airways and may
Some data also suggest that certain characteristics
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be activated by allergens through low-affinity IgE receptors to
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of Western
Airway diets, suchInas
Inflammation increased use of processed
Asthma
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inflammatory response98.
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vegetables),
The increased
clinical spectrum n-6 polyunsaturated
of asthma fatty and
is highly variable, acid
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feature. The airway inflammation in asthma is persistent increase may even be due to glucocorticosteroid therapy99 .
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disease 88
.
even though symptoms are episodic, and the relationship
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between
diet. Thethe roleseverity
of diet,ofparticularly
asthma and the intensity of
breast-feeding, in
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MECHANISMS OF
relation to the development of asthma has. been
inflammation is not clearly ASTHMA
established 91,92
The Figure
Figure 1-4:
1-5: Inflammatory CellsCells
Airway Structural in Asthmatic
Involved Airways
in the
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Pathogenesis of Asthma
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inflammationstudied
extensively affectsand,all airways
in general, including
the data in most
revealpatients
that Mast cells: Activated mucosal mast cells release
Asthma isrespiratory
an inflammatory disorder of its
thephysiological
airways, which
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involves several inflammatory cells and multiple mediators Airway epithelial cells their mechanical environment,
effects
a higherare most pronounced
incidence of whee ing in illnesses
medium-si ed bronchi.
in early childhood prostaglandin D2)inflammatory
93
. These cells are activated by allergens
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inflammation
non-allergic, is strongly
or aspirin-induced,associated and at with
all ages. hyper-
airway mast cell numbers in airway smooth muscle may be linked to
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effectiveness
survival; IL-4, asthma
which is treatment,
important because
for cell differentiation;
invariant natural killer T tocells and Tchanges,
helper often
2 lymphocytes
IL-13, needed
association
IL-13, needed
Prostaglandin with for for
the IgE
D2IgE presence formation.
is aformation. of inflammation
bronchoconstrictor in asthma
derived .
predominantly
108 ness,
airwayAirway the characteristic
thickening
hyperresponsiveness. due functional
structural abnormality
Airway of asthma,
termed
hyperresponsive-
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(Th2),
results which
“remodeling,”
in release
airwaymaynarrowing mediators
be importantininamore that contribute
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with asthma
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from mast cells and is involved in Th2 cell recruitment to the airways. ness,
Histamine is released from mast
Prostaglandin D2 is a bronchoconstrictor derived predominantly
Histamine is released from mast cells
cells and
and contributes
contributes to
to not the
symptoms fully characteristic
(Figure 1-4). functional
therapy.abnormality
Structural cells of the of asthma,
airways a also
reversible by current
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bronchoconstriction
from mast cells and is involved
bronchoconstriction and
and to to thein Th2
the inflammatory
cell recruitment
inflammatory response.
response. to the airways. response
results in to a stimulus
airway narrowing thatinwoulda patientbe innocuous
with asthma in in
produce inflammatory mediators, and contribute to the
Structural changes in the airways. In addition to the normal
Mucusperson.
hypersecretion In turn, maythis airway
lead to be narrowing
luminal leads
occlusion a to
in(“mucus
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Nitric oxide (NO), a potent vasodilator,
vasodilator, is is produced predominantly response
persistence to ofa stimulus that would innocuous 1-5).
Nitric oxide (NO), a potent produced predominantly plugging”) andinflammation
islimitation
a productand of in various
increased ways
mucus (Figure
secretion and
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Structural
from the
from action
the action response,
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of inducible
of inducible there
nitric
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airways.
oxide
oxide In addition
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epithelial variable
normal airflow
person.exudates.In turn, this intermittent
airway symptoms.
leads to Airway
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inflammatorymediators. Over 100 different arere-
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cells .. Exhaled described
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NO
NO is as airway
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is increasingly remodeling,
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used to in the
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to monitor the hyperresponsiveness
variable airflow limitation isand linked to both inflammation
intermittent symptoms. and
Airway
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cells 107
105
Exhaled increasingly being monitor the
now recognized to be involved in asthma and mediate the
airways
changes, of
effectiveness asthma
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described
of asthma patients as (Figure
treatment,
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treatment, because1-7).of
of Some
remodeling,
because its inof106
its reported
reported these
the pair of the airways and
hyperresponsiveness is partially
isresponse
linked toinboth reversible with therapy.
inflammation and1-6).
re-
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complex inflammatory the airways (Figure
association
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association
airways with
asthma the
the presence
related
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patients of
of inflammation
to the(Figure
presence severity in
of theSome
inflammation
1-7). asthma
disease
in asthma108
of these .. may
and airway
Its
pair
Oof thehyperresponsiveness.
mechanisms airways(Figure 1-9) are reversible
and is partially incompletely
Airway withunderstood.
hyperresponsive-
therapy.
result in relatively irreversible narrowing of the airways
and may . Itsness, the characteristic functional abnormalityunderstood.
of asthma,
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109, 110
changes are related
Prostaglandin
Prostaglandin D isto
D22 is the severity of the
a bronchoconstrictor
a bronchoconstrictor disease
derived
derived predominantly
predominantly mechanisms
Structural changes (Figure in the 1-9) are incompletely
airways. In addition to the
These changes may represent repair inofresponse thetoairways. results in airway narrowing in a patient with asthma in
T
from
frominmast
result mast cells
cells and
relatively and is involved
is involved
irreversible innarrowing
in Th2
Th2 cell recruitment
cell recruitment to the
the airways
to airways.
109, 110
. Figure 1-9:response, Mechanisms of are
Airway Hyperresponsiveness
O
Figure
inflammatory
Figure 1-7: 1-7: Structural
Structural
response, there Changes
Changes in Asthmaticstructural
are characteristic
in Asthmatic Airways
Airways variable airflow
from increased
Excessive limitation
volume
contraction
and/or and intermittent
contractility symptoms.
airway smooth Airway
toof airway smooth muscle may result
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changesmuscleare cellsrelated
. the severity of the disease and may
changes, often described as airway remodeling, in the hyperresponsiveness is linked to both inflammation and re-
112
Figure 1-7: Structural Changes in Asthmatic Airways from increased volume and/or contractility of airway smooth 107,108
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Subepithelial
Subepithelial fibrosis
fibrosis results
results fromfromthe thedeposition
depositionofofcollagen
collagenfibers fibers result in cells
relatively irreversible narrowing of the airways .
airways of asthma patients (Figure 1-7). Some of these pair
muscle of the airways
. and is partially
Uncoupling of airway contraction as a result of inflammatory reversible with therapy.
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112
and
and proteoglycans
proteoglycans under under the the basement
basementmembrane
membraneand andisisseen seenin in These changes may represent repair in response to chronic
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changes
Subepithelial are related
fibrosis resultsto thefrom severity of the
the deposition ofdisease
collagenand
onsetofofmay
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mechanisms in the airway (Figure
wall may 1-9)leadareatoincompletely understood.
excessive narrowing of the
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all asthmatic
all asthmatic patients,
patients, including
including children,
children,even
even before
before the
theonset Uncoupling
inflammation. of airway contraction as result of inflammatory
and proteoglycans
result in relatively under the basement
irreversible membrane
narrowing andairways
ofFibrosis
the is seen 109, in 110 airways and a loss of the maximum plateau of contraction found in
symptoms
symptoms but
but maymay be be influenced
influencedby bytreatment.
treatment. Fibrosis occursinin .
occurs changes in the airway wall may lead to excessive narrowing of the113
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all asthmatic patients, including children, even before the onset of normal ariways when bronchoconstrictor substances are inhaled .
These
other changes
other layers
layers for
for the
themayairway
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wall, withrepair
wall, with deposition
depositionin response
ofofcollagen
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and airways
Figureand a loss
1-9: of the maximum
Mechanisms plateauHyperresponsiveness
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113
other layers for the airway wall, with deposition of collagen and
proteoglycans. Airway narrowing
amplifies airway
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Airway
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division),
division), and and contributes
contributes to tothe
theincreased
increasedthickness
thicknessofofthe theairway
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Sensory
112
nerves to reasons
. may
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114 of airway narrowing
. ed by inflammation, leading to
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and
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by proteoglycans
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exaggerated bronchoconstriction in response to sensory stimuli. narrowing of the
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88DEFINITION
DEFINITION AND
ANDOVERVIEW
OVERVIEW
normal person. In turn, this airway narrowing leads to
al variable airflow limitation and intermittent symptoms. Airway
hyperresponsiveness is linked to both inflammation and re-
e pair of the airways and is partially reversible with therapy.
may Its mechanisms (Figure 1-9) are incompletely understood.
110
.
Figure 1-9: Mechanisms
Figure 1-9: Mechanisms of
of Airway
Airway Hyperresponsiveness
Hyperresponsiveness Smoking and asthma. Tobacco smoking makes
asthma more difficult to control, results in more frequent
Excessive contraction
Excessive contraction of of airway
airway smooth
smooth muscle may result
muscle may result exacerbations and hospital admissions, and produces
ys from increased
from increased volume
volume and/or
and/or contractility
contractilityofofairway
airwaysmooth
smooth a more rapid decline in lung function and an increased
muscle
muscle cells
cells112
112
.. risk of death117. Asthma patients who smoke may have a
rs neutrophil-predominant inflammation in their airways and
Uncoupling of
Uncoupling of airway
airway contraction
contractionas
as aa result
result of
ofinflammatory
inflammatory
n
changes in
changes in the
the airway
airway wall
wall may
may lead
lead to
to excessive
excessive narrowing
narrowing ofofthe
the are poorly responsive to glucocorticosteroids121,122.
airways and
airways and a loss of
a loss of the
the maximum
maximum plateau
plateau ofof contraction
contractionfound
foundinin
n
normal ariways
normal airways when
when bronchoconstrictor
bronchoconstrictorsubstances
substancesare areinhaled
inhaled.
113
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amplifies airway
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Initiative for Asthma (GINA). Available from http://www.
Acute exacerbations. Transient worsening of asthma may
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t may occur as a result of exposure to risk factors for ginasthma. org 2004.
occur as a result of exposure to risk factors for asthma
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asthma symptoms, or “triggers,” such as exercise, air
symptoms113, or “triggers,” such as exercise, air pollutants, 4. Yan DC, Ou LS, Tsai TL, Wu WF, Huang JL. Prevalence and
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and even certain weather conditions, e.g., thunderstorms86.
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severity of symptoms of asthma, rhinitis, and eczema in 13-
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More prolonged worsening is usually due to viral infections to 14-year-old children in Taipei, Taiwan. Ann Allergy Asthma
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95. Larche M, Robinson DS, Kay AB. The role of T lymphocytes
80. Nafstad P, Kongerud J, Botten G, Hagen JA, Jaakkola JJ. in the pathogenesis of asthma. J Allergy Clin Immunol
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1997;8(3):293-7. 96. Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J,
81. Environmental tobacco smoke: a hazard to children. American Kronenberg M, et al. CD4+ invariant T-cell-receptor+
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103. Leff AR. Regulation of leukotrienes in the management of Weiland SK, Williams H; ISAAC Phase Three Study Group.
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104. Barnes PJ. Cytokine modulators as novel therapies for asthma. sectional surveys. Lancet 2006 Aug 26;368(9537):733-43.
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M, Bellia V, et al. Airway remodeling in asthma. Chest to inhaled corticosteroids or leukotriene receptor antagonists in
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129. Schaub B, von ME. Obesity and asthma, what are the links?
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130. Weiss ST, Shore S. Obesity and asthma: directions for
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131. Shore SA. Obesity and asthma: possible mechanisms. J
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133. O’Byrne PM, Lamm CJ, Busse WW, Tan WC, Pedersen S;
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134. Noal RB, Menezes AM, Macedo SE, Dumith SC. Childhood
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JC, Rosner BA, Strunk RC, Zeiger RS, Weiss ST; Childhood
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AND
CHAPTER
DIAGNOSIS
CLASSIFICATION
KEY POINTS: CLINICAL DIAGNOSIS
• A clinical diagnosis of asthma is often prompted
by symptoms such as episodic breathlessness, Medical History
wheezing, cough, and chest tightness.
Symptoms. A clinical diagnosis of asthma is often
• Measurements of lung function (spirometry or peak prompted by symptoms such as episodic breathlessness,
expiratory flow) provide an assessment of the wheezing, cough, and chest tightness1. Episodic symptoms
severity of airflow limitation, its reversibility, and its after an incidental allergen exposure, seasonal variability
variability, and provide confirmation of the diagnosis of symptoms and a positive family history of asthma and
of asthma. atopic disease are also helpful diagnostic guides. Asthma
associated with rhinitis may occur intermittently, with the
• Measurements of allergic status can help to identify patient being entirely asymptomatic between seasons or it
risk factors that cause asthma symptoms in individual may involve seasonal worsening of asthma symptoms or
patients. a background of persistent asthma. The patterns of these
symptoms that strongly suggest an asthma diagnosis are
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• Extra measures may be required to diagnose asthma variability; precipitation by non-specific irritants, such as
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in children 5 years and younger and in the elderly, smoke, fumes, strong smells, or exercise; worsening at
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and occupational asthma. night; and responding to appropriate asthma therapy. In
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some sensitized individuals, asthma may be exacerbated
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• For patients with symptoms consistent with by seasonal increases in specific aeroallergens2. Examples
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asthma,but normal lung function, measurement include Alternaria, and birch, grass, and ragweed pollens.
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of airway responsiveness may help establish the
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diagnosis. Useful questions to consider when establishing a diagnosis
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of asthma are described in Figure 2-1.
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• Asthma has been classified by severity in previous
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treatment.
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• To aid in clinical management, a classification of • Does the patient wheeze or cough after exercise?
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asthma by level of control is recommended. • Does the patient experience wheezing, chest tightness, or
cough after exposure to airborne allergens or pollutants?
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• Clinical control of asthma is defined as: • Do the patient's colds “go to the chest” or take more than 10
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-No nocturnal symptoms or awakening because Cough-variant asthma. Patients with cough-variant
of asthma asthma3 have chronic cough as their principal, if not only,
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-No (twice or less/week) need for reliever treatment symptom. It is particularly common in children, and is often
-Normal or near-normal lung function more problematic at night; evaluations during the day can
-No exacerbations be normal. For these patients, documentation of variability
in lung function or of airway hyperresponsiveness, and
INTRODUCTION possibly a search for sputum eosinophils, are particularly
important4. Cough-variant asthma must be distinguished
A correct diagnosis of asthma is essential if appropriate from so-called eosinophilic bronchitis in which patients
drug therapy is to be given. Asthma symptoms may be have cough and sputum eoinophils but normal indices of
intermittent and their significance may be overlooked by lung function when assessed by spirometry and airway
patients and physicians, or, because they are non-specific, hyperresponsiveness5.
they may result in misdiagnosis (for example of wheezy
bronchitis, COPD, or the breathlessness of old age). This Other diagnoses to be considered are cough-induced
is particularly true among children, where misdiagnoses by angiotensin-converting-enzyme (ACE) inhibitors,
include various forms of bronchitis or croup, and lead to gastroesophageal reflux, postnasal drip, chronic sinusitis,
inappropriate treatment. and vocal cord dysfunction6.
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with an inhaled β2-agonist before exercise, supports a function do not correlate strongly with symptoms or other
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diagnosis of asthma. Some children with asthma present measures of disease control in either adults11 or children12,
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only with exercise-induced symptoms. In this group, or these measures provide complementary information about
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when there is doubt about the diagnosis, exercise testing different aspects of asthma control.
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is helpful. An 8-minute running protocol is easily performed
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in clinical practice and can establish a firm diagnosis of Various methods are available to assess airflow limitation,
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asthma9. but two methods have gained widespread acceptance for
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use in patients over 5 years of age. These are spirometry,
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Physical Examination
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particularly the measurement of forced expiratory volume in
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Because asthma symptoms are variable, the physical expiratory flow (PEF) measurement.
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The most usual abnormal physical finding is wheezing Predicted values of FEV1, FVC, and PEF based on age,
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on auscultation, a finding that confirms the presence of sex, and height have been obtained from population
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airflow limitation. However, in some people with asthma, studies. These are being continually revised, and with the
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wheezing may be absent or only detected when the person exception of PEF for which the range of predicted values is
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exhales forcibly, even in the presence of significant airflow too wide, they are useful for judging whether a given value
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limitation. Occasionally, in severe asthma exacerbations, is abnormal or not. If precision is needed, for example,
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severity, such as cyanosis, drowsiness, difficulty speaking, The terms reversibility and variability refer to changes in
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tachycardia, hyperinflated chest, use of accessory muscles, symptoms accompanied by changes in airflow limitation
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value of three recordings taken. As ethnic differences in 700
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spirometric values have been demonstrated, appropriate 600
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predictive equations for FEV1 and FVC should be
PEF L/min
500
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established for each patient. The normal range of values
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is wider and predicted values are less reliable in young 400
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people (< age 20) and in the elderly (> age 70). Because
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300
0
than these suggest airflow limitation.
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-1 0 1 2 3 4 5 6 7 8 9 10
Weeks of Inhaled Glucocorticosteroid Treatment
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Peak expiratory flow measurements are made using *PEF chart of a 27-year-old man with long-standing, poorly controlled asthma, before
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and after the start of inhaled glucocorticosteroid treatment. With treatment, PEF
a peak flow meter and can be an important aid in both
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levels increased, and PEF variability decreased, as seen by the increase in Min%Max
diagnosis and monitoring of asthma. Modern PEF meters (lowest morning PEF/highest PEF %) over 1 week.
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patients to use in home settings for day-to-day objective PEF monitoring is valuable in a subset of asthmatic
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of lung function such as FEV1 in either adults16 or children17. • To confirm the diagnosis of asthma. Although
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PEF can underestimate the degree of airflow limitation, spirometry is the preferred method of documenting
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particularly as airflow limitation and gas trapping worsen. airflow limitation, a 60 L/min (or 20% or more of pre-
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Because values for PEF obtained with different peak flow bronchodilator PEF) improvement after inhalation of
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meters vary and the range of predicted values is too wide, a bronchodilator20, or diurnal variation in PEF of more
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PEF measurements should preferably be compared to the than 20% (with twice daily readings, more than 10% 21)
patient’s own previous best measurements18 using his/her suggests a diagnosis of asthma.
own peak flow meter. The previous best measurement is
usually obtained when the patient is asymptomatic or on full • To improve control of asthma, particularly in patients
treatment and serves as a reference value for monitoring with poor perception of symptoms10. Asthma
the effects of changes in treatment. management plans which include self-monitoring
of symptoms or PEF for treatment of exacerbations
Careful instruction is required to reliably measure PEF have been shown to improve asthma outcomes22. It is
because PEF measurements are effort-dependent. Most easier to discern the response to therapy from a PEF
commonly, PEF is measured first thing in the morning chart than from a PEF diary, provided the same chart
before treatment is taken, when values are often close to Inhaled glucocorticosteroids
800
700
600
commenced
format is consistently used23.
PEF L/min
500
400
300
200
310/700 500/710 620/720
100
= 44% = 70% = 86%
0
-1 0 1 2 3 4 5 6 7 8 9 10
Weeks of Inhaled Glucocorticosteroid Treatment
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
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asthma symptoms, sometimes called “triggers,” and the control does not improve control or enable reduction in
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test results are usually expressed as the provocative dose of inhaled glucocorticosteroid55.
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concentration (or dose) of the agonist causing a given fall
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(often 20%) in FEV1 (Figure 2-3). These tests are sensitive Measurements of allergic status. Because of the strong
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for a diagnosis of asthma, but have limited specificity25. association between asthma and allergic rhinitis, the
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This means that a negative test can be useful to exclude a presence of allergies, allergic diseases, and allergic rhinitis
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diagnosis of persistent asthma in a patient who is not taking in particular, increases the probability of a diagnosis of
inhaled glucocorticosteroid treatment, but a positive test PY
asthma in patients with respiratory symptoms. Moreover,
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does not always mean that a patient has asthma26. This is the presence of allergies in asthma patients (identified by
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because airway hyperresponsiveness has been described skin testing or measurement of specific IgE in serum) can
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in patients with allergic rhinitis27 and in those with airflow help to identify risk factors that cause asthma symptoms in
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limitation caused by conditions other than asthma, such individual patients. Deliberate provocation of the airways
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as cystic fibrosis28, bronchiectasis, and chronic obstructive with a suspected allergen or sensitizing agent may be
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pulmonary disease (COPD)29. helpful in the occupational setting, but is not routinely
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Figure 2-3. Measuring Airway Responsiveness* diagnosis, requires considerable expertise and can result in
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life-threatening bronchospasm35.
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and has to be based largely on clinical judgment and an • Recurrent viral lower respiratory tract infections
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assessment of symptoms and physical findings. Since •
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Cystic fibrosis
the use of the label “asthma” for wheezing in children has
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• Bronchopulmonary dysplasia
important clinical consequences, it must be distinguished •
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Tuberculosis
from other causes persistent and recurrent wheeze.
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• Congenital malformation causing narrowing of the
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intrathoracic airways
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Episodic wheezing and cough is very common even in • Foreign body aspiration
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children who do not have asthma and particularly in those • Primary ciliary dyskinesia syndrome
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under age 336. Three categories of wheezing have been • Immune deficiency
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prematurity and parental smoking. cardiovascular signs suggest an alternative diagnosis and
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These children typically have recurrent episodes A useful method for confirming the diagnosis of
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of wheezing associated with acute viral respiratory asthma in children 5 years and younger is a trial of
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infections, have no evidence of atopy37 and, unlike treatment with short-acting bronchodilators and inhaled
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children in the next category of late onset wheezing/ glucocorticosteroids. Marked clinical improvement during
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are still present at age 12 in a large proportion of other measures recommended for older children and
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children. The cause of the episode is usually the adults such as airway responsiveness and markers of
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respiratory syncytial virus in children younger than airway inflammation is difficult and several require complex
age 2, while other viruses predominate in older equipment41 making them unsuitable for routine use.
preschool children. However, children 4 to 5 years old can be taught to use a
PEF meter, but to ensure reliability parental supervision is
• Late-onset wheezing/asthma. These children have required42.
asthma which often persists throughout childhood
and into adult life38, 39. They typically have an Older Children and Adults
atopic background, often with eczema, and airway
pathology is characteristic of asthma. A careful history and physical examination, together
with the demonstration of reversible and variable airflow
The following categories of symptoms are highly suggestive obstruction (preferably by spirometry), will in most
of a diagnosis of asthma: frequent episodes of wheeze instances confirm the diagnosis. The following categories of
(more than once a month), activity-induced cough or alternative diagnoses need to be considered:
wheeze, nocturnal cough in periods without viral infections,
Because asthma is a common disease, it can be found Since the management of occupational asthma frequently
in association with any of the above diagnoses, which requires the patient to change his or her job, the diagnosis
complicates the diagnosis as well as the assessment of carries considerable socioeconomic implications and it is
severity and control. This is particularly true when asthma important to confirm the diagnosis objectively. This may
is associated with hyperventilation, vocal cord dysfunction, be achieved by specific bronchial provocation testing46,
or COPD. Careful assessment and treatment of both the although there are few centers with the necessary facilities
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asthma and the comorbidity is often necessary to establish for specific inhalation testing. Another method is to monitor
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IB
the contribution of each to a patient’s symptoms. PEF at least 4 times a day for a period of 2 weeks when
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the patient is working and for a similar period away from
The Elderly
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work47-50. The increasing recognition that occupational
D
asthma can persist, or continue to deteriorate, even
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Undiagnosed asthma is a frequent cause of treatable in the absence of continued exposure to the offending
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respiratory symptoms in the elderly, and the frequent agent51, emphasizes the need for an early diagnosis so
presence of comorbid diseases complicates the diagnosis. PY
that appropriate strict avoidance of further exposure and
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Wheezing, breathlessness, and cough caused by left pharmacologic intervention may be applied. Publications
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T
ventricular failure is sometimes labeled “cardiac asthma,” provide an evidence-based approach to the identification
O
a misleading term, the use of which is discouraged. of occupational asthma and compare specific inhalation
N
O
The presence of increased symptoms with exercise and challenge testing with alternative tests for confirming the
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ventricular failure. Use of beta-blockers, even topically (for Distinguishing Asthma from COPD
E R
and physical examination, combined with an ECG and Both asthma and COPD are major chronic obstructive
M
chest X-ray, usually clarifies the picture. In the elderly, airways diseases that involve underlying airway
D
distinguishing asthma from COPD is particularly difficult, inflammation. COPD is characterized by airflow limitation
TE
and may require a trial of treatment with bronchodilators that is not fully reversible, is usually progressive, and is
H
IG
Asthma treatment and assessment and attainment of asthma who are exposed to noxious agents (particularly
O
control in the elderly are complicated by several factors: cigarette smoking) may develop fixed airflow limitation and
C
poor perception of symptoms, acceptance of dyspnea as a mixture of “asthma-like” inflammation and “COPD-like”
being “normal” in old age, and reduced expectations of inflammation. Thus, even though asthma can usually be
mobility and activity. distinguished from COPD, in some individuals who develop
chronic respiratory symptoms and fixed airflow limitation,
Occupational Asthma it may be difficult to differentiate the two diseases. A
symptom-based questionnaire for differentiating COPD
Asthma acquired in the workplace is a diagnosis that and asthma for use by primary health care professionals is
is frequently missed. Because of its insidious onset, available53,54.
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
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identified.
severe asthma or in the context of research.
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Phenotype
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Asthma Control
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There is increasing awareness of heterogeneity in the
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Asthma control may be defined in a variety of ways. In
manifestations of asthma and in its response to treatment.
R
lay terms, control may indicate disease prevention, or
O
This is often described in terms of ‘phenotypes’57,58, the
even cure. However, in asthma, where neither of these
PY
characteristics which result from the interaction between a
are realistic options at present, it refers to control of the
O
patient’s genetic makeup and their environment. Several
manifestations of disease. The aim of treatment should be
C
T
O
N
Daytime symptoms None (twice or More than twice/week Three or more features of
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asthma*†
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symptoms/awakening
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B. Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side-effects)
Features that are associated with increased risk of adverse events in the future include:
Poor clinical control, frequent exacerbations in past year*, ever admission to critical care for asthma, low
FEV1, exposure to cigarette smoke, high dose medications
* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate
† By definition, an exacerbation in any week makes that an uncontrolled asthma week
‡ Without administration of bronchodilator.
Lung function is not a reliable test for children 5 years and younger
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pharmacological agents are more effective in improving guided treatment appears, primarily, to be of value in
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IB
features of clinical control, while others are relatively more asthma phenotypes in which there is dissociation between
TR
effective at reducing exacerbations. Thus, for some patient measures of clinical control and airway inflammation. For
IS
phenotypes, treatment may be selected to address the example, treatment based on the proportion of eosinophils
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predominant problem. in sputum has resulted in a reduction of exacerbations
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or minimization of doses of inhaled glucocorticosteroids
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Figure 2-4 describes the clinical characteristics of in patients with uncontrolled asthma in spite of moderate
Controlled, Partly Controlled and Uncontrolled asthma. This PY
levels of treatment77,78.
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is a working scheme based on current opinion and has not
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T
been formally validated. However, this classification has However, in primary care, because of the cost and/or
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been shown to correlate well with the Asthma Control Test67 unavailability of tests such as endobronchial biopsy and
N
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and with assessment of asthma control according to the measurement of sputum eosinophils and exhaled nitric
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US National Expert Panel Report 3 guidelines68,69. In clinical oxide30-34, the current recommendation is that treatment
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practice, this classification should be used in conjunction should be aimed at controlling the clinical features of
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with an assessment of the patient’s clinical condition and disease, including lung function abnormalities.
ER
Asthma Severity
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control of asthma have been developed, which score the For patients not receiving inhaled glucocorticosteroid
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goals of treatment as continuous variables and provide treatment, previous GINA documents subdivided asthma
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IG
numerical values to distinguish different levels of control. by severity based on the level of symptoms, airflow
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Examples of validated instruments are the Asthma Control limitation, and lung function variability into four categories:
PY
the Asthma Control Test (ACT) (www.asthmacontrol. Severe Persistent, although this classification was often
C
com)71, the Childhood Asthma Control Test (C-ACT)72, erroneously applied to patients already on treatment79.
the Asthma Therapy Assessment Questionnaire (ATAQ) A copy of this classification system is archived at
(www.ataqinstrument.com)73, and the Asthma Control www.ginasthma.org. It is important to recognize, however,
Scoring System74. Few of these instruments include a that asthma severity involves both the severity of the
measure of lung function. They are being promoted for underlying disease and its responsiveness to treatment80.
use not only in research but for patient care as well, even Thus, asthma could present with severe symptoms and
in the primary care setting. Some are suitable for self- airflow obstruction, but become completely controlled with
assessment of asthma control by patients75, and some low-dose treatment. In addition, severity is not a static
are available in many languages, on the Internet, and in feature of an individual patient’s asthma, but may change
paper form and may be completed by patients prior to, or over months or years. The main limitation of this previous
during, consultations with their health care provider. They method of classification of asthma severity was its poor
have the potential to improve the assessment of asthma value in predicting what treatment would be required and
control, providing a reproducible objective measure that what a patient’s response to that treatment might be. For
may be charted over time (week by week or month by this reason, an assessment of asthma control at initial
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severe could become mild. 10. Killian KJ, Watson R, Otis J, St Amand TA, O’Byrne PM.
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Symptom perception during acute bronchoconstriction. Am J
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Terminology around asthma severity is confusing because Respir Crit Care Med 2000;162(2 Pt 1):490-6.
IS
“severity” is also used to describe the magnitude of airway
11. Kerstjens HA, Brand PL, de Jong PM, Koeter GH, Postma DS.
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obstruction or the intensity of symptoms. Patients will often
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perceive their asthma as severe if they have intense or Influence of treatment on peak expiratory flow and its relation to
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frequent symptoms, but it is important to convey that this airway hyperresponsiveness and symptoms. The Dutch CNSLD
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may merely represent inadequate treatment. Because the Study Group. Thorax 1994;49(11):1109-15.
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terms “control” and “severity” are used in other contexts
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12. Brand PL, Duiverman EJ, Waalkens HJ, van Essen-
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of asthma.
and hyperresponsiveness during long-term treatment with
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and level of exposure in occupational asthma due to
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54. Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ, Isonaka prospective health maintenance organization-based study.
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74. Boulet LP, Boulet V, Milot J. How should we quantify asthma
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75. Schatz M, Mosen DM, Kosinski M, Vollmer WM, Magid DJ,
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ASTHMA
CHAPTER
TREATMENTS
KEY POINTS: ASTHMA MEDICATIONS: ADULTS
• Medications to treat asthma can be classified as
controllers or relievers. Controllers are medications
Route of Administration
taken daily on a long-term basis to keep asthma
under clinical control chiefly through their anti-
Asthma treatment for adults can be administered in
inflammatory effects. Relievers are medications
different ways—inhaled, orally or parenterally (by
used on an as-needed basis that act quickly
subcutaneous, intramuscular, or intravenous injection).
to reverse bronchoconstriction and relieve its
The major advantage of inhaled therapy is that drugs are
symptoms.
delivered directly into the airways, producing higher local
• Asthma treatment can be administered in different concentrations with significantly less risk of systemic side
ways—inhaled, orally, or by injection. The major effects.
advantage of inhaled therapy is that drugs are
delivered directly into the airways, producing higher Inhaled medications for asthma are available as
pressurized metered-dose inhalers (MDIs), breath-actuated
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local concentrations with significantly less risk of
MDIs, dry powder inhalers (DPIs), soft mist inhalers, and
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systemic side effects.
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nebulized or “wet” aerosols* . Inhaler devices differ in
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• Inhaled glucocorticosteroids are the most effective their efficiency of drug delivery to the lower respiratory
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controller medications currently available. tract, depending on the form of the device, formulation of
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medication, particle size, velocity of the aerosol cloud or
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• Rapid-acting inhaled β2-agonists are the medications plume (where applicable), and ease with which the device
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of choice for relief of bronchoconstriction can be used by the majority of patients. Individual patient
and for the pretreatment of exercise-induced
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preference, convenience, and ease of use may influence
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bronchoconstriction, in both adults and children of
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not only the efficiency of drug delivery but also patient
all ages.
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treatment.
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INTRODUCTION
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The goal of asthma treatment is to achieve and maintain upon the atmospheric ozone layer, and are being replaced
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medications taken daily on a long-term basis to keep change in efficacy at the same nominal dose2. However, for
asthma under clinical control chiefly through their anti- some glucocorticosteroids, the HFA formulations provide
inflammatory effects. They include inhaled and systemic an aerosol of smaller particle size that results in less oral
glucocorticosteroids, leukotriene modifiers, long- deposition (with associated reduction in oral side effects),
acting inhaled β2-agonists in combination with inhaled and correspondingly greater lung deposition3-5. Clinicians
glucocorticosteroids, sustained-release theophylline, are advised to consult the package inserts of each product
cromones, and anti-IgE. Inhaled glucocorticosteroids to confirm the recommended dose equivalent to currently
are the most effective controller medications currently used drugs. Some of these comparisons are provided in
available. Relievers are medications used on an as-needed Figure 3-1.
basis that act quickly to reverse bronchoconstriction and
relieve its symptoms. They include rapid-acting inhaled β2-
agonists, inhaled anticholinergics, short-acting theophylline,
and short-acting oral β2-agonists.
30 ASTHMA TREATMENTS
*Information on various inhaler devices available can be found on the GINA Website
(http://www.ginasthma.org).
Pressurized MDIs may be used by patients with asthma of clinical control follows within weeks to months in a
of any severity, including during exacerbations. Breath- proportion of patients14,15.
actuated aerosols may be helpful for patients who have
difficulty using the “press and breathe” pressurized MDI6. Inhaled glucocorticosteroids differ in potency and
Soft mist inhalers appear to require less coordination. bioavailability, but because of relatively flat dose-response
Dry powder inhalers are generally easier to use, but they relationships in asthma relatively few studies have been
require a minimal inspiratory flow rate and may prove able to confirm the clinical relevance of these differences191.
difficult for some patients. DPIs differ with respect to the Figure 3-1 lists approximately equipotent doses of different
fraction of ex-actuator dose delivered to the lung. For some inhaled glucocorticosteroids based upon the available
drugs, the dose may need to be adjusted when switching efficacy literature, but the categorization into dosage
from an MDI6 to a DIP7. Nebulized aerosols are rarely categories does not imply that clear dose-response
indicated for the treatment of chronic asthma in adults8. relationships have been demonstrated for each drug.
The efficacy of some products varies when administered
CONTROLLER MEDICATIONS via different inhaler devices16. Most of the benefit from
inhaled glucocorticosteroids is achieved in adults at
Inhaled glucocorticosteroids* relatively low doses, equivalent to 400 ug of budesonide
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per day17. Increasing to higher doses provides little further
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IB
Role in therapy -Inhaled glucocorticosteroids are currently benefit in terms of asthma control but increases the risk
TR
the most effective anti-inflammatory medications for the of side effects17,18. However, there is marked individual
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treatment of persistent asthma. Studies have demonstrated variability of responsiveness to inhaled glucocorticosteroids
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their efficacy in reducing asthma symptoms9, improving and because of this and the recognized poor adherence to
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quality of life9, improving lung function9, decreasing airway treatment with inhaled glucocorticosteroids, many patients
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hyperresponsiveness10, controlling airway inflammation11, will require higher doses to achieve full therapeutic benefit.
reducing frequency and severity of exacerbations12, and PY
As tobacco smoking reduces the responsiveness to inhaled
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reducing asthma mortality13. However, they do not cure glucocorticosteroids, higher doses may be required in
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asthma, and when they are discontinued deterioration patients who smoke240.
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N
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Figure 3-1. Estimated Equipotent Daily Doses of Inhaled Glucocorticosteriods for Adults†
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Drug Low Daily Dose (µg) Medium Daily Dose (µg) High Daily Dose (µg)‡
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NOTES:
• The most important determinant of approprioate dosing is the clinician’s judgement of the patient’s response therapy. The clinician must monitor the patient’s response in terms
of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should carefully be titrated to the minimum dose required to
maintain control, thus reducing the potential for adverse effects.
• Designation of low, medium, and high doses is provided from manufacturers’ recommendations where possible. Clear demonstration of dose-response relationships is seldom
provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient, as higher doses may not be more effective and are likely to
be associated with greater potential for adverse effects
• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the equivalent correct dosage.
*In this section recommendations for doses of inhaled glococorticosteriods are given as “µ/day budesonide
or equivalent,” because a majority of the clinical literature on these medications uses this standard
ASTHMA TREATMENTS 31
To reach clinical control, add-on therapy with another One difficulty in establishing the clinical significance of
class of controller is preferred over increasing the dose such adverse effects lies in dissociating the effect of
of inhaled glucocorticosteroids211. There is, however, high-dose inhaled glucocorticosteroids from the effect
a clear relationship between the dose of inhaled of courses of oral glucocorticosteroids taken by patients
glucocorticosteroids and the prevention of severe acute with severe asthma. There is no evidence that use
exacerbations of asthma12, although there appear to of inhaled glucocorticosteroids increases the risk of
be differences in response according to symptom/ pulmonary infections, including tuberculosis, and inhaled
inflammation phenotype212. Therefore, some patients with glucocorticosteroids are not contraindicated in patients with
severe asthma may benefit from long-term treatment with active tuberculosis33.
higher doses of inhaled glucocorticosteroids.
Leukotriene modifiers.
Side effects: Local adverse effects from inhaled
glucocorticosteroids include oropharyngeal candidiasis, Role in therapy -Leukotriene modifiers include cysteinyl-
dysphonia, and occasionally coughing from upper airway leukotriene 1 (CysLT1) receptor antagonists (montelukast,
irritation. For pressurized MDIs the prevalence of these pranlukast, and zafirlukast) and a 5-lipoxygenase
effects may be reduced by using certain spacer devices1. inhibitor (zileuton). Clinical studies have demonstrated
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Mouth washing (rinsing with water, gargling, and spitting that leukotriene modifiers have a small and variable
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out) after inhalation may reduce oral candidiasis. The
IB
bronchodilator effect, reduce symptoms including cough34,
use of prodrugs that are activated in the lungs but not in
TR
improve lung function, and reduce airway inflammation
the pharynx (e.g., ciclesonide19 and beclometasone), and
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and asthma exacerbations35-37. They may be used as an
new formulations and devices that reduce oropharyngeal
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alternative treatment for adult patients with mild persistent
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deposition, may minimize such effects without the need for asthma38-40, and some patients with aspirin-sensitive
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a spacer or mouth washing. asthma respond well to leukotriene modifiers41. However,
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when used alone as controller, the effect of leukotriene
O
Inhaled glucocorticosteroids are absorbed from the lung,
modifiers are generally less than that of low doses of
C
asthma control42,43.
metabolism (conversion to inactive metabolites) in the
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have demonstrated that ciclesonide, budesonide, and may improve asthma control in patients whose asthma
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adults, systemic effects of inhaled glucocorticosteroids are study that demonstrated equivalence in preventing
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not a problem at doses of 400 µg or less budesonide or exacerbations48, several studies have demonstrated that
PY
The systemic side effects of long-term treatment with release formulation of zileuton allows this medication to be
high doses of inhaled glucocorticosteroids include easy used on a twice daily basis with effects equivalent to that of
bruising24, adrenal suppression1,20, and decreased bone standard zileuton used four times a day203.
mineral density25,26. A meta-analysis of case-control
studies of non-vertebral fractures in adults using inhaled Side effects -Leukotriene modifiers are well tolerated,
glucocorticosteroids (BDP or equivalent) indicated that and few if any class-related effects have so far been
in older adults, the relative risk of non-vertebral fractures recognized. Zileuton has been associated with liver
increases by about 12% for each 1000 µg/day increase in toxicity204, and monitoring of liver tests is recommended
the dose BDP or equivalent but that the magnitude of this during treatment with this medication. No association was
risk was considerably less than other common risk factors found between Churg-Strauss syndrome and leukotriene
for fracture in the older adult213. Inhaled glucocorticosteroids modifiers after controlling for asthma drug use, although it
have also been associated with cataracts27,29 and glaucoma is not possible to rule out modest associations given that
in cross-sectional studies28, but there is no evidence of Churg-Strauss syndrome is so rare and so highly correlated
posterior-subcapsular cataracts in prospective studies30-32. with asthma severity52.
32 ASTHMA TREATMENTS
Long-acting inhaled bronchodilators Tiotropium, a long-acting inhaled anticholinergic bronchodilator,
has been studied in adults with uncontrolled asthma
Role in therapy - Long-acting inhaled β2-agonists, and compared with salmeterol, doubling the dose of
including formoterol and salmeterol, should not be used inhaled glucocorticosteroid and as add-on to inhaled
as monotherapy in asthma as these medications do glucocorticosteroids and salmeterol231,233. One study showed
not appear to influence airway inflammation in asthma. comparable bronchodilator effects with no significant
They are most effective when combined with inhaled changes on asthma control232. Another study showed
glucocorticosteroids55,56,193, and this combination therapy that adding tiotropium to patients not controlled on inhaled
is the preferred treatment when a medium dose of inhaled glucocorticosteroids and long-acting β2-agonists improved
glucocorticosteroid alone fails to achieve control of lung function but not symptoms233. The studies have been
asthma. The addition of long-acting inhaled β2-agonists relatively short-term and no effect on exacerbations has so far
to a daily regimen of inhaled glucocorticosteroids been reported. There are no data about these medications in
improves symptom scores, decreases nocturnal asthma children.
symptoms, improves lung function, decreases the use of
rapid-acting inhaled β2-agonists57-59, reduces the number Side effects - Therapy with long-acting inhaled β2-
of exacerbations12,57-62, does not increase the risk of agonists causes fewer systemic adverse effects—such as
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asthma-related hospitalizations214, and achieves clinical cardiovascular stimulation, skeletal muscle tremor, and
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hypokalemia—than oral therapy. The regular use of rapid-
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control of asthma in more patients, more rapidly, and at
acting β2-agonists in both short and long acting forms may
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a lower dose of inhaled glucocorticosteroids than inhaled
lead to relative refractoriness to β2-agonists74. Based on
IS
glucocorticosteroids given alone63.
data indicating a possible increased risk of asthma-related
D
R
This greater efficacy of combination treatment has led death associated with the use of salmeterol in a small
O
to the development of fixed combination inhalers that group of individuals75 long-acting β2-agonists should not be
PY
deliver both glucocorticosteroid and long-acting β2-agonist used as a substitute for inhaled or oral glucocorticosteroids,
O
simultaneously (fluticasone propionate plus salmeterol, and should only be used in combination with an appropriate
C
Fixed combination inhalers are more convenient for receiving long-acting β2-agonists in combination with
IA
patients, may increase compliance66, and ensure that inhaled glucocorticosteroids, when compared to inhaled
R
glucocorticosteroid. In addition, combination inhalers are extremely small and need to be balanced against
M
containing formoterol and budesonide may be used for both the benefits in improved asthma control and reduction in
D
ASTHMA TREATMENTS 33
Additionally in such patients the withdrawal of sustained- and skeletal muscle tremor. Adverse cardiovascular
release theophylline has been associated with deterioration reactions may also occur with the combination of oral β2-
of control84. As add-on therapy, theophylline is less effective agonists and theophylline. Regular use of long-acting oral
than long-acting inhaled β2-agonists85,86. β2-agonists as monotherapy is likely to be harmful and
these medications must always be given in combination
Side effects -Side effects of theophylline, particularly at with inhaled glucocorticosteroids.
higher doses (10 mg/kg body weight/day or more), are
significant and reduce their usefulness. Side effects can Anti-IgE*
be reduced by careful dose selection and monitoring,
and generally decrease or disappear with continued use. Role in therapy -Anti-IgE (omalizumab) is a treatment
Adverse effects include gastrointestinal symptoms, loose option limited to patients with elevated serum levels
stools, cardiac arrhythmias, seizures, and even death. of IgE. Its current indication is for patients with severe
Nausea and vomiting are the most common early events. allergic asthma89 who are uncontrolled on inhaled
Monitoring is advised when a high dose is started, if the glucocorticosteroids, although the dose of concurrent
patient develops an adverse effect on the usual dose, when treatment has varied in different studies. Improved
expected therapeutic aims are not achieved, and when asthma control is reflected by fewer symptoms, less need
TE
conditions known to alter theophylline metabolism exist. For for reliever medications, and fewer exacerbations90,91,
U
IB
example, febrile illness, pregnancy, and anti-tuberculosis although this was not confirmed in all studies235. Further
TR
medications87 reduce blood levels of theophylline, while investigations will likely provide additional clarification of the
IS
liver disease, congestive heart failure, and certain role of anti-IgE in other clinical settings.
D
drugs including cimetidine, some quinolones, and some
R
macrolides increase the risk of toxicity. Lower doses of Side effects: As indicated by several studies involving
O
theophylline, which have been demonstrated to provide the asthma patients ages 12 years and older207, who were
full anti-inflammatory benefit of this drug82, are associated PY
already receiving treatment with glucocorticosteroids
O
with less frequent side effects, and plasma theophylline (inhaled and/or oral) and long-acting β2-agonists89, anti-
C
T
levels in patients on low-dose therapy need not be IgE appears to be safe as add-on therapy92-94 , including
O
measured unless overdose is suspected. patients generally considered to be at high risk for
N
O
Cromones: sodium cromoglycate and nedocromil facilitated by anti-IgE therapy has led to unmasking
L-
Role in therapy – The role of sodium cromoglycate and glucocorticosteroid withdrawal using anti-IgE should be
AT
and they are less effective than a low dose of inhaled Role in therapy -Long-term oral glucocorticosteroid
R
glucocorticosteroid88. therapy (that is, for periods longer than two weeks as a
PY
Side effects -Side effects are uncommon and include uncontrolled asthma, but its use is limited by the risk
C
coughing upon inhalation and sore throat. Some patients of significant adverse effects. The therapeutic index
find the taste of nedocromil sodium unpleasant. (effect/side effect) of long-term inhaled glucocortico-
steroids is always more favorable than long-term
Long-acting oral β2-agonists. systemic glucocorticosteroids in asthma95,96. If oral
glucocorticosteroids have to be administered on a long-
Role in therapy -Long acting oral β2-agonists include term basis, attention must be paid to measures that minimi
slow release formulations of salbutamol, terbutaline, and e the systemic side effects. Oral preparations are preferred
bambuterol, a prodrug that is converted to terbutaline in over parenteral (intramuscular or intravenous) for long-
the body. They are used only on rare occasions when term therapy because of their lower mineralocorticoid
additional bronchodilation is needed. effect, relatively short half-life, and lesser effects on
striated muscle, as well as the greater flexibility of dosing
Side effects -The side effect profile of long-acting oral β2- that permits titration to the lowest acceptable dose that
agonists is higher than that of inhaled β2-agonists, and maintains control.
includes cardiovascular stimulation (tachycardia), anxiety,
*Visit GINA website, www.ginasthma.org for GRADE review of question “In adults with asthma, does
34 ASTHMA TREATMENTS monoclonal anti-IgE, omalizumab, compared to placebo improve patient outcomes?”
Figure 3-2. Glucocorticosteroids and Osteoporosis
Asthma patients on high-dose inhaled glucocorticosteroids or oral glucocorticosteroids at any dose are considered at risk of developing
osteoporosis and fractures, but it is not certain whether this risk exists for patients on lower doses of inhaled glucocorticosteroids 1. Physicians
should consider monitoring patients who are at risk. The following summarizes monitoring and management but more detailed guidelines for
the management of steroid-induced osteoporosis are available2,3.
Screening - Chest X-rays should be reviewed for the presence of vertebral fractures. Wedging, compressions, and cod-fishing of vertebral
bodies are synonymous with fractures, and indicate those who are at the highest risk for future fractures. In men, this may be a better predictor
of fracture risk than bone mineral density (BMD). BMD measurements by dual energy X-ray absorptiomety (DXA scan) should be undertaken in:
• Any patient with asthma who has been taking oral glucocorticosteroids for over 6 months duration at a mean daily dose of 7.5 mg
prednisone/prednisolone or above.
• Post-menopausal women taking over 5 mg prednisone/prednisolone daily for more than 3 months.
• Any patient with asthma and a history of vertebral or other fractures that may be related to osteoporosis.
Bone density measurements should also be offered to:
• Post-menopausal women taking > 2 mg inhaled BDP or equivalent daily
• Any patient who is receiving frequent short courses of high-dose oral glucocorticosteroids
TE
Osteoporosis is present if the bone density in lumbar spine or femoral neck shows :
U
• T-score below -2.5 (2.5 standard deviations below the mean value of young normal subjects of the same sex in patients 19-69 years).
IB
• Z-score below -1 (1 standard deviation below the predicted value for age and sex).
TR
follow-up scanning - Repeat scanning should be done:
IS
D
• In 2 years in those whose initial scan was not osteoporotic but in whom treatment (as above) with oral glucocorticosteroids continues.
R
• In 1 year for those with osteoporosis on the first scan who are started on osteoporosis treatment.
O
Management
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• General measures include avoidance of smoking, regular exercise, use of the lowest dose of oral glucocorticosteroid possible, and a good
O
dietary intake of calcium.
C
• For women with osteoporosis up to 10 years post-menopausal offer bisphosphonates or hormone therapy4,5,6 (Evidence A).
T
O
• For men, pre-menopausal women, and women more than 10 years since menopause consider treatment with a bisphosphonate7 (Evidence A).
N
O
References
D
1. Goldstein MF, Fallon JJ, Jr., Harning R. Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease. Chest 1999; 116:1733-1749.
L-
2. Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis:
IA
3. Sambrook PN, Diamond T, Ferris L, Fiatarone-Singh M, Flicker L, MacLennan A et al. Corticosteroid induced osteoporosis. Guidelines for treatment. Aust Fam
E
AT
postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
D
5. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-
TE
Wende J, Watts NB. "Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density." JAMA 2003;290(13):1729-1738.
H
6. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-34.
IG
7. Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R et al. Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev 2000;CD001347.
R
PY
Side effects -The systemic side effects of long-term infections have been reported among patients who
O
oral or parenteral glucocorticosteroid treatment include are exposed to these viruses while taking systemic
C
ASTHMA TREATMENTS 35
Side effects -Sedation is a potential side effect of some of conjunctivitis up to 7 years after treatment termination208.
these medications. However, in view of the relatively modest effect of allergen-
specific immunotherapy compared to other treatment
Other controller therapies. options, these benefits must be weighed against the risk
of adverse effects and the inconvenience of the prolonged
Role in therapy -Various therapeutic regimens to reduce course of injection therapy, including the minimum half-hour
the dose of oral glucocorticosteroids required by patients wait required after each injection. Specific immunotherapy
with severe asthma have been proposed. These should be considered only after strict environmental
medications should be used only in selected patients avoidance and pharmacologic intervention, including
under the supervision of an asthma specialist, as their inhaled glucocorticosteroids, have failed to control a
potential steroid-sparing effects may not outweigh the risk patient’s asthma113. There are no studies that compare
of serious side effects. Two meta-analyses of the steroid- specific immunotherapy with pharmacologic therapy
sparing effect of low-dose methotrexate showed a small for asthma. The value of immunotherapy using multiple
overall benefit, but a relatively high frequency of adverse allergens does not have support.
effects102,103. This small potential to reduce the impact of Side effects -Local and systemic side effects may occur in
glucocorticosteroid side effects is probably insufficient to conjunction with specific immunotherapy administration.
TE
offset the adverse effects of methotrexate104. Cyclosporin105 Reactions localized to the injection site may range from
U
IB
and gold106,107 have also been shown to be effective in a minimal immediate wheal and flare to a large, painful,
TR
some patients. The macrolide, troleandomycin, has a delayed allergic response. Systemic effects may include
IS
small steroid-sparing effect when used with systemic anaphylactic reactions, which may be life threatening,
D
methylprednisolone, but its effect may result from the as well as severe exacerbations of asthma. Deaths from
R
macrolide decreasing metabolism of the glucocorticosteroid specific immunotherapy have occurred in patients with
O
and therefore not improving safety. However, other effects severe asthma.
of the long-term use of macrolides in asthma remain under PY
O
study108. The use of intravenous immunoglobulin is not Reliever Medications
C
T
against tumor necrosis factor (TNF)-alpha suggest that the Reliever medications act quickly to relieve bronchoconstriction
N
O
risk benefit equation does not favor the use of this class of and its accompanying acute symptoms.
D
nausea, vomiting, and abdominal pain and occasionally Role in therapy -Rapid-acting inhaled β2-agonists are the
AT
liver toxicity. Methotrexate also causes gastrointestinal medications of choice for relief of bronchospasm during
M
symptoms, and on rare occasions hepatic and diffuse acute exacerbations of asthma and for the pretreatment
D
Allergen-specific immunotherapy. agonist, is approved for symptom relief because of its rapid
PY
Role in therapy -The role of specific immunotherapy in in patients on regular controller therapy with inhaled
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36 ASTHMA TREATMENTS
such as tremor and tachycardia than occur with inhaled Theophylline.
preparations.
Role in therapy -Short-acting theophylline may be
Systemic glucocorticosteroids. considered for relief of asthma symptoms119. The role
of theophylline in treating exacerbations remains
Role in therapy -Although systemic glucocorticosteroids controversial. Short-acting theophylline may provide no
are not usually thought of as reliever medications, additive bronchodilator effect over adequate doses of rapid-
they are important in the treatment of severe acute acting β2-agonists, but it may benefit respiratory drive.
exacerbations because they prevent progression of the
asthma exacerbation, reduce the need for referral to Side effects -Theophylline has the potential for significant
emergency departments and hospitalization, prevent adverse effects, although these can generally be avoided
early relapse after emergency treatment, and reduce by appropriate dosing and monitoring. Short-acting
the morbidity of the illness. The main effects of systemic theophylline should not be administered to patients already
glucocorticosteroids in acute asthma are only evident after on long-term treatment with sustained-release theophylline
4 to 6 hours. Oral therapy is preferred and is as effective unless the serum concentration of theophylline is known to
as intravenous hydrocortisone114. A typical short course of be low and/or can be monitored.
TE
oral glucocorticosterods for an exacerbation is 40-50 mg115
U
Short-acting oral β2-agonists.
IB
prednisolone given daily for 5 to 10 days depending on the
TR
severity of the exacerbation. When symptoms have
IS
subsided and lung function has approached the patient’s Short-acting oral β2-agonists are appropriate for use in the
D
personal best value, the oral glucocorticosteroids can be few patients who are unable to use inhaled medication.
R
stopped or tapered, provided that treatment with inhaled However, their use is associated with a higher prevalence
O
glucocorticosteroids continues116. Intramuscular injection of of adverse effects.
glucocorticosteroids has no advantage over a short course PY
O
of oral glucocorticosteroids in preventing relapse114,116. Complementary And Alternative Medicine
C
T
O
Side effects -Adverse effects of short-term high-dose The roles of complementary and alternative medicine
N
O
systemic therapy are uncommon but include reversible in adult asthma treatment are limited because these
D
abnormalities in glucose metabolism, increased appetite, approaches have been insufficiently researched and
L-
fluid retention, weight gain, rounding of the face, mood their effectiveness is largely unproven. Generally, these
IA
alteration, hypertension, peptic ulcer, and aseptic necrosis therapies have not been validated by conventional
E R
in asthma include ipratropium bromide and oxitropium performance of the large, multicenter, placebo-controlled
R
bromide. Inhaled ipratropium bromide is a less effective randomized studies required to confirm efficacy. However,
PY
reliever medication in asthma than rapid-acting inhaled without these the relative efficacy of these alternative
O
ASTHMA TREATMENTS 37
Evidence from the most rigorous studies available to the choice of inhaler device should include consideration
date indicates that spinal manipulation is not an effective of the efficacy of drug delivery, cost, safety, ease of use,
treatment for asthma121. Systematic reviews indicate that convenience, and documentation of its use in the patient’s
homeopathic medicines have no effects beyond placebo222. age group123-125. In general, a metered-dose inhaler (MDI)
A systematic review of yoga interventions for asthma found with spacer is preferable to nebulized therapy due to
no convincing evidence of benefit; the quality of studies its greater convenience, more effective lung deposition,
was generally poor236. lower risk of side effects, and lower cost. Based on these
considerations, a general strategy for choosing inhalers in
Several studies of breathing and/or relaxation techniques children is given in Figure 3-3.
for asthma and/or dysfunctional breathing, including the
Buteyko method and the Papworth method210, have shown
improvements in symptoms, short-acting β2-agonist use, Figure 3-3: Choosing an Inhaler Device for
quality of life and/or psychological measures, but not in Children with Asthma*
physiological outcomes. A study of two physiologically- Age Group Preferred Device Alternate Device
contrasting breathing techniques, in which contact with Younger than 4 years Pressurized metered- Nebulizer with face
health professionals and instructions about rescue dose inhaler plus
TE
mask
inhaler use were matched, showed similar improvements dedicated spacer
U
in reliever and inhaled glucocorticosteroid use in both with face mask
IB
TR
groups122. This suggests that perceived improvement with 4 – 6 years Pressurized metered- Nebulizer with
breathing techniques may be largely due to factors such as dose inhaler plus mouthpiece
IS
dedicated spacer
D
relaxation, voluntary reduction in use of rescue medication, with mouthpiece
R
or engagement of the patient in their care. Breathing
O
Older than 6 years Dry powder inhaler, Nebulizer with
techniques may thus provide a useful supplement to or breath-actuated
PY
mouthpiece
conventional asthma management strategies, particularly O pressurized metered-
in anxious patients or those habitually over-using rescue dose inhaler, or
C
pressurized metered-
medication. The cost of some programs may be a potential
T
limitation.
N
*Based on efficacy of drug delivery, cost effectiveness, safety, ease of use, and
Side effects -Acupuncture-associated hepatitis B, bilateral
L-
convenience.
pneumothorax, and burns have been described. Side
IA
effects of other alternative and complementary medicines Spacers retain large drug particles that would normally
ER
are largely unknown. However, some popular herbal be deposited in the oropharynx, reducing oral and
AT
medicines could potentially be dangerous, as exemplified gastrointestinal absorption and thus systemic availability
M
by the occurrence of hepatic veno-occlusive disease of the inhaled drug. This is mainly important when
D
associated with the consumption of the commercially inhaled glucocorticosteroids with first-pass metabolism
TE
available herb comfrey. Comfrey products are sold as (beclomethasone dipropionate, flunisolide, triamcinolone,
H
IG
herbal teas and herbal root powders, and their toxicity is and budesonide) are given via pressurized MDI. Use of a
R
due to the presence of pyrroli idine alkaloids. spacer also reduces oropharyngeal side effects. During
PY
ASTHMA TREATMENT: CHILDREN** correctly coordinate inhalation with actuation of the MDI.
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* Approved for once-daily dosing in mild patients.
U
Notes
IB
TR
• The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. The clinician must monitor the
patient’s response in terms of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should be
IS
carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effects.
D
• Designation of low, medium, and high doses is provided from manufacturers’ recommendations where possible. Clear demonstration of dose-
R
response relationships is seldom provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient,
O
as higher doses may not be more effective and are likely to be associated with greater potential for adverse effects.
PY
• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the correct
O
equivalent dosage.
C
T
O
Controller medications for children include inhaled and inhaled glucocorticosteroids controls asthma symptoms,
L-
systemic glucocorticosteroids, leukotriene modifiers, long- reduces the frequency of acute exacerbations and the
IA
acting inhaled β2-agonists, theophylline, cromones, and number of hospital admissions, improves quality of life,
E R
Role in Therapy -Inhaled glucocorticosteroids are the course of months) and sometimes higher doses may be
H
IG
most effective controller therapy, and are therefore the required to achieve maximum improvements in airway
R
recommended treatment for asthma for children of all ages. hyperresponsiveness10. When glucocorticosteroid treatment
PY
Figure 3-4 lists approximately equipotent doses of different is discontinued, asthma control deteriorates within weeks to
O
ASTHMA TREATMENTS 39
The clinical benefits of intermittent systemic or inhaled the child’s bone age corresponds to his or her height140,141
glucocorticosteroids for children with intermittent, viral- Ultimately, adult height is not decreased, although it is
induced wheeze remain controversial. A one year study reached at a later than normal age. The use of 400 µg
of intermittent treatment with inhaled glucocorticosteroids inhaled budesonide or equivalent per day to control asthma
was equally effective as daily treatment, and reduced has less impact on growth than does low socioeconomic
the total glucocorticosteroid dose threefold in preschool status141. A summary of the findings of studies on inhaled
children with frequent wheezing and a high asthma glucocorticosteroids and growth is provided in Figure 3-5.
predictive index238. Some studies in older children found
small benefits while another study in young children Bones. The potential clinically relevant adverse effects
found no effects on wheezing symptoms139. There is no of inhaled glucocorticosteroids on bones in children
evidence to support the use of maintenance low-dose are osteoporosis and fracture. Several cross-sectional
inhaled glucocorticosteroids for preventing early transient and longitudinal epidemiologic studies have assessed
wheezing136,139,199. the effects of long-term inhaled glucocorticosteroid
treatment on these outcomes132,143-149. The conclusions are
Side effects -The majority of studies evaluating the summarized in Figure 3-6.
systemic effects of inhaled glucocorticosteroids have been
TE
undertaken in children older than 5 years. Figure 3-6. Summary: Bones and
U
IB
Glucocorticosteroids in Children10,143,144
TR
Growth. When assessing the effects of inhaled
IS
glucocorticosteroids on growth in children with asthma, it
• No studies have reported any statistically significant
D
is important to consider potential confounding factors. For
R
example, many children with asthma receiving inhaled increased of risk of fractures in children taking inhaled
O
glucocorticosteroids experience a reduction in growth glucocorticosteroids.
PY
rate toward the end of the first decade of life140. This • Oral or systemic glucocorticosteroid use increases the risk of
O
reduced growth rate continues into the mid-teens and is fracture. The risk of fracture increases along with the number
C
courses.
O
associated with a delay in skeletal maturation, so that several cross-sectional studies found no adverse effects
L-
density.
Figure 3-5. Summary: Glucocorticosteroids and
E
• Uncontrolled or severe asthma adversely affects growth and to re¬duce the amount of oral corticosteroids used in these
children218 .
H
40 ASTHMA TREATMENTS
Central nervous system effects. Although isolated case Side effects -No safety concerns have been demonstrated
reports have suggested that hyperactive behavior, from the use of leukotriene modifiers in children.
aggressiveness, insomnia, uninhibited behavior, and
impaired concentration may be seen with inhaled Long-acting inhaled β2-agonists.
glucocorticosteroid treatment, no increase in such effects
has been found in a long-term controlled trial of inhaled Role in therapy -Long-acting inhaled β2-agonists are
budesonide132. primarily used as add-on therapy in children older than 5
years whose asthma is insufficiently controlled by medium
Oral candidiasis, hoarseness, and bruising. Clinical thrush doses of inhaled glucocorticosteroids or as single-dose
is seldom a problem in children treated with inhaled or therapy before vigorous exercise. Monotherapy with long-
systemic glucocorticosteroids. This side effect seems to acting inhaled β2-agonists should be avoided75,234.
be related to concomitant use of antibiotics, high daily
doses, dose frequency, and inhaler device. Spacers Children older than 5 years. Long-acting inhaled β2-
reduce the incidence of oral candidiasis151. Mouth rinsing agonists have mainly been studied in children older
is beneficial152. The occurrence of hoarseness or other than 5 years as add-on therapy for patients whose
noticeable voice changes during budesonide treatment is asthma is not controlled on low to high doses of inhaled
TE
similar to placebo30. Treatment with an average daily dose glucocorticosteroids. Significant improvements in peak
U
IB
of 500 µg budesonide for 3 to 6 years is not associated with flow and other lung function measurements have been
TR
an increased tendency to bruise30. found in most studies55,165-169, 234. However, the effects
IS
on other outcomes such as symptoms and need for
D
Dental side effects. Inhaled glucocorticosteroid treatment is reliever medication have been less consistent and
R
not associated with increased incidence of caries. However, have only been observed in about half of the trials
O
the increased level of dental erosion reported in children conducted. Add-on treatment with long-acting inhaled β2-
with asthma153 may be due to a reduction in oral pH that PY
agonists has not been shown to reduce the frequency of
O
may result from inhalation of β2-agonists154. exacerbations170. Inhalation of a single dose of long-acting
C
T
Other local side effects. The long-term use of inhaled bronchoconstriction for several hours171. With daily therapy
N
O
glucocorticosteroids is not associated with an increased the duration of the protection is somewhat reduced171, but is
D
incidence of lower respiratory tract infections, including still longer than that provided by short-acting β2-agonists.
L-
Children older than 5 years. Leukotriene modifiers provide inhalers. Fixed combination inhalers ensure that the
D
clinical benefit in children older than 5 years at all levels long-acting β2-agonists is always accompanied by a
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ASTHMA TREATMENTS 41
Theophylline. 28 week, randomized, double-blind, placebo-controlled
study223, 224 included 334 children with moderate to severe
Role in therapy -Theophylline has been shown to be allergic asthma who were well controlled on inhaled
effective as monotherapy and as add-on treatment to glucocorticosteroid doses equivalent to 200-500 µg/day
inhaled or oral glucocorticosteroids in children older than of beclomethasone. There was no difference in clinical
5 years. It is significantly more effective than placebo at effects between placebo and anti-IgE during a 16-week
controlling day and night symptoms and improving lung stable inhaled glucocorticosteroid dose period. During a
function172-174. Maintenance treatment offers a marginal 12-week tapering period urgent, unscheduled physician
protective effect against exercise-induced broncho- visits were significantly reduced from by 30.3% in the
constriction175. Add-on treatment with theophylline has anti-IgE compared with placebo (12.9%) group223, and
been found to improve asthma control and reduce the there were significant improvements in quality of life in
maintenance glucocorticosteroid dose necessary in the patients receiving anti-IgE, both during stable inhaled
children with severe asthma treated with inhaled or oral glucocorticosteroid dosing and during tapering224. The
glucocorticosteroids176,177. A few studies in children 5 years remaining outcomes were very similar in the two treatment
and younger also suggest some clinical benefit. However, groups.
the efficacy of theophylline is less than that of low-dose
TE
inhaled glucocorticosteroids. A one-year study evaluated the efficacy and safety of anti-
U
IB
IgE in 627 children with IgE-mediated asthma inadequately
TR
Most clinical evidence regarding the use of theophylline in controlled on doses of inhaled glucocorticosteroid
IS
children has been obtained from studies in which plasma equivalent to 200 µg/day fluticasone propionate or higher
D
theophylline levels were maintained within the therapeutic (mean dose 500 µg/day)225. Anti-IgE treatment was
R
range of 55-110 µmol/L (5-10 µg/ml). Further studies associated with a significantly lower exacerbation rate
O
suggest that its controller functions may occur at lower and the overall incidence of serious adverse events was
plasma levels (corresponding to doses of around 10 mg/ PY
significantly lower in the children receiving anti-IgE than
O
kg/day). Sustained-release products are preferable for placebo.
C
T
Sustained-release products with reliable absorption profiles A substantial number of children with difficult asthma
N
O
and complete bioavailability with and without concomitant will have higher IgE levels than the upper limit of IgE
D
food intake are preferred. recommended for therapy (1,300 IU)226. It is unknown if
L-
Theophylline elimination may vary up to tenfold between these patients will still benefit from omalizumab therapy.
IA
individuals. Measurement of plasma theophylline levels There are no tests that can currently be recommended in
E R
is not necessary in otherwise healthy children when order to predict who will respond227.
AT
higher doses are used or when drugs that may increase Anti-IgE therapy is expensive and requires regular
D
theophylline levels are also used chronically, plasma injections and observation after each injection. A cost
TE
theophylline levels should be measured two hours before benefit analysis suggested that there would be a fiscal
H
IG
administration of the next dose once steady state has been saving if this treatment is given to children with five or more
R
reached (after 3 days). hospital admissions and cumulatively twenty days or more
PY
in hospital228.
O
are anorexia, nausea, vomiting, and headache178. Mild Side effects: Drug-related adverse events in anti-IgE
central nervous stimulation, palpitations, tachycardia, treated patients are mild to moderate in severity and
arrhythmias, abdominal pain, diarrhea, and, rarely, gastric include urticaria, rash, flushing, and pruritus223. The long-
bleeding may also occur. These side effects are mainly seen term (beyond one year) safety and efficacy has not yet
at doses higher than 10 mg/kg/day. The risk of adverse been studied.
effects is reduced if treatment is initiated with daily doses
around 5 mg/kg/day and then gradually increased to 10 mg/ Cromones: sodium cromoglycate and nedocromil sodium.
kg/day. Severe overdosing with theophylline can be fatal.
Role in therapy -Sodium cromoglycate and nedocromil
Anti-IgE. sodium have a limited role in the long-term treatment of
asthma in children. One meta-analysis has concluded
Role in therapy - Anti-IgE (omalizumab) has proven efficacy that long-term treatment with sodium cromoglycate is not
in children age 6 to 12 years with moderate-to-severe significantly better than placebo for management of asthma
and severe persistent allergic (IgE-mediated) asthma. A in children179. Another has confirmed superiority of low dose
42 ASTHMA TREATMENTS
inhaled glucocorticosteroids over sodium cromoglycate in Side effects -Skeletal muscle tremor, headache,
persistent asthma, but as there were no placebo arms in palpitations, and some agitation are the most common
these studies, the efficacy of sodium cromoglycate cannot complaints associated with high doses of ß2-agonists
be confirmed from the studies reviewed; no between in children. These complaints are more common after
treatment difference in safety was observed180. systemic administration and disappear with continued
treatment189.
Nedocromil sodium has been shown to reduce
exacerbations, but its effect on other asthma outcomes Anticholinergics.
is not superior to placebo. A single dose of sodium
cromoglycate or nedocromil sodium attenuates broncho- Role in therapy -Inhaled anticholinergics are not recommended
spasm induced by exercise or cold air181. Studies of the use for long-term management of asthma in children190.
of these medications in children 5 years and younger are
sparse and results are conflicting. REFERENCES
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MD. Growth and adrenal suppression in asthmatic children
treated with high-dose fluticasone propionate. Lancet 164. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L,
1996;348(9019):27-9. Menten J, et al. Montelukast reduces asthma exacerbations in
2-to 5-year-old children with intermittent asthma. Am J Respir
151. Selroos O, Backman R, Forsen KO, Lofroos AB, Niemisto Crit Care Med 2005;171(4):315-22.
M, Pietinalho A, et al. Local side-effects during 4-year
treatment with inhaled corticosteroids--a comparison between 165. Russell G, Williams DA, Weller P, Price JF. Salmeterol
pressurized metered-dose inhalers and Turbuhaler. Allergy xinafoate in children on high dose inhaled steroids. Ann Allergy
1994;49(10):888-90. Asthma Immunol 1995;75(5):423-8.
ASTHMA TREATMENTS 49
166. Malone R, LaForce C, Nimmagadda S, Schoaf L, House K, 179. Tasche MJ, Uijen JH, Bernsen RM, de Jongste JC, van Der
Ellsworth A, et al. The safety of twice-daily treatment with Wouden JC. Inhaled disodium cromoglycate (DSCG) as
fluticasone propionate and salmeterol in pediatric patients with maintenance therapy in children with asthma: a systematic
persistent asthma. Ann Allergy Asthma Immunol 2005;95(1):66- review. Thorax 2000;55(11):913-20.
71.
180. Guevara JP, Ducharme FM, Keren R, Nihtianova S, Zorc
167. Zimmerman B, D’Urzo A, Berube D. Efficacy and safety of J. Inhaled corticosteroids versus sodium cromoglycate in
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treatment in children with asthma. Pediatr Pulmonol 2006(2):CD003558.
2004;37(2):122-7.
181. Spooner CH, Saunders LD, Rowe BH. Nedocromil sodium for
168. Meijer GG, Postma DS, Mulder PG, van Aalderen WM. Long- preventing exercise-induced bronchoconstriction. Cochrane
term circadian effects of salmeterol in asthmatic children Database Syst Rev 2000;2.
treated with inhaled corticosteroids. Am J Respir Crit Care Med
1995;152(6 Pt 1):1887-92. 182. Armenio L, Baldini G, Bardare M, Boner A, Burgio R, Cavagni
G, et al. Double blind, placebo controlled study of nedocromil
169. Bisgaard H. Long-acting beta(2)-agonists in management of sodium in asthma. Arch Dis Child 1993;68(2):193-7.
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Pulmonol 2000;29(3):221-34. 183. Kuusela AL, Marenk M, Sandahl G, Sanderud J, Nikolajev
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K, Persson B. Comparative study using oral solutions of
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bambuterol once daily or terbutaline three times daily in 2-5
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exacerbation rates of asthma in children. Pediatr Pulmonol
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Group. Pediatr Pulmonol 2000;29(3):194-201.
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171. Simons FE, Gerstner TV, Cheang MS. Tolerance to the
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184. Zarkovic JP, Marenk M, Valovirta E, Kuusela AL, Sandahl G,
bronchoprotective effect of salmeterol in adolescents
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with exercise-induced asthma using concurrent inhaled Persson B, et al. One-year safety study with bambuterol once
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glucocorticoid treatment. Pediatrics 1997;99(5):655-9. daily and terbutaline three times daily in 2-12 year-old children
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with asthma. The Bambuterol Multicentre Study Group. Pediatr
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173. Bierman CW, Pierson WE, Shapiro GG, Furukawa CT. Is a concentrations. Eur J Respir Dis 1984;134 Suppl:205-10S.
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optimal asthma therapy in the adolescent patient? Am JMed 186. Williams SJ, Winner SJ, Clark TJ. Comparison of inhaled
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1981;36(8):629-32.
174. Pedersen S. Treatment of nocturnal asthma in children with
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a single dose of sustained-release theophylline taken after 187. Dinh Xuan AT, Lebeau C, Roche R, Ferriere A, Chaussain M.
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supper. Clin Allergy 1985;15(1):79-85. Inhaled terbutaline administered via a spacer fully prevents
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175. Magnussen H, Reuss G, Jorres R. Methylxanthines inhibit double-blind, randomized, placebo-controlled study. J Int Med
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192. Deykin A, Wechsler ME, Boushey HA, Chinchilli VM, 203. Nelson H, Kemp J, Berger W, Corren J, Casale T, Dube L,
Kunselman SJ, Craig TJ, DiMango E, Fahy JV, Kraft M, Leone Walton-Bowen K, LaVallee N, Stepanians M. Efficacy of
F, Lazarus SC, Lemanske RF Jr, Martin RJ, Pesola GR, Peters zileuton controlled-release tablets administered twice daily
SP, Sorkness CA, Szefler SJ, Israel E; National Heart, Lung, in the treatment of moderate persistent asthma: a 3-month
and Blood Institute’s Asthma Clinical Research Network. randomized controlled study. Ann Allergy Asthma Immuno 2007
Combination therapy with a long-acting beta-agonist and a Aug;99(2):178-84.
leukotriene antagonist in moderate asthma. Am J Respir Crit
Care Med 2007 Feb 1;175(3):228-34. 204. Watkins PB, Dube LM, Walton-Bowen K, Cameron CM, Kasten
LE. Clinical pattern of zileuton-associated liver injury: results
193. Gibson PG, Powell H, Ducharme FM. Differential effects of a 12-month study in patients with chronic asthma. Drug Saf
of maintenance long-acting beta-agonist and inhaled 2007;30(9):805-15.
corticosteroid on asthma control and asthma exacerbations. J
Allergy Clin Immunol 2007 Feb;119(2):344-50. 205. Bateman E, Nelson H, Bousquet J, Kral K, Sutton L, Ortega
H, Yancey S. Meta-analysis: effects of adding salmeterol to
194. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. inhaled corticosteroids on serious asthma-related events. Ann
Effect of budesonide in combination with formoterol for reliever Intern Med 2008 Jul 1;149(1):33-42.
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double-blind study. Lancet 2006 Aug 26;368(9537):744-53. 206. Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose
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HJ, Goldman M. Effect of ADRB2 polymorphisms on response
195. Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman
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to long-acting beta2-agonist therapy: a pharmacogenetic
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M, Anderson WH, Dorinsky PM. Salmeterol response is not
analysis of two randomised studies. Lancet 2007 Dec
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affected by beta2-adrenergic receptor genotype in subjects with
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persistent asthma. J Allergy Clin Immunol 2006 Oct;118(4):809-
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207. Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S,
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Wenzel S, et al. The effect of treatment with omalizumab, an
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196. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy of
anti-IgE antibody, on asthma exacerbations and emergency
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sublingual immunotherapy in asthma: systematic review of
randomized-clinical trials using the Cochrane Collaboration medical visits in patients with severe persistent asthma. Allergy
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method. Allergy 2006 Oct;61(10):1162-72. 2005;60(3):302-8.
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197. Shaheen SO, Newson RB, Rayman MP, Wong AP, Tumilty
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MK, Phillips JM, Potts JF, Kelly FJ, White PT, Burney PG. S, Høst A, et al; (The PAT investigator group). Specific
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Randomised, double blind, placebo-controlled trial of selenium immunotherapy has long-term preventive effect of seasonal
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supplementation in adult asthma. Thorax 2007 Jun;62(6):483- and perennial asthma: 10-year follow-up on the PAT study.
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CM. Sahaja yoga in the management of moderate to severe An evaluation of levalbuterol HFA in the prevention of exercise-
induced bronchospasm. J Asthma 2007 Nov;44(9):729-33.
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199. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic 210. Holloway EA, West RJ. Integrated breathing and relaxation
A; 210. Holloway EA, West RJ. Integrated breathing and training (the Papworth method) for adults with asthma in
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relaxation IFWIN study team. Secondary prevention of asthma primary care: a randomised controlled trial. Thorax 2007
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214. Jaeschke R, O’Byrne PM, Mejza F, Nair P, Lesniak W, Brozek 225. Lanier B, Bridges T, Kulus M, Fowler Taylor A, Berhane I,
J, et al. The safety of long-acting beta-agonists among patients Vidaurre CF. Omalizumab for the treatment of exacerbations
with asthma using inhaled corticosteroids: systematic review in children with inadequately controlled allergic (IgE-mediated)
and metaanalysis. Am J Respir Crit Care Med. 2008 Nov asthma. J Allergy Clinical Immunol 2009;124(6):1210-1216
15;178(10):1009-16.
226. Bossley CJ, Saglani S, Kavanagh C, Payne DN, Wilson N,
215. Cates CJ, Cates MJ. Regular treatment with salmeterol for Tsartsali L, Rosenthal M, Balfour-Lynn IM, Nicholson AG, Bush
chronic asthma: serious adverse events. Cochrane Database A. Corticosteroid responsiveness and clinical characteristics in
of Systematic Reviews 2008, Issue 3. Art. No.: CD006363 childhood difficult asthma. Eur Respir J. 2009;34(5):1052-9;
216. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, 227. Wahn U, Martin C, Freeman P, Blogg M, Jimenez P.
Dahlén SE, et al; T03 Asthma Investigators. A randomized, Relationship between pretreatment specific IgE and the
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alpha blockade in severe persistent asthma. Am J Respir Crit
Care Med. 2009 Apr 1;179(7):549-58. 228. Oba Y, Salzman GA. Cost-effectiveness analysis of
omalizumab in adults and adolescents with moderate-to-severe
217. Pogson ZE, Antoniak MD, Pacey SJ, Lewis SA, Britton JR, allergic asthma. J Allergy Clin Immunol 2004;114(2):265-9.
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A randomized controlled trial. Am J Respir Crit Care Med. 2008 229. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu
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Jul 15;178(2):132-8. AH, et al. Randomized trial of omalizumab (anti-IgE)for asthma in
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inner-city children. N Engl J Med. 2011 Mar 17;364(11):1005-15.
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218. Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green RP,
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Strunk RC; CAMP Research Group. Effect of long-term 230. Welsh EJ, Cates CJ. Formoterol versus short-acting
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corticosteroid use on bone mineral density in children: a beta-agonists as relief medication for adults and children
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prospective longitudinal assessment in the childhood Asthma with asthma. Cochrane Database Syst Rev. 2010 Sep
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Management Program (CAMP) study. Pediatrics. 2008 8;(9):CD008418.
Jul;122(1):e53-61.
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231. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R,
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219. Strunk RC, Bacharier LB, Phillips BR, Szefler SJ, Zeiger Ameredes BT et al. National Heart, Lung, and Blood Institute
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RS, Chinchilli VM, et al.; CARE Network. Azithromycin or Asthma Clinical Research Network. Tiotropium bromide step-
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220. Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Gahlemann M, Sigmund R, Engel M, van Noord JA. Tiotropium
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Boushey HA, Calhoun WJ, et al. National Heart, Lung and improves lung function in patients with severe uncontrolled
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of beta2-adrenergic receptor polymorphism on response to 2011 Aug;128(2):308-14.
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Chest 2009;136(2):507-18.
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223. Milgrom, H, Berger W, Nayak A, Gupta N, Pollard S, 235. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in
McAlary M, et al. Treatment of Childhood Asthma with Anti- severe allergic asthma Inadequately controlled with standard
Immunoglobulin E Antibody (Omalizumab). Pediatrics 2001; therapy: a randomized trial. Ann Internal Med 2011;154:573-82.
108(2): 6-45
236. Posadzki P, Ernst E. Yoga for asthma? A systematic review of
224. Lemanske R, Nayak A, McAlary M, Everhard F, Fowler-Taylor randomized clinical trials. J Asthma. 2011 Aug;48(6):632-9.
A, Gupta N. Omalizumab improves asthma-related quality of
life in children with allergic asthma. Pediatrics 2002;110(5): 237. Lavorini F, Fontana GA. Targeting drugs to the airways: The
e55-9 role of spacer devices. Expert Opin Drug Deliv 2009;6:91-102.
52 ASTHMA TREATMENTS
238. Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD,
Lemanske RF Jr, et al; CARE Network of the National Heart,
Lung, and Blood Institute. Daily or intermittent budesonide in
preschool children with recurrent wheezing. N Engl J Med.
2011 Nov 24;365(21):1990-2001
239. Guilbert TW, Mauger DT, Allen DB, Zeiger RS, Lemanske
RF Jr, Szefler SJ, et al; Childhood Asthma Research and
Education Network of the National Heart, Lung, and Blood
Institute. Growth of preschool children at high risk for asthma
2 years after discontinuation of fluticasone. J Allergy Clin
Immunol. 2011 Nov;128(5):956-63.
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4
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ASTHMA
CHAPTER
PREVENTION
MANAGEMENT
CHAPTER 4: ASTHMA MANAGEMENT AND PREVENTION
COMPONENT 1: DEFINITION
INTRODUCTION COMPONENT 1: DEVELOP
Asthma has a significant impact on individuals, their PATIENT/DOCTOR PARTNERSHIP
families, and society. Although there is no cure for asthma,
appropriate management that includes a partnership KEY POINTS:
between the physician and the patient/family most often
results in the achievement of control. • The effective management of asthma requires
the development of a partnership between the
The goals for successful management of asthma are to: person with asthma and his or her health care
• Achieve and maintain control of symptoms professional(s) (and parents/caregivers, in the case
• Maintain normal activity levels, including exercise of children with asthma).
• Maintain pulmonary function as close to normal as • The aim of this partnership is guided self-
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• possible management—that is, to give people with asthma the
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• Prevent asthma exacerbations ability to control their own condition with guidance
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• Avoid adverse effects from asthma medications from health care professionals.
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• Prevent asthma mortality. • The partnership is formed and strengthened as
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patients and their health care professionals discuss
These goals for therapy reflect an understanding of
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and agree on the goals of treatment, develop a
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asthma as a chronic inflammatory disorder of the airways personalized, written asthma action plan including
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characterized by recurrent episodes of wheezing, Oself-monitoring, and periodically review the patient’s
breathlessness, chest tightness, and coughing. Clinical treatment and level of asthma control.
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studies have shown that asthma can be effectively
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controlled by intervening to suppress and reverse the • Education should be an integral part of all
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and related symptoms. Furthermore, early intervention patients, and is relevant to asthma patients of all
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airway may help improve the control of asthma and reduce • Personal written asthma action plans help individuals
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medication needs. Experience in occupational asthma with asthma make changes to their treatment in
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indicates that long-standing exposure to sensitizing agents response to changes in their level of asthma control,
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may lead to irreversible airflow limitation. as indicated by symptoms and/or peak expiratory
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guidelines.
different ways, depending on the availability of the various
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scientific understanding of asthma. They are based as The effective management of asthma requires the
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far as possible on controlled clinical studies, and the text development of a partnership between the person with
references many of these studies. For those aspects of asthma and his or her health care professional(s) (and
the clinical management of asthma that have not been the parents/caregivers in the case of children with asthma). The
subject of specific clinical studies, recommendations are aim of this partnership is to enable patients with asthma
based on literature review, clinical experience, and expert to gain the knowledge, confidence, and skills to assume
opinion of project members. a major role in the management of their asthma. The
partnership is formed and strengthened as patients and
The recommendations for asthma management are laid out their health care professionals discuss and agree on the
in five interrelated components of therapy: goals of treatment, develop a personalized, written asthma
action plan including self-monitoring, and periodically
1. Develop Patient/Doctor Partnership review the patient’s treatment and level of asthma control
2. Identify and Reduce Exposure to Risk Factors (Figure 4.1-1).
3. Assess, Treat, and Monitor Asthma
4. Manage Asthma Exacerbations
5. Special Considerations.
Guided self-management may involve varying degrees Goal: To provide the person with asthma, their family, and other
of independence, ranging broadly from patient-directed caregivers with suitable information and training so that they can
self-management in which patients make changes without keep well and adjust treatment according to a medication plan
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reference to their caregiver, but in accordance with a prior developed with the health care professional.
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written action plan, to doctor-directed self-management in
Key Components:
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which patients rely follow a written action plan, but refer
o Focus on the development of the partnership
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most major treatment changes to their physician at the
o Acceptance that this is a continuing process
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o A sharing of information
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Figure 4.1-1. Essential Features of the o Full discussion of expectations
Doctor-Patient Partnership to Achieve Guided
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o Expression of fears and concerns
Self-Management in Asthma
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• Regular review of asthma control, treatment, and skills by a o Prevention of symptoms and attacks
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• Written action plan. The person with asthma is taught which o Monitoring control of asthma
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medications to use regularly and which to use as needed, and o How and when to seek medical attention
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• Self-monitoring is integrated with written guidelines for both the The person then requires:
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long-term treatment of asthma and the treatment of asthma o A written asthma action plan
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time of planned or unplanned consultations. Cochrane or willingness to take responsibility similarly differs. Thus
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systematic reviews13,15-18 have examined the role of all individuals require certain core information and skills,
education and self-management strategies in the care of but most education must be personalized and given to
asthma patients. the person in a number of steps. Social and psychological
support may also be required to maintain positive
behavioral change.
ASTHMA EDUCATION
Good communication is essential as the basis for subsequent
Education should be an integral part of all interactions good compliance/adherence19-22,414 (Evidence B). Key
between health care professionals and patients, and is factors that facilitate good communication are23:
relevant to asthma patients of all ages. Although the focus
of education for small children will be on the parents and • A congenial demeanor (friendliness, humor, and
caregivers, children as young as 3 years of age can be attentiveness)
taught simple asthma management skills. Adolescents • Engaging in interactive dialogue
may have some unique difficulties regarding adherence • Giving encouragement and praise
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significant improvements in compliance with treatment personal best rather than percent predicted peak flow32.
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recommendations25. Lay educators can be recruited Patients experience a one-third to two-thirds reduction
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and trained to deliver a discrete area of respiratory care in hospitalizations, emergency room visits, unscheduled
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(for example, asthma self-management education) with visits to the doctor for asthma, missed days of work,
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comparable outcomes to those achieved by primary care and nocturnal wakening. It has been estimated that the
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based practice nurses362 (Evidence B). implementation of a self-management program in 20
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patients prevents one hospitalization, and successful
At the Initial Consultation PY
completion of such a program by eight patients prevents
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one emergency department visit16-18,23 . Less intensive
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Early in the consultation the person with asthma interventions that involve self-management education but
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needs information about the diagnosis and simple not a written plan are less effective15. The efficacy is similar
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information about the types of treatment available, the regardless of whether patients self-adjust their medications
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rationale for the specific therapeutic interventions being according to an individual written plan or adjustments
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recommended, and strategies for avoiding factors that of medication are made by a doctor15 (Evidence B).
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cause asthma symptoms374. Different inhaler devices can Thus, patients who are unable to undertake guided self-
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be demonstrated, and the person with asthma encouraged management can still achieve benefit from a structured
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to participate in the decision as to which is most suitable for program of regular medical review. Although interactive
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them. Some of these devices and techniques for their use computerized asthma education programs may improve
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are illustrated on the GINA Website (http://www.ginasthma. patient asthma knowledge and symptoms, their effect on
org). Criteria for initial selection of inhaler device include objective clinical outcomes is less consistent353 .
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of the health professional and patient26-28 . Patients Examples of written asthma action plans that have been
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should be given adequate opportunity to express their recommended can be found on several Websites (UK
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expectations of both their asthma and its treatment. A frank National Asthma Campaign Plan, www.asthma.org.uk;
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appraisal should be made of how far their expectations may International Asthma Management Plan “Zone System,”
or may not be met, and agreement should be made about www.nhlbisupport.com/asthma/index.html; New Zealand
specific goals for therapy. “Credit Card” System, www.asthmanz.co.nz. An example
of the contents for an asthma plan for patients to maintain
At the initial consultation, verbal information should be control of asthma, and respond to worsening asthma, is
supplemented by the provision of written or pictorial29, 30 shown in Figure 4.1-3.
information about asthma and its treatment. The GINA
Website (http://www.ginasthma.org) contains patient
Follow-Up and Review
educational materials, as well as links to several asthma Follow-up consultations should take place at regular
websites. The patient and his or her family should be intervals. At these visits, the patient’s questions are
encouraged to make a note of any questions that arise from discussed, and any problems with asthma and its initial
reading this information or as a result of the consultation, treatment are reviewed. Patients should be asked to
and should be given time to address these during the next demonstrate their inhaler device technique at every visit,
consultation. with correction and re-checking if it is inadequate33,375.
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Waking at night because of asthma? No Yes
have been developed363, studies of adults and children
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The need to use your [rescue medication] more than 2 times? No Yes
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If you are monitoring peak flow, peak flow less than______? No Yes with asthma34 have shown that around 50% of those on
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if you answered YeS to three or more of these questions, your asthma is Long-term therapy fail to take medications as directed at
uncontrolled and you may need to step up your treatment.
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least part of the time. Patient concern about side-effects of
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HOW TO INCREASE TREATMENT inhaled glucocorticosteroids whether real or perceived may
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STEP-UP your treatment as follows and assess improvement every day: influence adherence342. Non-adherence may be defined in a
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_________________________________ [Write in next treatment step here]
nonjudgmental way as the failure of treatment to be taken as
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Maintain this treatment for _____________ days [specify number]
agreed upon by the patient and the health care professional.
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WHEN TO CALL THE DOCTOR/CLINIC. Non-adherence may be identified by prescription monitoring,
Call your doctor/clinic: _______________ [provide phone numbers]
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3If you have severe shortness of breath, and can only speak in short sentences,
often you actually take the medicine?”). Short questionnaires
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3If you need your reliever medication more than every 4 hours and are not
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improving.
adherence information to clinicians does not improve use
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3. Seek medical help: Go to ________________; Address______________ unless clinicians are sufficiently interested in adherence to
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Phone: _______________________
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Figure 4.1-4.
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Self-Management in Children
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Specific advice about asthma and its management should
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be offered to school teachers and physical education
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instructors, and several organizations produce materials for
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this purpose. Schools may need advice on improving the
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environment and air quality for children with asthma35 . It is
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also helpful for employers to have access to clear advice
about asthma. Most occupations are as suitable for those PY
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with asthma as for those without, but there may be some
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• At this time, few measures can be recommended this process, and no strategies can be recommended to
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for prevention of asthma because the development prevent allergic sensitization prenatally415. Prescription of
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of the disease is complex and incompletely an antigen-avoidance diet to a high-risk woman during
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understood. pregnancy is unlikely to reduce substantially her risk of
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giving birth to an atopic child39. Moreover, such a diet may
• Asthma exacerbations may be caused by a variety
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have an adverse effect on maternal and/or fetal nutrition.
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of risk factors, sometimes referred to as "triggers",
including allergens, viral infections, pollutants, and
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The role of diet, particularly breast-feeding, in relation to the
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drugs.
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development of asthma has been extensively studied and,
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• Reducing a patient’s exposure to some categories in general, infants fed formulas of intact cow’s milk or soy
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Vacuum cleaners with integral HEPA filter Weak None
allergens, viral infections400, pollutants, and drugs. and double-thickness bags
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Reducing a patient’s exposure to some of these categories Remove, hot wash, or freeze soft toys None None
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of risk factors (e.g., smoking cessation, reducing exposure
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to secondhand smoke, reducing or eliminating exposure Pets
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to occupational agents known to cause symptoms, and Remove cat/dog from the home Weak None
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avoiding foods/additives/drugs known to cause symptoms)
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Keep pet from main living areas/bedrooms Weak None
improves the control of asthma and reduces medication
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HEPA-filter air cleaners Some None
needs. In the case of other factors (e.g., allergens, viral O
Wash pet Weak None
infections and pollutants), measures where possible
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usually impractical and very limiting to the patient. Thus, *Adapted from Custovic A, Wijk RG. The effectiveness of measures to change the
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indoor environment in the treatment of allergic rhinitis and asthma: ARIA update
medications to maintain asthma control have an important
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factors when their asthma is under good control. Patients Domestic mites. Domestic mite allergy is a universal
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with well-controlled asthma are less likely to experience health problem59. Since mites live and thrive in many
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exacerbations than those whose asthma is not well- sites throughout the house, they are difficult to reduce
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Among the wide variety of allergen sources in human asthma symptoms in adults55,60-62 (Evidence A). One study
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dwellings are domestic mites, furred animals, cockroaches, showed some efficacy of mattress encasing at reducing
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and fungi. However, there is conflicting evidence airway hyperresponsiveness in children63 (Evidence B).
about whether measures to create a low-allergen An integrated approach including barrier methods, dust
environment in patients' homes and reduce exposure removal, and reduction of microhabitats favorable to mites
to indoor allergens are effective at reducing asthma has been suggested, although its efficacy at reducing
symptoms54,55 . The majority of single interventions symptoms has only been confirmed in deprived populations
have failed to achieve a sufficient reduction in allergen with a specific environmental exposure58 (Evidence B) and
load to lead to clinical improvement55-57. It is likely that a recommendation for its widespread use cannot be made.
no single intervention will achieve sufficient benefits to
be cost effective.However, among inner-city children Furred animals. Complete avoidance of pet allergens is
with atopic asthma, an individualized, home-based, impossible, as the allergens are ubiquitous and can be
comprehensive environmental intervention decreased found in many environments outside the home64, including
exposure to indoor allergens and resulted in reduced schools65, public transportation, and cat-free buildings66.
asthma-associated morbidity58. More properly powered Although removal of such animals from the home is
and well-designed studies of combined allergen-reduction encouraged, even after permanent removal of the animal
strategies in large groups of patients are needed.
TE
spores can best be reduced by removing or cleaning mold- relationship to increased levels of air pollution, and this
U
IB
laden objects69. In tropical and subtropical climates, fungi may be related to a general increase in pollutant levels
TR
may grow on the walls of the house due to water seepage or to an increase in specific allergens to which individuals
IS
and humidity. To avoid this, the walls could be tiled or are sensitized76-78. Most epidemiological studies show a
D
cleaned as necessary. Air conditioners and dehumidifiers significant association between air pollutants–such as
R
may be used to reduce humidity to levels less than 50% ozone, nitrogen oxides, acidic aerosols, and particulate
O
and to filter large fungal spores. However, air conditioning matter–and symptoms or exacerbations of asthma. On
and sealing of windows have also been associated with PY
occasion, certain weather and atmospheric conditions,
O
increases in fungal and house dust mite allergens70.
C
e.g., thunderstorms78 favor the development of asthma
T
changes in temperature/humidity.
D
reduced by closing windows and doors, remaining indoors is usually unnecessary for patients whose asthma is
E R
when pollen and mold counts are highest, and using controlled. For patients with asthma that is difficult
AT
air conditioning if possible. Some countries use radio, to control, practical steps to take during unfavorable
M
television, and the Internet to provide information on environmental conditions include avoiding strenuous
D
TE
outdoor allergen levels. The impact of these measures is physical activity in cold weather, low humidity, or high air
difficult to assess. pollution; avoiding smoking and smoke-filled rooms; and
H
IG
Occupational Exposures
O
C
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severe asthma exacerbations but the likelihood of a
U
IB
reaction is dependent on the nature of the food, the level Emotional Stress
TR
of residual sulfite, the sensitivity of the patient, the form of
IS
residual sulfite and the mechanism of the sulfite-induced Emotional stress may lead to asthma exacerbations
D
reaction85 . The role of other dietary substances—including in children402 and adults. Extreme emotional
R
the yellow dye tartrazine, benzoate, and monosodium expressions (laughing, crying, anger, or fear) can lead
O
glutamate—in exacerbating asthma is probably minimal; to hyperventilation and hypocapnia that can cause
confirmation of their relevance requires double-blind PY
airway narrowing95,96. Panic attacks, that are rare but not
O
C
challenge before making specific dietary restrictions. exceptional in some patients with asthma, have a similar
T
Drugs
N
Some medications can exacerbate asthma. Aspirin and Other Factors That May Exacerbate Asthma
L-
severe exacerbations and should be avoided in patients Rhinitis, sinusitis, and polyposis are frequently associated
E
with a history of reacting to these agents86. There is some with asthma and need to be treated. In children, antibiotic
AT
evidence that exposure to acetaminophen increases the treatment of bacterial sinusitis has been shown to
M
risk of asthma and wheezing in children401 and adults but reduce the severity of asthma99. However, sinusitis and
D
TE
further studies are needed379. asthma may simply coexist. Apart from sinusitis, there
H
Beta-blocker drugs administered orally or intraocularly may asthma. Gastroesophageal reflux can exacerbate
R
exacerbate bronchospasm (Evidence A) and close medical asthma, especially in children, and asthma sometimes
PY
supervision is essential when these are used by patients improves when the reflux is corrected100,101. Many women
O
C
with asthma87. Beta blockers have a proven benefit in the complain that their asthma is worse at the time of
management of patients with acute coronary syndromes menstruation, and premenstrual exacerbations have been
and for secondary prevention of coronary events. Data documented102. Similarly, asthma may improve, worsen,
suggest that patients with asthma who receive newer more or remain unchanged during pregnancy103. A randomized
cardio-selective beta blockers within 24 hours of hospital clinical trial of a self-regulation, telephone counseling
admission for an acute coronary event have lower in- intervention emphasizing sex and gender role factors in
hospital mortality rates366, 367. the management of asthma indicated that a program with
a focus on asthma management problems particular to
Influenza Vaccination women can significantly assist female asthma patients358.
TE
driven by the patients’ asthma control status. If
asthma is not controlled on the current treatment control measures (e.g., Asthma Control Test105, Asthma
U
Control Questionnaire106-108, Asthma Therapy Assessment
IB
regimen, treatment should be stepped up until
TR
control is achieved. When control is maintained for Questionnaire109, Asthma Control Scoring System110)
have been developed and are being validated for various
IS
at least three months, treatment can be stepped
D
down. applications, including use by health care providers to
R
assess the state of control of their patients' asthma and by
O
• In treatment-naïve patients with persistent asthma, patients for self-assessments as part of a written personal
PY
treatment should be started at Step 2, or, if very asthma action plan. Uncontrolled asthma may progress
O
symptomatic (uncontrolled), at Step 3. For Steps 2 to the point of an exacerbation, and immediate steps,
C
through 5, a variety of controller medications are described in Component 4, should be taken to regain
T
O
available. control.
N
INTRODUCTION
IG
Daytime symptoms None (twice or More than twice/week Three or more features of
less/week) partly controlled
asthma*†
Limitation of activities None Any
TE
U
Lung function (PEF or Normal <80% predicted or
IB
FEV1)‡ personal best (if known)
TR
IS
B. Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side-effects)
D
R
O
Features that are associated with increased risk of adverse events in the future include:
PY
Poor clinical control, frequent exacerbations in past year*, ever admission to critical care for asthma, low
O
FEV1, exposure to cigarette smoke, high dose medications
C
* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate
T
O
Lung function is not a reliable test for children 5 years and younger.
D
L-
IA
Most of the medications available for asthma patients, Step 1: as-needed reliever medication. Step 1 treatment
M
when compared with medications used for other chronic with an as-needed reliever medication is reserved for
D
diseases, have extremely favorable therapeutic ratios. untreated patients with occasional daytime symptoms
TE
Each step represents treatment options that, although not (cough, wheeze, dyspnea occurring twice or less per
H
of identical efficacy, are alternatives for controlling asthma. week, or less frequently if nocturnal) of short duration
IG
for Step 5 where issues of availability and safety influence asthma (Figure 4.3-1). Between episodes, the patient is
O
the selection of treatment. Step 2 is the initial treatment asymptomatic with normal lung function and there is no
C
for most treatment-naïve patients with persistent asthma nocturnal awakening. When symptoms are more frequent,
symptoms. If symptoms at the initial consultation suggest and/or worsen periodically, patients require regular
that asthma is severely uncontrolled (Figure 4.3-1), controller treatment (see Steps 2 or higher) in addition to
treatment should be commenced at Step 3. as-needed reliever medication111-113 (Evidence B).
At each treatment step, a reliever medication (rapid- For the majority of patients in Step 1, a rapid-acting
onset bronchodilator, either short-acting or long- inhaled β2-agonist is the recommended reliever
acting) should be provided for quick relief of symptoms. treatment114 (Evidence A). An inhaled anticholinergic,
However, regular use of reliever medication is one of the short-acting oral β2-agonist, or short-acting theophylline
elements defining uncontrolled asthma, and indicates that may be considered as alternatives, although they have
controller treatment should be increased. Thus, reducing a slower onset of action and higher risk of side effects
or eliminating the need for reliever treatment is both an (Evidence A).
important goal and measure of success of treatment. For
Steps 2 through 5, a variety of controller medications are
Management Y
ears,A dolescentsandA dults Approach
Older ThanBased 5
ecud
On Control
Reduce
Level of Control Treatment Action
Increase
TE
Exacerbation Treat as exacerbation
U
IB
TR
IS
D
Treatment Steps
R
Reduce Increase
O
PY
O
Step 1 Step 2 Step 3 Step 4 Step 5
C
T
O
(If step-up treatment is being considered for poor symptom control, first check inhaler technique, check adherence, and confirm symptoms are due to asthma.)
O
D
As needed rapid-
As needed rapid-acting β2-agonist
L-
acting β2-agonist
IA
R
Medium-or high-dose
M
β2-agonist
TE
Controller
H
Alternative reliever treatments include inhaled anticholinergics, short-acting oral β2-agonists, some long-acting β2-agonists, and short-acting theophylline.
Regular dosing with short and long-acting β2-agonists is not advised unless accompanied by regular use of an inhaled glucocorticorsteriod.
For management of asthma in children 5 years and younger, refer to the Global Strategy for the Diagnosis and Management
of Asthma in Children 5 Years and Younger, available at http://www.ginasthma.org.
TE
bronchoconstriction118,119 (Evidence B). Information on addition of a long-acting β2-agonist may not be as effective
U
IB
treatment of exercise-induced asthma in athletes can as increasing the dose of inhaled glucocorticosteroids in
TR
be found in a Joint Task Force Report prepared by the reducing exacerbations151-153 . However, the interpretation
IS
European Respiratory Society, the European Academy of of some studies is problematic as not all children received
D
Allergy and Clinical Immunology, and GA(2)LEN359 and the concurrent inhaled glucocorticosteroids152,153 .
R
World Anti-Doping Agency website (www.wada-ama.org).
O
If a combination inhaler containing formoterol and
Step 2: Reliever medication plus a single controller. PY
budesonide is selected, it may be used for both rescue
O
Treatment Steps 2 through 5, combine an as-needed and maintenance. This approach has been shown to
C
T
reliever treatment with regular controller treatment. result in reductions in exacerbations and improvements
O
At Step 2,a low-dose inhaled glucocorticosteroid is in asthma control in adults and adolescents at relatively
N
patients of all ages111,120 (Evidence A). Equivalent doses approach can be employed with other combinations of
L-
of inhaled glucocorticosteroids, some of which may be controller and reliever requires further study.
IA
adults and in Figure 3-4 for children older than 5 years. Another option for both adults and children, but the
AT
modifiers121-123 (Evidence A), appropriate particularly (Evidence A). For patients of all ages on medium-or
TE
for patients who are unable or unwilling to use inhaled high-dose of inhaled glucocorticosteroid delivered by a
H
IG
glucocorticosteroids, or who experience intolerable side pressurized metered-dose inhaler, use of a spacer device
R
effects such as persistent hoarseness from inhaled is recommended to improve delivery to the airways,
PY
glucocorticosteroid treatment and those with concomitant reduce oropharyngeal side effects, and reduce systemic
O
Other options are available but not recommended for routine Another option at Step 3 is to combine a low-dose inhaled
use as initial or first-line controllers in Step 2. Sustained- glucocorticosteroid with leukotriene modifiers165-173
release theophylline has only weak anti-inflammatory (Evidence A). Alternatively, the use of sustained-release
and controller efficacy126-130 (Evidence B) and is commonly theophylline given at low-dose may be considered129
associated with side effects that range from trivial to (Evidence B). These options have not been fully studied
intolerable131,132 . Cromones (nedocromil sodium and in children 5 years and younger.
sodium cromoglycate) have comparatively low efficacy,
though a favorable safety profile133-136 (Evidence A). Step 4: Reliever medication plus two or more
controllers. The selection of treatment at Step 4 depends
Step 3: Reliever medication plus one or two controllers. on prior selections at Steps 2 and 3. However, the order in
At Step 3, the recommended option for children403 and which additional medications should be added is based,
adolescents and adults is to combine a low-dose of as far as possible, upon evidence of their relative efficacy
inhaled glucocorticosteroid with an inhaled long- in clinical trials. Where possible, patients who are not
TE
(Evidence B). Prolonged use of high-dose inhaled Figure 4.3-1 or a validated composite measure of control.
U
The frequency of health care visits and assessments
IB
glucocorticosteroids is also associated with increased
depends upon the patient’s initial clinical severity, and the
TR
potential for adverse effects. At medium-and high-doses,
patient’s training and confidence in playing a role in the
IS
twice-daily dosing is necessary for most but not all inhaled
on-going control of his or her asthma. Typically, patients
D
glucocorticosteroids176 (Evidence A). With budesonide,
R
efficacy may be improved with more frequent dosing are seen one to three months after the initial visit, and
O
(four times daily)177 (Evidence B). (Refer to Figure 3-1 for every three months thereafter. After an exacerbation,
adults and Figure 3-4 for children older than 5 years for PY
follow-up should be offered within two weeks to one month
O
recommendations on dosing and frequency for different (Evidence D). General practitioners should be encouraged
C
inhaled glucocorticosteroids.)
O
than that achieved with the addition of a long-acting β2- For most classes of controller medications, improvement
E R
agonist165-168,175,178 (Evidence A). The addition of a low- begins within days of initiating treatment, but the full
AT
dose of sustained-release theophylline130 to medium-or benefit may only be evident after 3 or 4 months 360. In
M
high-dose inhaled glucocorticosteroid and long-acting β2- severe and chronically undertreated disease, this can take
D
Step 5: Reliever medication plus additional controller The reduced need for medication once control is achieved
R
options. Addition of oral glucocorticosteroids to other is not fully understood, but may reflect the reversal of
PY
controller medications may be effective179 (Evidence D) some of the consequences of long-term inflammation of
O
but is associated with severe side effects180 (Evidence the airways. Higher doses of anti-inflammatory medication
C
A) and should only be considered if the patient’s asthma may be required to achieve this benefit than to maintain
remains severely uncontrolled on Step 4 medications with it. Alternatively, the reduced need for medication might
daily limitation of activities and frequent exacerbations. simply represent spontaneous improvement as part of the
Patients should be counseled about potential side effects cyclical natural history of asthma. Rarely, asthma may go
and all other alternative treatments must be considered. into remission particularly in children aged 5 years and
younger and during puberty. Whatever the explanation,
Addition of anti-IgE treatment to other controller in all patients the minimum controlling dose of treatment
medications has been shown to improve control of must be sought through a process of regular follow-up and
allergic asthma when control has not been achieved on staged dose reductions.
combinations of other controllers including high-doses of
inhaled or oral glucocorticosteroids181-186 (Evidence B). At other times treatment may need to be increased either
in response to loss of control or threat of loss of control
(return of symptoms) or an acute exacerbation, which is
defined as a more acute and severe loss of control that
TE
treatment is needed, some recommendations can be The need for repeated doses over more than one or
U
IB
made based on the current evidence: two days signals the need for review and possible
TR
increase of controller therapy.
IS
• When inhaled glucocorticosteroids alone in • In the context of asthma self-management
D
medium-to high-doses are being used, a 50% studies, action plans in which the dose of inhaled
R
reduction in dose should be attempted at 3 month
O
glucocorticosteroids was at least doubled were
intervals189-191 (Evidence B).
PY
Oassociated with improved asthma outcomes and
• Where control is achieved at a low-dose of inhaled reduced health care utilisation32. In placebo-
C
glucocorticosteroids alone, in most patients treatment controlled trials, temporarily doubling the dose of
T
O
may be switched to once-daily dosing192,193 (Evidence inhaled glucocorticosteroids was not effective404
N
TE
step-up therapy with long-acting β2-agonist bronchodilator presence of COPD must be excluded. Vocal cord
U
dysfunction must be considered.
IB
was significantly more likely to provide the best
TR
response than either step-up therapy with inhaled • Investigate and confirm adherence with treatment.
IS
glucocorticosteroids or leukotriene receptor antagonist. Incorrect or inadequate use of medications and
D
However, many children had a best response to inhaled inhalers405 remains the most common reason for
R
glucocorticosteroids or leukotriene receptor antagonist failure to achieve good control. In patients with
O
step-up therapy, highlighting the need to regularly monitor difficult-to-treat asthma, improved adherence and
and appropriately adjust each child’s asthma therapy382. PY
improved health outcomes can be achieved with a
O
C
comprehensive concordance intervention416.
T
maintenance treatment can generally be resumed at that may aggravate asthma. Chronic sinusitis,
PY
previous levels unless the exacerbation was associated gastroesophageal reflux, and obesity/obstructive
O
with a gradual loss of control suggesting chronic sleep apnea have been reported in higher
C
undertreatment. In this case, provided inhaler technique percentages in patients with difficult-to-treat asthma.
has been checked, a step-wise increase in treatment Psychological and psychiatric disorders should also
(either in dose or number of controllers) is indicated. be considered. If found, these comorbidities should
be addressed and treated as appropriate, although
Difficult-to-Treat Asthma the ability to improve asthma control by doing so
remains unconfirmed200,348.
Although the majority of asthma patients can obtain the
targeted level of control (Figure 4.3-1), some patients When these reasons for lack of treatment response have
will not do so even with the best therapy104. Patients who been considered and addressed, a compromise level of
do not reach an acceptable level of control at Step 4 control may need to be accepted and discussed with the
(reliever medication plus two or more controllers) can patient to avoid futile over-treatment (with its attendant
be considered to have difficult-to-treat asthma198. These cost and potential for adverse effects). The objective is
patients may have an element of poor glucocorticosteroid then to minimize exacerbations and need for emergency
responsiveness, and require higher doses of inhaled medical interventions while achieving as high a level of
TE
special focus on asthma may be helpful and patients
U
may benefit from phenotyping into categories such as
IB
TR
allergic, aspirin-sensitive, and/or eosinophilic asthma201.
Patients categorized as allergic might benefit from anti-IgE
IS
D
therapy183, and leukotriene modifiers can be helpful for
R
patients determined to be aspirin sensitive (who are often
O
eosinophilic as well)172 .
PY
O
Thermoplasty
C
T
O
research on thermoplasty:
O
D
L-
TE
hospital that provides emergency access for patients with
bronchodilators, the early introduction of systemic acute asthma. Close objective monitoring (PEF) of the
U
IB
glucocorticosteroids, and oxygen supplementation. response to therapy is essential.
TR
• The aims of treatment are to relieve airflow obstruction
IS
and hypoxemia as quickly as possible, and to plan the The primary therapies for exacerbations include—in
D
prevention of future relapses. the order in which they are introduced, depending
R
on severity— repetitive administration of rapid-acting
O
• Severe exacerbations are potentially life threatening,
PY
inhaled bronchodilators, early introduction of systemic
and their treatment requires close supervision. Most
glucocorticosteroids, and oxygen supplementation202.
O
patients with severe asthma exacerbations should be
C
The aims of treatment are to relieve airflow obstruction
treated in an acute care facility. Patients at high risk of
T
flow of less than 20%, nocturnal awakening, and Patients at high risk of asthma-related death require closer
L-
increased use of short acting β2-agonists can usually attention and should be encouraged to seek urgent care
IA
R
be treated in a community setting. early in the course of their exacerbations. These patients
E
include those:
AT
M
INTRODUCTION
TE
breath, cough, wheezing, or chest tightness, or some • Who are currently using or have recently stopped
O
TE
Breathless Walking Talking At rest
U
Infant—softer Infant stops feeding
IB
shorter cry;
TR
difficulty feeding
IS
Can lie down Prefers sitting Hunched forward
D
Talks in Sentences Phrases Words
R
O
Alertness May be agitated Usually agitated Usually agitated Drowsy or confused
PY
Respiratory rate Increased Increased O Often > 30/min
Normal rates of breathing in awake children:
C
Age Normal rate
T
retractions
E R
end expiratory
M
*Note: The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation.
†Note: Kilopascals are also used internationally; conversion would be appropriate in this regard.
TE
limitation and sleep disturbance; all current medications,
repeated administration of rapid-acting inhaled β-agonists
U
including dose (and device) prescribed, dose usually
IB
(2 to 4 puffs every 20 minutes for the first hour) is usually
taken, dose taken in response to the deterioration, and the
TR
the best and most cost-effective method of achieving rapid
patient’s response (or lack thereof) to this therapy; time
IS
reversal of airflow limitation. After the first hour, the dose
of onset and cause of the present exacerbation; and risk
D
of β-agonist required will depend on the severity of the
factors for asthma-related death.
R
exacerbation. Mild exacerbations respond to 2 to 4 puffs
O
every 3 to 4 hours; moderate exacerbations will require 6
PY
The physical examination should assess exacerbation
to 10 puffs every 1 or 2 hours. Treatment should also be
O
severity by evaluating the patient’s ability to complete a
C
titrated depending upon the individual patient’s response, sentence, pulse rate, respiratory rate, use of accessory
T
164,211
delivered via nebulizer. At the clinic level, this route of made before treatment is initiated, although spirometry may
delivery is the most cost effective212, provided patients are
H
able to use an MDI. No additional medication is necessary measurements should be made at intervals until a clear
R
t t
TE
Criteria for Severe Episode:
Criteria for Moderate Episode: • History of risk factors for near fatal asthma
U
• PEF 60-80% predicted/personal best
IB
• PEF < 60% predicted/personal best
• Physical exam: moderate symptoms, accessory muscle use
TR
• Physical exam: severe symptoms at rest, chest retraction
Treatment: • No improvement after initial treatment
IS
• Oxygen
Treatment:
D
• Inhaled 2-agonist and inhaled anticholinergic every 60 min • Oxygen
R
• Oral glucocorticosteroids • Inhaled 2-agonist and inhaled anticholinergic
O
• Continue treatment for 1-3 hours, provided there is improvement • Systemic glucocorticosteroids
PY
• Intravenous magnesium
O
C
t t
T
t t t
D
Good Response within 1-2 Hours: • Risk factors for near fatal asthma
Hours:
IA
treatment
E
• P O2 < 60mm Hg
TE
TE
Oxygen. To achieve arterial oxygen saturation of 90% ( routinely indicated during asthma exacerbations.
U
IB
95% in children), oxygen should be administered by nasal
TR
cannulae, by mask, or rarely by head box in some infants. Additional bronchodilators.
IS
For severe asthma exacerbations, controlled oxygen
D
therapy using pulse oximetry to maintain oxygen saturation Ipratropium bromide. A combination of nebulized β2-agonist
R
at 90 – 93% is associated with better physiological with an anticholinergic (ipratropium bromide) may produce
O
outcomes, compared to high flow 100% oxygen therapy218, better bronchodilation than either drug alone231 (Evidence
419
. Oxygen therapy should be titrated against pulse PY
B) and should be administered before methylxanthines
O
are considered. Combination β2-agonist/anticholinergic
C
oximetry to maintain a satisfactory oxygen saturation219.
therapy is associated with lower hospitalization rates212,232,233
T
Rapid-acting inhaled ß2–agonists. Rapid-acting inhaled in the pediatric literature212 (Evidence A). However, once
L-
which has both a rapid onset of action and a long duration safety of rapid-acting β2-agonists, theophylline has a
of effect, has been shown to be equally effective without
H
increasing side effects, though it is considerably more is associated with severe and potentially fatal side effects,
R
TE
Daily doses of systemic glucocorticosteroids equivalent to
children.
U
60-80 mg methylprednisolone as a single dose, or 300-
IB
400 mg hydrocortisone in divided doses, are adequate
TR
for hospitalized patients, and 40 mg methylprednisolone Helium oxygen therapy. A systematic survey of studies
IS
or 200 mg hydrocortisone is probably adequate in most that have evaluated the effect of a combination of helium
D
cases238,242 (Evidence B). An oral glucocorticosteroid dose and oxygen, compared to helium alone, suggests there is
R
no routine role for this intervention. It might be considered
O
of 1 mg/kg daily is adequate for treatment of exacerbations
for patients who do not respond to standard therapy257.
PY
in children with mild persistent asthma243. A 7-day course O
in adults has been found to be as effective as a 14-day
Leukotriene modifiers. There are little data to suggest
C
course244, and a 3-to 5-day course in children is usually
T
considered appropriate (Evidence B). Two days of a role for leukotriene modifiers in acute asthma258. Small
O
exacerbations, but there are concerns about metabolic but clinical relevance requires more study.
D
in acute asthma provided greater bronchodilation than discharged from the emergency department or admitted to
salbutamol alone247 (Evidence B), and conferred greater the hospital have been succinctly reviewed and stratified
benefit than the addition of systemic glucocorticosteroids based on consensus260 . Patients with a pre-treatment FEV1
across all parameters, including hospitalizations, especially or PEF < 25% percent predicted or personal best, or those
for patients with more severe attacks248 . with a post-treatment FEV1 or PEF < 40% percent predicted
or personal best, usually require hospitalization. Patients
Inhaled glucocorticosteroids can be as effective as oral with post-treatment lung function of 40-60% predicted
glucocorticosteroids at preventing relapses249,250. Patients may be discharged, provided that adequate follow-up is
discharged from the emergency department on prednisone available in the community and compliance is assured.
and inhaled budesonide have a lower rate of relapse than Patients with post-treatment lung function
those on prednisone alone237 (Evidence B). A high-dose 60% predicted can be discharged.
of inhaled glucocorticosteroid (2.4 mg budesonide daily
in four divided doses) achieves a relapse rate similar to Management of acute asthma in the intensive care unit
40 mg oral prednisone daily251 (Evidence A). Cost is a is beyond the scope of this document and readers are
significant factor in the use of such high-doses of inhaled referred to recent comprehensive reviews261 .
*Visit GINA website, www.ginasthma.org for GRADE review of question “In adults with acute
78 ASTHMA MANAGEMENT AND PREVENTION exacerbations of asthma, does intravenous magnesium sulphate compared to placebo improve patient
important outcomes?”
For patients discharged from the emergency department: opportunity to review patient understanding of the causes
of asthma exacerbations, avoidance of factors that may
• At a minimum, a 7-day course of oral cause exacerbations (including, where relevant smoking
glucocorticosteroids for adults and a shorter course cessation), the purposes and correct uses of treatment, and
(3-5 days) for children should be prescribed, along the actions to be taken to respond to worsening symptoms
with continuation of bronchodilator therapy. or peak flow values263 (Evidence A).
• The bronchodilator can be used on an as-needed Referral to an asthma specialist should be considered for
basis, based on both symptomatic and objective hospitalized patients. Following discharge from continuous
improvement, until the patient returns to his or her pre- supervision, the patient should be reviewed by the family
exacerbation use of rapid-acting inhaled β2-agonists. health care professional or asthma specialist regularly over
the subsequent weeks until personal best lung function is
• Ipratropium bromide is unlikely to provide additional reached. Use of incentives improves primary care follow up
benefit beyond the acute phase and may be quickly but has shown no effect on long term outcomes264. Patients
discontinued. who come to the emergency department with an acute
• Patients should initiate or continue inhaled exacerbation should be especially targeted for an asthma
glucocorticosteroids. education program, if one is available.
TE
• The patient’s inhaler technique and use of peak flow
U
IB
meter to monitor therapy at home should be reviewed.
TR
Patients discharged from the emergency department
IS
with a peak flow meter and action plan have a better
D
response than patients discharged without these
R
resources8.
O
PY
• The factors that precipitated the exacerbation should O
be identified and strategies for their future avoidance
C
implemented.
T
O
exacerbations.
IG
TE
and in the remaining one-third it remains unchanged during leukotriene antagonists, inhaled glucocorticosteroids
are considered the mainstay of asthma treatment in this
U
pregnancy265-267.
IB
population385, 386.
TR
Although there is a general concern about the use of any
IS
medication in pregnancy, poorly controlled asthma can Although asthma is not more often over-diagnosed in
D
have an adverse effect on the fetus, resulting in increased obese compared to non-obese patients, it is particularly
R
O
perinatal mortality, increased prematurity, and low birth important to confirm the diagnosis by objective measures
PY
weight266,267. The overall perinatal prognosis for children of variable airway obstruction or bronchial hyper-
responsiveness, as respiratory symptoms associated to
O
born to women with asthma that is well-managed during
C
pregnancy is comparable to that for children born to women obesity may mimic asthma388. Weight loss in the obese
T
without asthma268. For this reason, using medications to patient improves asthma control, lung function and reduces
O
N
obtain optimal control of asthma is justified even when medication needs and should be included in the treatment
O
Inhaled glucocorticosteroids have been shown to prevent The likelihood of these complications depends on the
H
exacerbations of asthma during pregnancy269,270 (Evidence severity of asthma at the time of surgery, the type of
IG
B). As in other situations, the focus of asthma treatment surgery (thoracic and upper abdominal surgeries pose the
R
PY
must remain on control of symptoms and maintenance greatest risks), and type of anesthesia (general anesthesia
of normal lung function271. Acute exacerbations should with endotracheal intubation carries the greatest risk).
O
C
be treated aggressively in order to avoid fetal hypoxia. These variables need to be assessed prior to surgery
Treatment should include nebulized rapid-acting β2- and pulmonary function should be measured. If possible,
agonists and oxygen and systemic glucocorticosteroids this evaluation should be undertaken several days before
should be instituted when necessary. surgery to allow time for additional treatment. In particular,
if the patient’s FEV1 is less than 80% of personal best,
While all patients should have adequate opportunity to a brief course of oral glucocorticosteroids should be
discuss the safety of their medications, pregnant patients considered to reduce airflow limitation274,275 (Evidence
with asthma should be advised that the greater risk to their C). Furthermore, patients who have received systemic
baby lies with poorly controlled asthma, and the safety of glucocorticosteroids within the past 6 months should
most modern asthma treatments should be stressed. Even have systemic coverage during the surgical period (100
with a good patient/health care professional relationship, mg hydrocortisone every 8 hours intravenously). This
independent printed material, such as a statement from the should be rapidly reduced 24 hours following surgery, as
US National Asthma Education and Prevention Program on prolonged systemic glucocorticosteroid therapy may inhibit
the treatment of asthma during pregnancy272, will provide wound healing276 (Evidence C).
important additional reassurance265,273.
TE
outdoor allergens such as house dust mites, animal dander, assessed for cystic fibrosis and immotile cilia syndrome.
U
IB
and, less commonly, pollen affecting both the nose and Nasal polyps are quite responsive to topical
TR
bronchi281,282, occupational sensitizers283, and non-specific glucocorticosteroids288. A limited number of patients with
IS
factors like aspirin. For these reasons, the Allergic Rhinitis glucocorticosteroid-refractory polyps may benefit from
D
and its Impact on Asthma (ARIA) initiative recommends that surgery.
R
the presence of asthma must be considered in all patients
O
with rhinitis, and that in planning treatment, both should be Occupational Asthma
considered together284. PY
O
C
Once a diagnosis of occupational asthma is established,
T
Both asthma and rhinitis are considered to be complete avoidance of the relevant exposure is ideally an
O
inflammatory disorders of the airway, but there are some important component of management300-302,412. Occupational
N
O
differences between the two conditions in mechanisms, asthma may persist even several years after removal
D
clinical features, and treatment approach. Although the from exposure to the causative agent, especially when
L-
inflammation of the nasal and bronchial mucosa may be the patient has had symptoms for a long time before
IA
similar, nasal obstruction is largely due to hyperemia in cessation of exposure303,304. Continued exposure may
E R
rhinitis, while airway smooth muscle contraction plays a lead to increasingly severe and potentially fatal asthma
AT
Treatment of rhinitis may improve asthma symptoms286,287 permanently impaired lung function306 . Pharmacologic
(Evidence A). Anti-inflammatory agents including therapy for occupational asthma is identical to therapy for
H
IG
glucocorticosteroids and cromones as well as leukotriene other forms of asthma, but it is not a substitute for adequate
R
modifiers and anticholinergics can be effective in both avoidance. Consultation with a specialist in asthma
PY
conditions. However, some medications are selectively management or occupational medicine is advisable.
O
against asthma (e.g., β2-agonists)288 (Evidence A). Use The British Occupational Health Research Foundation
of intra-nasal glucocorticosteroids for concurrent rhinitis Guidelines for the prevention, identification, and
has been found to have a limited benefit in improving management of occupational asthma are available at http://
asthma and reducing asthma morbidity in some but not all www.bohrf.org.uk/downloads/asthevre.pdf. (See also
studies289-291. Leukotriene modifiers125,292, allergen-specific reference 421.)
immunotherapy284,293, and anti-IgE therapy294,295 are effective
in both conditions (Evidence A). Respiratory Infections
Additional information on this topic from the Allergic Rhinitis Respiratory infections have an important relationship
and its Impact on Asthma (ARIA) initiative can be found at to asthma as they provoke wheezing and increased
http://www.whiar.org284. symptoms in many patients307 and are commonly found
in children with asthma exacerbation391. Epidemiological
Sinusitis. Sinusitis is a complication of upper respiratory studies have found that infectious microorganisms
infections, allergic rhinitis, nasal polyps, and other forms associated with increased asthma symptoms are often
TE
is evidence that viral infections are an “adjuvant” to the In summary, despite a high prevalence of asymptomatic
U
IB
inflammatory response and promote the development of gastroesophageal reflux among patients with poorly
TR
airway injury by enhancing airway inflammation313. controlled asthma, treatment with proton-pump inhibitors
IS
does not improve asthma control in adults392-394 or
D
Treatment of an infectious exacerbation follows the same children422. Asymptomatic gastroesophageal reflux is
R
principles as treatment of other asthma exacerbations— not a likely cause of poorly controlled asthma. Surgery
O
that is, rapid-acting inhaled β2-agonists and early for gastroesophageal reflux is reserved for the severely
introduction of oral glucocorticosteroids or increases PY
symptomatic patient with well-documented esophagitis and
O
in inhaled glucocorticosteroids by at least four-fold are failure of medical management. In patients with asthma,
C
T
recommended. Because increased asthma symptoms can it should be demonstrated that the reflux causes asthma
O
often persist for weeks after the infection is cleared, anti- symptoms before surgery is advised321,322.
N
O
The role of chronic infection with Chlamydia pneumoniae Up to 28% of adults with asthma, but rarely children with
E R
and Mycoplasma pneumoniae in the pathogenesis or asthma, suffer from asthma exacerbations in response
AT
worsening of asthma is currently uncertain314. The benefit to aspirin and other nonsteroidal anti-inflammatory drugs
M
from macrolide antibiotics remains unclear315-317. A relatively (NSAIDs). This syndrome is more common in severe
D
asthma323 .
benefit from the addition of clarithromycin to adults with
H
IG
mild to moderately severe asthma on low dose inhaled The clinical picture and course of aspirin-induced asthma
R
glucocorticosteroids413. However, further research in this (AIA) are characteristic324. The majority of patients first
PY
TE
A characteristic history of reaction is considered adequate urticaria, and angioedema; upper and lower airway
U
for initiating avoidance strategies. However, the diagnosis
IB
involvement such as stridor, dyspnea, wheezing, or apnea;
TR
can only be confirmed by aspirin challenge, as there dizziness or syncope with or without hypotension; and
are no suitable in vitro tests for diagnosis. The aspirin
IS
gastrointestinal symptoms such as nausea, vomiting,
D
challenge test is not recommended for routine practice cramping, and diarrhea. Exercise-induced anaphylaxis,
R
as it is associated with a high risk of potentially fatal often associated with medication or food allergy, is a unique
O
consequences and must only be conducted in a facility physical allergy and should be differentiated from exercise-
with cardiopulmonary resuscitation capabilities331. Further
PY
induced bronchoconstriction338.
O
safeguards are that patients should only be challenged
C
greater than 70% of predicted or personal best. Bronchial of asthma attacks in severe asthma and the relative
N
are safer than oral challenges and may be performed agonists180. If there is a possibility that anaphylaxis is
L-
in specialized centers332,333. Once aspirin or NSAID involved in an asthma attack, epinephrine should be the
IA
hypersensitivity develops, it is present for life. Patients bronchodilator of choice. Prompt treatment for anaphylaxis
R
other analgesics that inhibit COX-1, and often also injectable antihistamine, intravenous hydrocortisone,
M
epinephrine syringes339.
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CHAPTER 5: IMPLEMENTATION OF ASTHMA
GUIDELINES IN HEALTH SYSTEMS
problem worldwide. Barriers to implementation range from
KEY POINTS: poor infrastructure that hampers delivery of medicines to
remote parts of a country, to cultural factors that make
• In order to effect changes in medical practice and patients reluctant to use recommended medications (e.g.,
consequent improvements in patient outcomes, inhaled preparations), suboptimal use of medications21, and
evidence-based guidelines must be implemented and lack of physician use of guidelines.
disseminated at the national and local levels.
An important barrier to the successful translation of asthma
• Implementation of asthma guidelines should involve guidelines into clinical practice is access to available
a wide variety of professional groups and other and affordable medication especially for patients in less
stakeholders, and take into account local cultural and developed economies where the cost of treatment is high in
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economic conditions. comparison to income and assets.
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• An important part of the implementation process is to
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establish a system to evaluate the effectiveness and GUIDELINE IMPLEMENTATION
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quality of care.
STRATEGIES
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• Those involved in the adaptation and implementation
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of asthma guidelines require an understanding of the
cost and cost effectiveness of various management Implementation of asthma guidelines should begin with the
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recommendations in asthma care. setting of goals and development of strategies for asthma
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• GINA has developed a number of resources and groups including both primary and secondary health care
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programs to aid in guideline implementation and professionals, public health officials, patients, asthma
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Figure 5-1.
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It has been demonstrated in a variety of settings that The next step is adaptation of guidelines on asthma
patient care consistent with recommendations in evidence- management for local use by teams of local primary and
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based asthma guidelines leads to improved outcomes. secondary care health professionals. Many low-and middle
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Guidelines are designed to ensure that all members of income countries do not consider asthma a high-priority
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a patient’s health care team are aware of the goals of health concern because other, more common respiratory
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treatment and of the different ways of achieving these diseases such as tuberculosis and pneumonia are of
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goals. They help set standards of clinical care, may serve greater public health importance1. Therefore, practical
as a basis for audit and payment, and act as a starting asthma guidelines for implementation in low-income
point for the education of health professionals and patients. countries should have a simple algorithm for separating
non-infectious from infectious respiratory illnesses; simple
However, in order to effect changes in medical practice objective measurements for diagnosis and management
and consequent improvements in patient outcomes, such as peak flow variability2; available, affordable, and
evidence-based guidelines must be implemented and low-risk medications recommended for asthma control; a
disseminated at national and local levels. Dissemination simple regime for recognizing severe asthma; and simple
involves educating clinicians to improve their diagnosis and management approaches relevant to the
awareness, knowledge, and understanding of guideline facilities and limited resources available.
recommendations. It is one part of implementation,
which involves the translation of evidence-based asthma Next, adapted guidelines must be widely disseminated in
guidelines into real-life practice with improvement of health multiple venues and using multiple formats. This can be
outcomes for the patient. Implementation remains a difficult accomplished, for example, by publication in professional
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sets of data to audit health outcomes. There are a variety
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• What treatments are currently used?
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of assessment tools which provide a consistent and
• How affordable and accessible are medications and services to
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the patient?
objective assessment of asthma morbidity or control (e.g.,
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Asthma Control Test9, Asthma Control Questionnaire10-12 ,
• What other treatments are available, cheap enough for
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purchase, and stable in local climatic conditions?
Asthma Therapy Assessment Questionnaire13). Results
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of these assessments should be recorded at each visit,
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• Can inhaler devices and medicines be standardized to reduce
providing a record of the long-term clinical response of
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cost/storage/availability problems?
the patient to treatment. Direct feedback provides several
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• Who will provide emergency care?
benefits-a means for the patient/caregiver to become
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professionals?
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• Who will take responsibility for the education of people with culturally appropriate direct feedback of clinical outcomes
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• How can asthma education and treatment be integrated into patients may be important for general practitioners who
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patients accordingly.
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majority of exacerbation-related treatment costs. In clinical standardized, validated, and culturally adapted instruments
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trials of asthma treatments, exacerbations are customarily for assessing these measures in a variety of populations.
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characterized by use of health care resources, alone or
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in combination with symptom and lung function data, Determining the Economic Value of Interventions
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especially when the primary study outcome is reduction in Asthma
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in the exacerbation frequency or time to an exacerbation
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event. Routine collection of health care resource Economic evaluations require the selection of three main
consumption data can be undertaken in the field through PY
outcome parameters-estimates of treatment-related health
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patient or caregiver self-report. In some circumstances, benefits, treatment-related risks, and treatment-related
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automated data from clinical or billing records can costs. These parameters can be determined directly from
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Composite definitions of asthma control16,17 may include evaluations determine the choices of health benefit
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one or more health care utilization items. These items measures. When the decision to be considered is at the
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an exacerbation-related treatment in precise and valid in a government-sponsored health care program or the
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terms. Many of the published composite measures benefits package of a health insurer, economic evaluations
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of asthma control have included hospitalization and require the use of a common metric such as life years
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emergency treatment data, such as unscheduled or urgent gained, improvement in generic quality of life, or quality-
care visits or use of nebulized β2-agonists and/or oral
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glucocorticosteroids17 . Although health care utilization support comparison of cost-effectiveness ratios across
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elements are essential to any pragmatic definition of different disease states and patient populations. However,
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asthma control, as yet unanswered in the literature is which in asthma, QALYs are difficult to measure, particularly
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include:
a World Health Organization initiative (http://www.
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who.int/respiratory/gard/en/). The goal of GARD is to
Gina Website -www.ginasthma.org. The Internet is
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facilitate collaboration among existing governmental
creating a conduit for the access, sharing, and exchange
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and nongovernmental programs interested in chronic
of information and permits the global distribution of
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respiratory diseases to assure more efficient utilization
medical information. Although it is still not widely available,
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of resources and avoid duplication of efforts. The
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especially in low-income countries, the global trend is for
participating organizations will develop a comprehensive
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increasing use of the Internet for medical education by
global approach to the prevention and control of
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asthma patients and their health care providers. Thus, to
chronic respiratory diseases, with a special emphasis
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facilitate communication with health professionals, health
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REFERENCES
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first Tuesday in May, World Asthma Day is organized 1. Stewart AW, Mitchell EA, Pearce N, Strachan DP, Weilandon
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by GINA in collaboration with health care groups and SK. The relationship of per capita gross national product to the
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asthma educators throughout the world. World Asthma prevalence of symptoms of asthma and other atopic diseases
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Day activities focus on dissemination of information in children (ISAAC). Int J Epidemiol 2001;30(1):173-9.
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about asthma among the general population, health care 2. Higgins BG, Britton JR, Chinn S, Cooper S, Burney PG,
Tattersfield AE. Comparison of bronchial reactivity and peak
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with asthma and their relatives, these activities foster studies. Am Rev Respir Dis 1992;145(3):588-93.
an appreciation of the importance of asthma on a local,
3. Partridge MR, Harrison BD, Rudolph M, Bellamy D,
regional, national, and international level. Activities include Silverman M. The British Asthma Guidelines--their production,
sporting events; meetings of people with asthma and their dissemination and implementation. British Asthma Guidelines
families with health professionals; meetings with local Co-ordinating Committee. Respir Med 1998;92(8):1046-52.
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5. Bero LA, Grilli R, Grimshaw JM, Harvey E, Oxman AD,
Regional Initiatives. To examine the formation of networks Thomson MA. Closing the gap between research and practice:
to facilitate the process of guideline implementation, two an overview of systematic reviews of interventions to promote
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‘wellcontrolled’ and ‘not well-controlled’ asthma using the
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Asthma Control Questionnaire. Respir Med 2005.
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12. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement
properties and interpretation of three shortened versions of the
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asthma control questionnaire. Respir Med 2005;99(5):553-8.
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Chiesi
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GlaxoSmithKline
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Novartis
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Quintiles
Takeda