Philippine College of Chest Physicians

Transcription

CPM 9TH EDITION
Philippine College of Chest Physicians
ASthma
84-A Malakas St., East Ave., Quezon City
Tel No. 924-9204; Fax No. 924-0144
E-mail: [email protected]
Website: http://www.philchest.org
Officers and Board of Trustees
President
Vice President
Secretary
Treasurer
Board Members
Immediate Past President
Renato B. Dantes, M.D., FPCCP
Mario Joselito M. Juco, M.D., FPCCP
Gracita Rigonan-Ramos, M.D., FPCCP
Sylvia Banal-Yang, M.D., FPCCP
Abundio A. Balgos, M.D., FPCCP
Charles Y. Yu, M.D., FPCCP
Ma. Encarnita Blanco-Limpin, M.D., FPCCP
Isagani C. Rodriguez, M.D., FPCCP
Celeste Mae L. Campomanes, M.D., FPCCP
Marilyn Ong-Mateo, M.D., FPCCP
Contributors
Chairperson, 1998-2004
Project Chairman
Project Secretary
Glen Elmer I. Alvarado, M.D., FPCCP
Eileen G. Aniceto, M.D., FPCCP
Roberto A. Barzaga, M.D., FPCCP
Ma. Elizabeth V. Cadena, M.D., FPCCP
Manuel C. Jorge II, M.D., FPCCP
Isaias A. Lanzona, M.D., FPCCP
Ma. Theresa C. Magtibay, M.D., FPCCP
Ma. Piedad R. Natividad, M.D., FPCCP
Dina V. Diaz, M.D., FPCCP
Tito C. Atienza, M.D., FPCCP
Eloisa S. de Guia, M.D., FPCCP
Josephine B. Ramos, M.D., FPCCP
Camilo C. Roa Jr., M.D., FPCCP
Ma. Bella R. Siasoco, M.D., FPCCP
Aileen D. Wang, M.D., FPCCP
Jennifer M. Wi, M.D., FPCCP
Sylvia B. Yang, M.D., FPCCP
Ricardo C. Zotomayor, M.D., FPCCP
139
ASthma
CPM 9TH EDITION
Consultant Panel of Reviewers/Advisers
Fernando G. Ayuyao, M.D., FPCCP
Rodolfo M. Carungin, M.D., FPCCP
Renato B. Dantes, M.D., FPCCP
Teresita S. de Guia, M.D., FPCCP
Tiburcio A. Leonin, Jr., M.D., FPCCP
Madeleine W. Sumpaico, M.D., FPSAI
Charles Y. Yu, M.D., FPCCP
Asthma Council
Tito C. Atienza, M.D., FPCCP, Chairman
Glen Elmer I. Alvarado, M.D., FPCCP
Eileen G. Aniceto, M.D., FPCCP
Angelo Arreza, M.D.
Roberto A. Barzaga, M.D., FPCCP
Ma. Theresa H. Bernardo, M.D., FPCCP
Elizabeth V. Cadena, M.D., FPCCP
Richmond B. Ceniza, M.D.
Eloisa S. De Guia, M.D., FPCCP
Gabriel E. De Leon, M.D.
Dina V. Diaz, M.D., FPCCP
Raymund F. Diga, M.D.
Anderson U. Dy, M.D.
Malbar G. Ferrer, M.D., FPCCP
Joven Roque V. Gonong, M.D.
Renato B. Herradura, M.D., FPCCP
Fidelinda E. Ilano, M.D.
Mari Cecilia I. Jocson, M.D.
Manuel Peter Paul C. Jorge II, M.D., FPCCP
Emmanuel Kasilag, M.D., FPCCP
Isaias A. Lanzona, M.D., FPCCP
Juliet Macahilas, M.D.
Aniceto Madronio, M.D.
Rogelito Don Maningas, M.D.
Lalaine Llamido-Mortera, M.D.
Ma. Piedad R. Natividad, M.D., FPCCP
Lalaine M. Nicolas, M.D.
Ogee Mer A. Panlaqui, M.D.
Marietto L. Partosa, Jr., M.D.
Ronald Allan R. Payumo, M.D.
Rosemarie R. Pingol, M.D., FPCCP
Josephine Blanco-Ramos. M.D., FPCCP
Glenford R. Refre, M.D.
Rhoderick Ian Reyes, M.D., FPCCP
Camilo C. Roa Jr., M.D., FPCCP
Shelley Romero, M.D.
Ma. Bella R. Siasoco, M.D., FPCCP
Rollin P. Tabuena, M.D.
Cynthia R. Talla, M.D., FPCCP
Samson Tan, M.D.
Esther Fredelyn M. Tomas, M.D.
Aileen David-Wang, M.D., FPCCP
Jennifer Ann Mendoza-Wi, M.D., FPCCP
Sylvia Banal-Yang, M.D., FPCCP
Raphael Ryan Zantua, M.D.
Ricardo C. Zotomayor, M.D. FPCCP
140
CPM 9TH EDITION
ASthma
algorithm for Asthma Management
1
Patient with
asthma presenting with
symptoms
3

2
In acute exacerbation?
Y

Classify and treat
based on Severity Classification of
Asthma in Acute
Exacerbation*
N

4
Currently on
controller
medications?
6
5
Y
Assess response to cur rent treatment

Increased or
continued need
for relievers?
Y
12
11
Classify using Spirometry results in Clas sification of Chronic
Severity**
Classified as
Severe?

Y
Treat as Severe Persistent
 Asthma
N

Treat as Mild to Moderate Persistent Asthma
N

Classify using
Symptom Frequency in Classification of Chronic
Severity**
Step-up controllers


10
13
14

Maintain on current
Controllers
N
Spirometry
results available?
Y
N
8
9
7
15

Asthma
symptoms
persistent?
Treat as Intermittent
Asthma*
Y
Classified as
Severe?

19
Y
Treat as Severe Persistent
 Asthma*
N

N

18
17
16
Treat as Mild to
Moderate Persistent
Asthma*
* Refer to Phil Consensus Report on Asthma Diagnosis & Treatment 1996
** Refer to Table 1.3.
141
ASthma
CPM 9TH EDITION
Philippine Consensus Report on Asthma 2004
Chapter 1
Epidemiology, Diagnosis and Classification of
Asthma
Question No. 1:
Is asthma a common condition worldwide?
Answer:
Yes, asthma is a common disease worldwide and, over
the past two decades, is showing an increasing trend for
all ages, sex, and racial groups.
Summary of Evidence:
In 1995, the International Study of Asthma and Allergies
in Children (ISAAC) conducted Phase I of a worldwide
study to describe the prevalence and severity of asthma,
rhinitis, and eczema among school children. One
hundred fifty five centers in 56 countries participated,
including the Philippines.1 More than 450,000 children
were interviewed using a one-page written questionnaire
or a video asthma questionnaire. The study showed that
the prevalence of asthma symptoms in children varied
greatly in different populations with differences ranging
between 20- and 60-fold. The highest prevalence was
found from centers in the United Kingdom, Australia
and New Zealand.2,3
Prevalence of asthma is increasing by 4% each year.4
In the United States, the prevalence of asthma cases
was noted to be increasing since the early 1980s for all
ages, sex, and racial groups.5,6 The prevalence is higher
among children than adults and higher among blacks
than whites. In the general population, the prevalence of
asthma is higher among females, however, in children,
the prevalence is higher among males. Furthermore, the
prevalence among impoverished inner city children has
been much higher.7,8
References:
1. Asher MI, Keil U, Anderson HR, et al. International Study
of Asthma and Allergies in Childhood (ISAAC): rationale
and methods. Eur. Respir J. 1995;8:483-91.
2. Asher MI, Anderson HR, Stewart AW, et al. The International Study of Asthma and Allergies in Childhood
(ISAAC) Steering Committee. Worldwide variations in
the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic dermatitis: ISAAC. Eur. Respir.
J. 1998;12:315-35.
3. Beasley R, Keil U, von Mutius E, Pearce N. ISAAC Steering Committee: Worldwide variations in the prevalence
of symptoms of asthma, allergic rhinoconjunctivitis and
atopic dermatitis: ISAAC. Lancet. 1998;351:1225-32.
4. Barbers R. Asthma in Y2K and beyond. Curr Opin Pulm.
Med. 2000;6:1-3.
5. U.S. Department of Health and Human Services. National
Heart, Lung and Blood Institute Data Fact Sheet Asthma
Statistics. 1999. Jan.
6. Mannimo DM, Homa DM, Pertowski CA, et al. Surveillance for asthma - United States, 1950-1995. MMWR
142
Mortal. Morb. Wkly Rep. 1998;47;1-27.
7. Crain EF, Weiss KB, Bijur PE, Hersh M, Westbrook
L, Stein RE. An estimate of the prevalence of asthma
and wheezing among inner-city children. Pediatrics.
1994;94:356-62.
8. Persky VW, Slezak J, Contreras A, et al. Relationship of
race and socioeconomic status with prevalence, severity,
and symptoms of asthma in Chicago school children. Ann.
Aller. Asthma Immunol. 1998;81:266-71.
Question No. 2:
How common is asthma in the Philippines?
Answer:
There are no available nationwide data published on
asthma prevalence. However, the limited reports gathered showed a prevalence of 12% in children aged 13-14
years and 17-22% in older age groups.
Three thousand two hundred and seven children in
Metro Manila aged 13-14 years participated in the
ISAAC.1 Participants accomplished a 12-month preva
lence of self-reported asthma symptoms from written
questionnaires and from video questionnaires. The
results showed that approximately 12% and 8% prevalence based on responses to the written questionnaire
and to the video questionnaire respectively. In a subsequent study, 12.3% of the same population reported
wheezing.2 [LEVEL 3]
A local study estimating the prevalence of asthma and
allergies in adults was completed in Malolos, Bulacan
in 1998.3 [LEVEL 3] One thousand five (1,005) adults
(ages 18-44 years) were interviewed using a pre-tested
questionnaire adapted from the European Community
Health Survey (ECHRS) and the ISAAC. The study
showed a prevalence of 17.2% for asthma and 49.9%
for allergy among adults. Another study conducted at
the Lung Center of the Philippines reported a prevalence
of 22% in adults.4
References:
1. Asher MI, Anderson HR, Stewart AW, et al. The International Study of Asthma and Allergies in Childhood
(ISAAC) Steering Committee. Worldwide variations in
the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic dermatitis: ISAAC. Eur. Respir.
J. 1998;12:315-35.
2. Beasley R, Keil U, von Mutius E, Pearce N. ISAAC Steering Committee: Worldwide variations in the prevalence
of symptoms of asthma, allergic rhinoconjunctivitis and
atopic dermatitis: ISAAC. Lancet. 1998;351:1225-32.
3. Cua-Lim F, Roa CC, Pagkatipunan R. Prevalence of adult
asthma and allergies in Malolos, Bulacan, Metro Manila,
Philippines. Presented as a poster study at the 3rd Asian
Pacific Congress of Allergology and Clinical Immunology,
PICC, Manila, Philippines, 1998. Dec 9-11.
4. Diaz DV. A prevalence survey of asthma in a Filipino
population in Metro Manila. Phil. J. Chest Dis. 1996;
4:68-73.
CPM 9TH EDITION
Question No. 3:
What is the current concept of asthma as a disease?
Answer:
In the last four decades, asthma was considered as
predominantly a disease of airway smooth muscle.1,2
However, based on the National Institute of Health
(NIH) guidelines in 1997, the understanding of asthma
has shifted from a disease of airway smooth muscle to
one of airway inflammation.3 This concept of bronchial
inflammation arose from studies of bronchial hyper
responsiveness, bronchioalveolar lavage (BAL), bron
chial biopsies and induced sputum from asthmatics,
and observations made postmortem of patients who
died from asthma.
Interestingly, structural abnormalities in the airways
have been observed even on patients maintained on
anti-inflammatory medications and on those with mild
asthma.4,5,6 Evidently, the incessant release of inflam
matory mediators from eosinophils and mast cells results
in persistent bronchial inflammation of the airways.
Eventually the airways undergo structural abnormalities
resulting in the following: fibrosis, increase in mass of
smooth muscle and mucus glands,7,8,9 epithelial shedding, thickening of the reticular basement membrane,10
and fibronectin deposition in the subepithelial layer.11
Histological sections show thickening of the airway
walls by 50-300% of normal.12 These changes in the
composition and organization of the cellular and molecular components of the airway wall result in a process
called airway remodeling.13 Figure 1 shows a proposed
mechanism of airway remodeling.14
ASthma
Airway remodeling results in the following physiologic
consequences: 1) increase in airway hyperresponsive
ness,15 2) non-reversibility of airway obstruction and
residual obstruction after bronchodilator and anti-inflammatory therapy,4,16 and 3) accelerated decline in
FEV1 in a subset of asthmatic patients.14
References:
1. Ciba Guest Symposium: Terminology, definitions and classifications of chronic pulmonary emphysema and related
conditions. Thorax. 1959;14:286-99.
2. American Thoracic Society. Definition and classification
of chronic bronchitis, asthma, and pulmonary emphysema.
Am. Rev. Respir. Dis. 1962;85:762-8.
3. National Asthma Education and Prevention Program.
Expert Panel Report 2: Guidelines for the Diagnosis and
Management of Asthma. U.S. Dept of Health, Education,
and Welfare. Bethesda, MD: National Institutes of Health;
National Heart, Lung, and Blood Institute 1997: NIH
Publication No. 97-4051A.
4. Lange P, Parner J, Vestibo J, Schnor P, Jensen G. A 15year follow-up study of ventilatory function in adults with
asthma. N. Engl. J. Med. 1998; 339:1194-200.
5. Urik CS. Outcome of asthma: longitudinal changes in lung
function. Eur. Respir. J. 1999; 13:904-18.
6. Roche WR, Beasley R, Williams JH et al. Subepithelial
fibrosis in the bronchi of asthmatics. Lancet 1989;1: 520-523.
7. Elias JA. Airway remodeling in asthma: unanswered
questions. Am. J. Respir. Crit. Care Med. 2000; 161:
S168-S171.
8. O’Hollaren MT. Airway remodeling; where’s the evidence? American College of Allergy, Asthma and Immunology Annual Meeting 1999.
9. Hossain S, Heard BE. Hyperplasia of bronchial muscle in
chronic bronchitis. J Pathol 1970;101:171-84.
10. Roche WR. Inflammatory and structural changes in the
143
ASthma
small airways in bronchial asthma. Am. J. Respir Crit.
Care Med. 1998;157:S191-S194.
11. Hocking DC. Fibronectin matrix deposition and cell
contractility. Chest 2002;122:S275- S278.
12. Jeffrey PK. Remodeling in asthma and chronic obstructive
lung disease. Am. J. Respir. Crit. Care Med. 2001;164:
S28-S38.
13. Nakano Y, Miller N, King G, et al. Quantitative assessment
of airway remodeling using high-resolution CT Chest.
2002;122:271S-275S.
14. Bousquet J, Jeffrey PK, Busse WW, et al. State-of-theArt: asthma-from bronchoconstriction to airways Inflammation and remodelling. Am J Respir Crit Care Med.
2000;161:1720-45.
15. Kips JC, Pauwells RA. Airway wall remodeling: Does it
occur and what does it mean? Clin. Exp. Allergy. 1999;
29:1457-66
16. Brown PJ, Greville HW, Finucane KE. Asthma and irre
versible airflow obstruction. Thorax. 1984;39:131-136.
Question No. 4:
How is asthma diagnosed?
Answer:
Asthma is diagnosed using a combination of history,
clinical findings and objective measurements of variable airflow obstruction and/or bronchial hyperrespon
siveness.
However, in some cases, the medical history and physi
cal examination may not be reliable in diagnosing
asthma. Furthermore, the physical examination may
be normal as asthma symptoms are characteristically
episodic. An objective measure is required to diagnose
asthma accurately. [GRADE A]
1. Screening Strategies
A. History
Asthma should be suspected in any patient who presents
with any of the following: (1) cough, which worsens at
night; (2) wheeze; (3) difficulty in breathing; and (4)
chest tightness.1,2 [LEVEL 1] The diagnostic accuracy
increases when more than one symptom is present.3
[LEVEL 3] Diagnosis of asthma is strengthened by the
presence of the following: history of temporal waxing
and waning of symptoms4 often provoked by exogenous
factors such as allergens, irritants, exercise, and virus
infections;5 a positive family history;6 and improvement
in symptoms from use of anti-asthma medications.7
B. Physical Examination
The physical examination of the respiratory system
may be normal in patients with asthma. Widespread,
high-pitched, musical wheezes are characteristic auscul
tatory findings,2 however, they are not very specific
for asthma.8,9,10 [LEVEL 1] The presence of wheezes
correlates poorly with the severity of airflow limitation.
Some patients with asthma may have normal ausculta
tion but exhibit significant airflow obstruction when
measured objectively. A better clinical parameter for
severity of airflow obstruction is prolonged forced expi
ratory time of six seconds or more, which correlates well
with FEV1 in patients with moderate to severe airway
144
CPM 9TH EDITION
obstruction.11,12 [LEVEL 1]
2. Strategies for Confirmation
A. Forced expiratory volume in 1 second (FEV1)
Spirometry is useful in documenting airflow obstruc
tion in asthma. Variable airflow obstruction can be
documented by a spontaneous variability in FEV1 or
by improvement 15 minutes after inhaled ß2-agonist
administration. A 12% (at least 200 mL) improvement
in FEV1, either spontaneously or after inhalation of a
ß2-agonist is considered significant.13,14 [LEVEL 1] A
positive test increases the likelihood that a symptomatic
patient with baseline airway obstruction has asthma. If
the initial test is not significant, asthma can be diagnosed
by demonstrating at least a 20% (minimum of 250 mL)
increase in FEV1 after one week with or without oral
steroids, or after two weeks of inhaled steroids.15,16
[LEVEL 4]
B. Peak Expiratory Flow Rate (PEFR)
In the absence of spirometry, home measurement of peak
expiratory flow (PEF), incorporating response to inhaled
ß2-agonist, may be used to document variable airflow
obstruction. PEF variability is computed as the mean
percentage difference between the post-bronchodilator
evening (p.m.) value and pre-bronchodilator morning
(a.m.) value over a period of several weeks. Another
method is the minimum morning pre-bronchodilator
PEF over 1 week expressed as a percent of the recent
best (Min%/Max). A PEF variability of 20% or more
is indicative of asthma. [LEVEL 4] PEF measurement
is also an important diagnostic tool in the clinic, emergency department and hospital. Demonstrating a 20%
or greater improvement in PEFR 15 minutes after the
administration of 200 to 400 µg inhaled salbutamol or
the equivalent may be used as an indicator of asthma.16
[LEVEL 4]
The PEFR correlates closely with the FEV1 (r= 0.85).17,18
However, this close correlation speaks more of PEFR
as a tool better suited for monitoring rather than for
diagnosis. There can be a wide variability when PEFR
and FEV1 are compared directly. PEFR is, therefore,
best used as an adjunct to and not as a substitute for
spirometry.19 [LEVEL4]
C. Airway hyperresponsiveness
If asthma is still suspected in subjects with a normal
FEV1, excessive bronchial hyperresponsiveness can
be documented by performing a methacholine or histamine inhalation challenge.20,21[LEVEL 1] The optimal
diagnostic value of these challenge tests occurs when
the pretest probability of asthma based on symptoms is
30-70%.22 [LEVEL 2] However, a negative broncho
provocation test is more reliable in excluding a diagnosis
of asthma.23 The test is usually available only in spe
cialized centers with a competent staff. Presently, local
guidelines on the performance, dosing, cut-off values,
and interpretations have not been established.
CPM 9TH EDITION
ASthma
References:
1.McFadden ER, Gilbert IA. Asthma. N. Engl. J. Med.
1992;327:1928-37.
2.Li JTC, O’Connel EJ. Clinical evaluation of asthma. Ann.
Allergy Asthma Immunol. 1996;76:1-14.
3. Pratter MR, Curley FJ, Dubois J, Irwin RS. Cause and
evaluation of chronic dyspnea in a pulmonary disease
clinic. Arch. Int. Med. 1989;149:2277-82.
4. Guidotti TL. Consistency of diagnostic criteria for asthma
from Laennec (1819) to the National Asthma Education
Program (1991). J. Asthma 1994;31:329-38.
5. McFadden ER. Asthma outcome variables. Discussant sec
tion. Am. J Respir. Crit. Care Med. 1994;149:S29-S30.
6. Sandford, AT, et al. The genetics of asthma. Am J Respir
Crit Care Med. 1996;153:1749-65.
7. Hargreave FE, Dolovich J, Newhouse MT. The assessment
and treatment of asthma: a conference report. J. Allergy
Clin. Immunol. 1990;85:1098-111.
8. Holleman DR and Simel DL. Does the clinical exami
nation predict airflow limitation? J. Am. Med. Assoc.
1995;273:313-19.
9. Straus SE, McAlister FA, Sackett DL, Decks JJ. The
accuracy of patient history, wheezing, and laryngeal mea
surements in diagnosing obstructive airway disease. J. Am
Med. Assoc. 2000;283:1853-7.
10. Hollerman DR Jr, Simel DL, Goldberg JS. Diagnosis of
obstructive airway disease from the clinical examination.
J. Gen. Int. Med. 1993:8:63-8.
11.Kern DG, Patel SR. Auscultated forced expiratory time
as a clinical and epidemiologic test of airway obstruction.
Chest. 1991;100:636-9.
12.Schapira RM, Schapira MM, Funahashi A et al. The
value of the forced expiratory time in the physical diag
nosis of obstructive airways disease. J. Am. Med. Assoc.
l993;270:731-6.
13. Crapo RO. Pulmonary function testing. N. Engl. J. Med.
1994;331:25-30.
14. Becklake M, Crapo RO, Buist AS, et al. Lung function
testing: selection of reference values and interpretative
strategies. Official Statement of the American Thoracic
Society. Am. Rev. Respir. Dis. 1991;144:1202-18.
15. British Thoracic Society. Guidelines for the management
of asthma in adults: I. Chronic persistent asthma. Br. Med.
J. 1990; 301:651-3.
16. Boulet LP (Chairman) for Summary of Recommendations
from the Canadian Asthma Consensus Report, CMAJJAMC. 1999;161 (11 Suppl) S1-S12.
17. Quanjer PH, Lebowitz MD, Gregg I, Miller MR, Pe
derson OF. Peak expiratory flow: conclusions and
recommendations of a Working Party of the European
Respiratory Society. Eur. Respir. J. 1997;24 Suppl: 2S8S.
18. Connelly CK, Chan NS. Relationship between different
measurements of respiratory function in asthma. Res
piration. 1987;52:22-33.
19. Nowak RM, Pensler MI, Sarkar DD, etal. Comparison of
peak expiratory flow and FEV1 admission criteria for acute
bronchial asthma. Ann. Emerg. Med. 1982; 11: 64-9.
20. Li JC. Do peak flow meters lead to better asthma control?
J. Respir Dis. 1995;16:381-98.
21. Adelroth E, Hargreave FE, Ransdale EH. Do physicians
need objective measurements to diagnose asthma? Am.
Rev. Respir. Dis. 1986;134:704-7.
22. American Thoracic Committee on Proficiency Standards
for Clinical Pulmonary Function Laboratories. Guidelines
for methacholine and exercise challenge testing-1999. Am.
J. Respir. Crit. Care Med. 2000; 161; 309-29.
23. Perpiña M, Pellicer C, de Diego A, Compte L, and Maclan
V. Diagnostic value of the bronchial provocation test with
methacholine in asthma. Chest. 1993; 104:149-54.
Question No. 5:
How is asthma classified?
Answer:
Asthma can be classified according to: 1) etiology, and
2) severity (clinical condition on presentation whether
the patient is in acute state or in a chronic state).1
A. Etiology
Classification of asthma according to etiology is limited
as no environmental cause can be identified. However,
a rigorous search for a specific environmental cause
Table 1.1 Asthma diagnosis confirmed by objective measures of variable airway obstruction
Objective measure
Indicator of significant airflow limitation
Spirometry
≥12% (minimum 200 mL in adults) improvement in FEV1 from the baseline after
use of inhaled bronchodilator
≥20% (minimum 250 mL in adults) improvement over time when symptoms are
stable or after 10-14 days of corticosteroid therapy
Serial measures of PEFR≥20% change after using a bronchodilator over time
Pre- and Post-broncho- ≥15% change after using inhaled bronchodilator in the clinic in the absence of
dilator PEFR spirometry
Methacholine challenge
Provocative concentration of methacholine resulting in a 20% fall in FEV1 from the
baseline (PC20) <8mg/mL
Adapted from:
1. Boulet LP (Chairman) for Summary of Recommendations from the Canadian Asthma Consensus Report, 1999 CMAJ-JAMC
1999: 161 (11 Suppl) S1-S12.
2. American Thoracic Society Statement Lung function testing: selection of reference values and interpretative strategies. Am
Rev. Respir. Dis 1991;144:1202-18.
3. Quanjer PH, Lebowitz MD, Gregg I, Miller MR, Pederson OF. Peak expiratory flow: conclusions and recommendations of
a Working Party of the European Respiratory Society. Eur. Respir. J. 1997;24 (Suppl): 2S-8S.
145
ASthma
CPM 9TH EDITION
should be part of the initial clinical assessment. Identifi
cation of the specific etiology will guide both the physi
cian and the patient on the use of avoidance strategies
in management.
B. Severity
Acute state (in exacerbation)
For the physician, the initial step is to recognize decisive
ly if the patient is in acute exacerbation. Such exacerba
tion can be fatal if not treated appropriately.2 It is important to emphasize that any patient with chronic asthma,
however mild, may have an acute exacerbation. Any
patient, even with mild symptoms, should be considered
as having an asthma exacerbation if there is: 1) history of
life threatening acute attacks; 2) hospitalization within
the previous year; 3) psychosocial problems; 4) history
of intubation for asthma; 5) recent reductions or cessation of glucocorticosteroid therapy; and 6) noncompliance with recommended medical therapy. These clinical
conditions are associated with a higher risk of asthma
mortality.3 Since acute exacerbation demands an urgent
need to intervene and to modify existing treatment, this
problem will be discussed in detail separately. (Refer
to Chapter 5)
Chronic State
Assessment of asthma severity follows the Global
Initiative on Asthma classification Classification of
severity is subdivided into four steps: intermittent, mild
persistent, moderate persistent and severe persistent.
(See Table 1.2)
Recent publications criticized the GINA classification
on severity based on symptoms and frequency of at
tacks,4,5 and PEF and FEV1 values.6 Long-term mental
retention of and adherence to the classification details
have not been satisfactory even after intensive dissem
mation workshops.7
Because asthma is a chronic inflammatory disease,
the severity of its chronic state exists in a continuum.
Numeric cut-off values of frequency and intensity of
symptoms, and parameters of physiologic dysfunction
currently used to classify asthma in different levels of
severity are artificial and transitory. Of note is the fact
that the l994 GINA severity classification, which was
recommended in the first Philippine Consensus Report
on Asthma Diagnosis and Management (1996)8, has
not been validated.
Table 1.3 shows a revised classification combining
mild persistent and moderate persistent categories into
one. This new asthma severity classification, beyond its
scientific soundness, is more comprehensible and readily
applicable to clinical work. [LEVEL 4]
References:
1. Guidelines for the Diagnosis and Management of Asthma;
National Asthma Education and Prevention Program.
Expert Panel Report 2. Bethesda, MD: National Institutes
of Health; National Heart, Lung and Blood Institute 1997;
NIH Publication No. 97-4051A.
2. Strunk SC. Identification of the fatality-prone subject with
asthma. J. Allergy Clin. Immunol. 1989: 83:477-85.
3. Jalaludin BB, Smith MA, Chey T, Orr NJ, Smith WT,
Leeder SR. Risk factors for asthma deaths: a population-based case-control study. Aust. NZ. J. Publ.Health.
1999;23:595-600.
Table 1.2 GINA Classification of Asthma Severity by Clinical Features
STEP 1: Intermittent Symptoms less than once a week
Brief exacerbations
Nocturnal symptoms not more than twice a month
- FEV1 or PEF >80% predicted
- PEF variability <20%
STEP 2: Mild Persistent
Symptoms more than once a week but less than once a day
Exacerbations may affect activity and sleep
Nocturnal symptoms more than twice a month
- FEV1 or PEF > 80% predicted
- PEF variability 20-30%
STEP 3: Moderate Persistent
Symptoms daily
Exacerbations may affect acitivity and sleep
Nocturnal symptoms not more than once a week
Daily use of short-acting β2-agonist
- FEV1 or PEF 60-80% predicted
- PEF variability >30%
STEP 4: Severe Persistent Symptoms daily
Frequent exacerbations
Frequent nocturnal activities
Limitation of activities
- FEV1 or PEF <60% predicted
- PEF variability >30%
146
CPM 9TH EDITION
ASthma
4. Garcia HJ. Does a classification of asthma based on its
severity make sense? Allergy Immuno. Clin 1999; 14(2):
102-5.
5. Osborne ML, Vollmer WM, Pedula KL, Wilken J, Buist
S, O’Hollaren M. Lack of correlation of symptoms with
specialist-assessed long term asthma severity. Chest
1999;115:85-91.
6. Sawyer G, Miles J, Lewis S, Fitzharris P, Pearce N,
Beasley R. Classification of asthma severity: should the
international guidelines be changed? Clin. Exp. Allergy.
1998;28:1565-70.
7. Alentajan-Aleta LT. A retrospective study on physicians’
adherence to the PCCP Philippine Consensus Report on
Bronchial Asthma at the general medical clinic, out-patient
department, UP-PGH. Phil. J. Chest Dis. 2002;9(1):303.
8. Philippine Consensus Report on Asthma Diagnosis and
Management 1996. Philippine College of Chest Physicians
Council on Asthma, 1997;1-5.
Research Recommendations
The wide range in the prevatence rates as reported in
the ISAAC and local studies emphasizes the need for
a national prevalence survey for asthma.
Classification of asthma severity should be validated.
Chapter 2
Objective Measures in the Diagnosis, Assess
ment of Severity and Monitoring of Asthma
Question No. 1:
Do clinical symptoms correlate with the degree of
airway obstruction?
Answer:
In patients with asthma, clinical symptoms may not
always correlate with the degree of airway obstruction.
Objective measures of airway obstruction are needed.
[Grade A]
Asthma symptoms, the visual analog scale and dyspnea
scores do not correlate with the level of FEV1 and PEF.1,2
[LEVEL 1] In a study by Osborne. a specialist’s assessment of long-term asthma severity did not correlate at all
with asthma symptoms.3 Likewise, two separate studies
conducted on intra-patient assessment of severity of
their own symptoms before and after treatment showed
no correlation with FEV1 and PEF.4,5 [LEVEL 2]
References:
1. Kendrick AH, Higgs CM, Whitfield MJ, et al. Accuracy
of perception of severity of asthma: patients treated in
general practice. Br. Med. J. 1993;307: 422-4.
2. Peiffer C, Marsac J, Lockhart A. Chronobiological study of
the relationship between dyspnea and airway obstruction
in symptomatic asthmatic subjects, Clin Sci. 1989:77:23744.
3. Osborne ML, Vollmer WM, Pedula KL, et al. Lack of correlation of symptoms with specialist-assessed long-term
asthma severity. Chest. 1999;115:85-91.
4. McFadden ER, Kiser R, de Groot WJ. Acute bronchial
asthma: relations between clinical and physiologic manifestations. N. Engl. J. Med. 1973;288:221-5.
5. Teeter JG, Bleecker ER. Relationship between airway
obstruction and respiratory symptoms in adults asthmatics.
Chest. 1998;113:272-7.
Question No. 2:
Is peak flow monitoring useful in chronic stable
astlima?
Answer:
Yes, peak flow monitoring is useful in chronic stable
asthma, especially in patients with moderate to severe
Table 1.3 New Classification of Chronic Asthma Severity
Parameter
Daytime symptoms
Nocturnal awakening
Rescue β2-agonist use
PEF or FEV1*
Treatment needed to
control asthma
Severity
Persistent
Intermittent
Mild-Moderate
Monthly
Less than monthly
Less than weekly
>80% pred.
Occasional prn β2-agonist only
Weekly
Monthly to weekly
Weekly to daily
60-80% pred.
Regular ICS +
LABA combination
Severe**
Daily
Nightly
Several times a day
<60% pred.
Combination ICS
+ LABA + OCS
* Objective measures take precedence over subjective complaints. The highest severity level of any domain will be the basis
of the final severity level.
** Patients who are high risk for asthma-related deaths are initially classified here.
ICS = inhaled corticosteroid
LABA = long-acting β2−agonist
OCS = oral corticosteroid
147
ASthma
persistent asthma. [GRADE C]
Although clinical trials show conflicting results, evi
dence suggests that PEFR monitoring improves patient
outcome.1 The Grampian Asthma Study of Integrated
Care Trial2 (GRASSIC) is a randomized controlled trial
comparing the effect of PEF-based self management
against conventional treatment on patient outcome. At
the end of a 12-month observation period, the authors
showed there was no statistically significant difference
in patient outcome between the two groups. However,
higher number of physician consultations was seen in
the PEF-based group, reflecting closer monitoring of
asthma by the health care professionals. PEF-based
self-management is especially beneficial for patients
with severe asthma since it will facilitate closer monito
ring by general practitioners and encourage prompt
administration of oral steroids whenever appropriate
[LEVEL 3].
References:
1. Jain P. Kavuru M, et al. Utility of peak expiratory flow
monitoring. Chest 1998;114:3:861-75.
2. Grampian Asthma Study of Integrated Care. Effectiveness
of routine self-monitoring of peak flow in patients with
asthma. Br. Med. J. 1994;308:564-7.
Question No. 3:
Does peak flow variability correlate with worsening
asthma?
Answer:
Yes, and despite the lack of clear evidence to support
its use, peak flow variability is a useful indicator of
worsening airflow obstruction [GRADE D]
Population-based studies show that excessive diurnal
PEF variation correlated with a higher incidence of
respiratory symptoms, poor asthma control, and sudden
death.l,2 [LEVEL 2]
Clinical and epidemiological studies have reported good
correlation between peak flow variability and the degree
of bronchial hyperresponsiveness (BHR) observed after
histamine or methacholine inhalation challenge. BHR
is currently considered the best available clue to the
presence of airway inflammation. Taken together, the
available data suggest that PEF variability is loosely
associated with the presence of airway inflammation.
This finding is further strengthened by studies that demonstrate improvement in PEF 3,4,5 and decrease in variability6,7,8 after effective control of airway inflammation
with inhaled corticosteroids (ICS). [LEVEL 3]
References:
1. Quackenboss JJ, Lebowitz MD, Krzyzanowski M. The
normal range of diurnal changes in peak expiratory flow
rates: relationship to symptoms and and respiratory disease. Am. Rev. Respir. Dis. 1991;143:323-30.
2. Boezen HM, Schouten JP, Postma DS, et al. Relation bet
ween respiratory symptoms, pulmonary function and peak
148
CPM 9TH EDITION
flow variability in adults. Thorax.1995;5; 50:121-6.
3. Haahtela T, Jarniven M, Kava T, et al. Comparison of
β2-agonist terbutaline with an inhaled corticosteroid
budesonide in newly detected asthma. N. Engl. J. Med.
1991;325:388-92.
4. Griffin E, Hakansson L, Formgren H, et al. Blood eosinophil number and activity in relation to lung function
in patients with asthma and eosinophilia. J. Allergy Clin.
Immunol. 1991;87:548-57.
5. Molema J, van Herwaarden CL, Folgering HT. Effects
of long-term treatment with inhaled cromoglycate
and budesonide on bronchial hyperresponsiveness in
patients with allergic asthma. Eur Respir. J. 1989;2:
308-16.
6. Waalkens HJ, Gerritsen J, Koeter GH, et al. Budesonide
and terbutaline or terbutaline alone in children with mild
asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow. Thorax 1991; 46:499-503.
7. Van Esne-Zandvliet EE, Hughes MD, et al. Effects of 22
months of treatment with inhaled corticosteroids and/or
β2-agonists on lung function, airway responsiveness, and
symptoms in children with asthma. The Dutch Chronic
Nonspecific Lung Disease Study Group. Am Rev. Respir.
Dis. 1992;146:547-54.
8. Kerstjens HA, Brand PL, de Jong PM, et al. Influence of
treatment on peak expiratory flow and its relation to airway
hyperresponsiveness and symptoms: the Dutch CNSLD
Study Group. Thorax 1994;49:1109-15.
Question No. 4:
Is peak flow monitoring useful in acute exacerbation
of asthma?
Answer:
Yes, the measurement of PEFR provides useful infor
mation on the severity of asthma attack, response to
therapy, need for hospital admission, and risk of early
relapse. [LEVEL 2]
The use of PEF monitoring in the treatment of acute asthma
has been shown to reduce unnecessary asthma-related hospital admissions from the emergency department (ED).1-7
In studies involving patients treated for acute asthma
exacerbation in the ED setting, PEF before and after
treatment were taken and compared for admitted and
discharged patients.2,3,4,5 Patients who eventually needed
hospitalization have lower PEF both at the beginning
and at the end of the ED treatment, indicating a greater
severity of airflow obstruction in those who need in-patient care. Other studies suggest that failure of FEV1 or
PEF to improve promptly after bronchodilator administration predicts longer ED stay and more frequent need
for hospital admission.6,7 [LEVEL 2]
Thus, available data indicate that individuals showing
higher pre-treatment PEFR and an early response to
initial bronchodilator administration are less likely to
require hospital admission. [LEVEL 2]
References:
1. Taylor MR. Asthma: audit of peak flow rate guidelines for
admission and discharge. Arch. Dis Child. 1994;70:4324.
2. Kwong T, Town I, Holst PE, et al. A study of the manage-
CPM 9TH EDITION
ment of asthma in a hospital emergency department. N.
Z. Med. J. 1989;102:547-9.
3. Chidley, KE, Wood-Baker R, Town GI, et al. Reassessment of asthma management in an accident and emergency
department. Respirol.Med. 1991;85:373-7.
4. Gibson PG, Talbot PI, Hancock J, et al. A prospective audit
of asthma management following emergency asthma treatment at a teaching hospital. Med. J. Aust. 1993;158:7758.
5. Kerem E, Tibshirani R, Canny G, et al. Predicting the need
for hospitalization in children with acute asthma. Chest.
1990;98:1355-61.
6. Stein LM, Cole RP. Early administration of corticosteroids
in emergency room treatment of acute asthma. Ann. Intern.
Med. 1990;112:822-7.
7. Rodrigo G, Rodrigo C. Assessment of the patient with
acute asthma in the emergency department: a factor analytic study. Chest. 1993;104:1325-8.
ASthma
Research Recommendation
Asthma. 1964;10:329.
2. Voorhorst AS. The house dust mite (Dermatophagoides
pteronyssinus) and the allergens it produces: identify
with the house dust allergen. J. Allergy Clin. Immunol.
1967;39:325.
3. Nagakura T, Yasueda H, Obata T, et al. Major dermato
phagoides mite allergen, Der I, in soft toys. Clin Exp
Allergy. 1996;26:585-9.
4. Platts-Mills TAE, Chapman MD. Dust mites: immunology,
allergic disease, and environmental control. J. Allergy Clin.
Immunol. 1987,80:755.
5. Maunsell K, Wraith DG, Cunnington AM. Mites and
house-dust allergy in bronchial asthma. Lancet. 1968;
1:1267.
6. Lecks HI. The mite and house dust allergy. A review
of current knowledge and its clinical significance. Clin
Pediatr. 1973;12:514.
7. Sears MR, Herbinson GP, Holdaway MD, et al. The rela
tive risks of sensitivity to grass pollen house, dust mite
and cat dander in the development of childhood asthma.
Clin. Exp. Allergy. 1989;19:419-24.
Further local setting studies validating the clinical
significance of peak expiratory flow measurements
and the predictive value of variability monitoring
are needed.
Question No. 2:
Are mechanical measures effective in reducing or
eradicating house dust mites?
Chapter 3
Control of Triggers
House Dust Mites
Question no. 1:
Are house dust mites a significant cause of asthma?
Answer:
Worldwide, investigators have found that the dust mite
is a significant cause of allergic asthma. [LEVEL 1]
Summary of evidence:
In 1964, mite extracts from house dust were found to
produce positive skin reactions. Moreover, patients who
had positive bronchoprovocative tests improved when
they were removed from contact with mites. These
findings led to the conclusion that Dermatophagoides
species was a principal source of house dust allergens.15
More recent studies confirmed Dermatophagoides
pteronyssinus to be the most abundant mite species
worldwide.6 [LEVEL 1]
The allergenic proteins are actually contained in the fecal pellets of the mite. The allergens fall mainly into two
immunologically important groups which are clinically
relevant to asthma, atopic dermatitis and allergic rhinitis.
These allergens persist for months despite eradication
of live mites.7 In investigating for the possibility of
exposure, it is best to measure mite allergens in dust
vacuumed from surfaces because the fecal pellets remain
aerosolized for only a few minutes after they are stirred
from a resting place.
References:
1. Voorhorst R, Spieksma-Boezman, MIA, Spieksma FThM.
Is mite the producer of the house dust allergen? Allergy
Answer:
Although mechanical removal methods are partly suc
cessful in reducing allergens and killing mites, there is
no evidence showing long-term improvement in allergy
symptoms among sensitized individuals.
The most effective, and probably the most important
avoidance measure is to encase mattresses, pillows,
and duvet with covers that are impermeable to mite allergens. By encasing beds and pillows in plastic, dust
mite populations were found to be reduced by as much
as 75% on both mattresses and surrounding carpets.1
[LEVEL 1 ]
Low humidity is an important requirement for dust mite
survival. The levels of mite allergens are dramatically
reduced at high altitude (>1500 m) where humidity
is too low to support mite populations. Theoretically,
if relative humidity is kept below 50% for prolonged
periods, the mites can be eradicated. Two separate
studies showed that mite-sensitive asthmatic children
had a progressive reduction in non-specific BHR2 and
a progressive improvement in asthma symptoms3 when
brought to higher altitude environments. Further studies
showed a reversal of this trend after 15 days of allergen
re-exposure at sea level.4 [LEVEL 1]
Investigations on the effectiveness of portable dehumi
difiers failed to show any reduction in house dust mite
population and allergen levels.5 Another approach in
reducing humidity levels is by using mechanical ventila
tion with a heat recovery unit. This method produced a
100% mite reduction in bedroom mattresses one month
after operation and 99.9% reduction after 2 months.6
Levels of antigen in carpets were found to drop by 86.7%
after steam-cleaning7 or wet cleaning rugs.8
149
ASthma
To kill mites by washing, the water temperature must
be >54.4oC. The dry cleaning process is found to be effective in eliminating mites.9 One study comparing the
effectiveness of dry cleaning with hot-water washing
showed that both cleaning methods successfully reduced
allergen levels on blankets.10
Other mechanical measures to eradicate house dust
mites remain to be controversial. Use of high efficiency
particulate air (HEPA) filters appears to be an insuffi
cient substitute for standard avoidance measures in
mite-sensitive patients.11 Increasing the frequency of
vacuuming to at least once per week is controversial
because although this practice has shown reduction in
mite numbers, the activity may reintroduce allergens
to the air.12
References:
1. Mulla MS, Harkrider JR, Galant SP, et al. Some house
dust mite control measures and abundance of Derma
tophagoides mites in California. J. Med. Entomol.
1975;12:5.
2. Platts-Mills TAE, Chapman MD. Dust mites: immunology,
allergic disease and environmental control. J. Allergy Clin.
Immunol. 1987;80:755-75.
3. BonerAL, Niero E,Antolini I, et al. Pulmonary function
and bronchial hyperreactivity in asthmatic children with
house dust mite allergy during prolonged stay in the Italian
Alps (Misuria 1756 m). Ann. Allergy. 1985; 54:42-5.
4. Piacentini GL, Martinati L, Fornari A, et al. Antigen avoidance in a mountain environment: influence on basophil
releasability in children with allergic asthma. J. Allergy
Clin. Immunol. 1993;92:644-50.
5. Custovic A. Taggart SCO, Kennaugh JH, et al. Portable
humidifiers in the control of house dust mites and mite
allergens. Clin. Exp. Allergy. 1995;25:312.
6. Htut T, Houlbrook K, Lumley E, et al. A novel physical
method to control mites and their allergens in bedding. Int
J Environ Health Res. 1996;6:233.
7. Collof MJ, Taylor C, Merretts TG. The use of domestic
steam cleaning for the control of house dust mites. Clin.
Exp. Allergy. 1995;25:1061.
8. de Boer R, van der Hoeven W, Kuller K. The control of
house dust mites in rugs through wet cleaning. J. Allergy
Clin. Immunol. 1996;97:1214.
9. McDonald LG, Tovey E. The role of water temperature
and laundry procedures on reducing house dust mite
populations and allergen content of bedding. J. Allergy
Clin. Immunol. 1992;90:599-608.
10. Watanabe M, Sagakuchi M, Inouve S, et al. Removal of
mite allergens from blankets: comparison of dry cleaning and hot water washing. J. Allergy Clin. Immunol.
1995;96:1010.
11. Antonicelli L. Bilo MB, Pucci S, et al. Efficacy of an aircleaning device equipped with a high efficiency particulate
air filter in house dust mite respiratory allergy. Allergy.
1991;46:594-600.
12. Massey JE, Massay DG. Effect of vacuum cleaning on
house dust mites. Hawaii Med. J. 1984:43:404.
Question No. 3:
Are chemical measures effective in reducing or eradi
cating house dust mites?
Answer:
Currently available chemical products for control of
150
CPM 9TH EDITION
dust mites and their allergens offer only short-term
effectivity. [GRADE A]
Current strategies for mite control frequently employ
chemicals that serve to either eradicate the mites or
denature the allergens. These chemicals include benzyl
benzoate, permethrin, pirimiphos methyl, phenyl sali
cylate, tannic acid, common household disinfectants,
combinations of these, and insect growth regulators.
Potential acaricides have had varying degrees of success
in both laboratory and clinical trials.1-3 [LEVEL 1]
However, allergen levels rebounded after two months
suggesting that repeated application every two to three
months is necessary to control mite allergen levels.
A study by Dietemann and colleagues4 showed that
application of benzyl benzoate in households of asth
matic patients improved their clinical symptoms over
a period of one year. However, another study using
benzyl benzoate5 showed that although the mite morta
lity drop is 100% two months after treatment, this has
decreased significantly to 60% by the third month. Phen
yl salicylate, a compound structurally similar to benzyl
benzoate, was observed to retain its acaricidal activity
three months post-application.
Varying degrees of success have been noted with the use
of pirimiphos methyl,6 an organophosphate insecticide,
and permethrin,7 a synthetic pyrethroid. Insect growth
regulators (e.g., methoprene and hydropene) act by
mimicking normal hormonal activity and significantly
suppress mite populations up to 30 days.8
Tannic acid, a denaturant capable of breaking down
mite fecal allergens,9 was shown to decrease bronchial
hyperreactivity in patients only on the eighth month
after treatment of mattress casings and carpets.10 A
major practical disadvantage of using tannic acid is
that it stains fabric.
Studies on combined products that employ various concentrations of an acaricide, denaturant and/or fungicide
to kill mites and remove allergens had only significant
short-term activity ranging from 10-16 weeks post-application.11-12
References:
1. Hayden ML, Rose G, Diduch KB, et al. Benzyl benzoate
moist powder: investigation of acaricidal activity in cultures and reduction of dust mite allergens in carpets. J.
Allergy Clin. Immunol 1992;89:536-45.
2. Huss RW, Huss K, Squire EN, et al. Mite allergen control
with acaricide fails. J. Allergy Clin. Immunol. 1994;94:2732.
3. Lau-Schadendorf S, Rusche AF, Weber AK, et al. Shortterm effects of solidified benzyl benzoate on mite allergen
concentration in house dust. J. Allergy Clin. Immunol.
1991;87:41.
4. Dietemann A, Bessot JC, Hoyet C, et al. A double-blind
placebo controlled trial of solidified benzyl benzoate applied
in dwellings of asthmatic patients sensitive to mite: clinical
efficacy and effect on mite allergens. J. Allergy Clin. Immunol 1993;91:738-46.
CPM 9TH EDITION
5.Kalpaklioglu AF, Ferizli AG, Misirligil A, et al. The effectiveness of benzylbenzoate and different chemicals as
acaricides. Allergy. 1996;51:164.
6.Mitchell EB, Wilkins S, Deighton J, Platts-Mills TAE.
Reduction of house dust mite allergen levels in the
home: uses of acaricide, pirimiphos methyl. Clin Allergy
1985;15:235-40.
7.Glass EV, Needhan GR. Evaluation of the acaricide
permethrin against all stages of the American house dust
mite Dermatophagoides farinae, in Mitchell R, Horn DJ,
Welbourn WC (eds): Acarology IX proceedings. Columbus, Ohio Biological Survey 1997; 693-5.
8.Downing AS, Wright CG, Farrier MH. Effects of five insect
growth regulators on laboratory populations of the North
American house-dust mite Dermatophagoides farinae.
Exp. Appl Acarology 1990;9:123.
9.Green WF. Abolition of allergens by tannic acid [Letter].
Lancet. 1984;2:160.
10. Ehnert B, Lau-Schadendorf S, Weber A, Beuttner P,
Schou C, Wahn U. Reducing domestic exposure to dust
mites allergen reduces bronchial hypersensitivity in
sensitive children with asthma. J. Allergy Clin. Immunol.
1992;90:135-8.
11. Green WF, Nicholas NR, Salome CM, et al. Reduction of
house dust mites and mite allergens: effects of spraying
carpets and blankets with Allersearch DMS, an acaricide
combined with an allergen reducing agent. Clin Exp Allergy 1989;19:203.
12. Hart BJ, Greurin B, Nolard N. In vitro evaluation of
acaricidal and fungicidal activity of the house dust mite
acaricide Allerbiocid. Clin Exp Allergy 1992; 22:923.
Question No. 4:
Will patients with asthma who are sensitized to house
dust mites benefit from measures designed to reduce
their exposure to mite antigen in the home?
Answer:
Current methods aimed at reducing exposure to allergens
from house dust mites seem to be ineffective and cannot
be recommended as prophylactic treatment for asthma
patients sensitive to mites [GRADE B]
A meta-analysis of randomized trials investigated the
effects of mite antigen reducing measures on asthma
compared to an untreated control group.1 There were 23
studies included, six of which used chemical methods,
13 used physical methods, and four used a combination
of both. Altogether, 41/113 patients exposed to treatment
interventions improved compared with 38/117 in the
control groups leading the investigators to conclude that
there is no clinical benefit from measures designed to
reduce exposure to mites among asthma mite-sensitive
patients. [LEVEL 1] The lack of benefit may be due to
failure of the methods used to adequately reduce levels
of mite antigen.
Some studies were able to show effective reduction in
mite exposure, but these did not show more positive
results when compared to studies that failed to reduce
mite exposure. This may be because patients with asthma
who are sensitive to mites are usually also sensitive to
other allergens. Therefore, the successful elimination of
only one allergen may be of limited benefit.
ASthma
Reference:
1. Gotzche PC, Hammarquist C, Burr M. House dust mite
control measures in the management of asthma: metaanalysis. Br. Med. J. 1998;317:1105-10.
Conclusion and Recommendation
House dust mite antigens are significant causes of
asthma in mite-sensitive individuals.
Despite the absence of larger and more rigorous
studies on methods of mite control, health care
givers should continue to institute avoidance and
control measures.
Cockroach Allergens
Question No. 1:
Are cockroach allergens an important risk factor for
asthma?
Answer:
Yes, among the insects, cockroaches are the most recog
nized common source of allergens [LEVEL 1]
Cockroaches are tropical in origin and thrive in houses
that are continuously warm. However, unlike mites, they
are not dependent on ambient humidity and show great
talent in finding water sources within a building. Of the
seven or eight indoor species, the American cockroach
(Periplaneta americana) is the most common cockroach
in the Philippines.
Cockroaches can be safely presumed to cause significant
asthma in areas where crowded living conditions exist
such as urban slums. Socio-economic status and race are
independent risk factors for cockroach allergen exposure
both in the home and school settings.1,2 There is also a
clear dose-response relationship between cockroach
allergen exposure and sensitization in children with
asthma.3 [LEVEL 1]
References:
1. Sarpong SB, Hamilton RG, Eggleston PA, Adkinson NF
Jr. Socio-economic status and race as risk factors for cockroach allergen exposure and sensitization in children with
asthma. J. Allergy Clin. Immunol. 1996; 97:1393-401.
2. Sarpong SB, Wood RA, Karrison T, et al. Cockroach allergen (Bla g1) in school dust. J. Allergy Clin. Immunol.
1997;99:486-92.
3. Sarpong SB, Corey JP. Assessment of indoor environment
in respiratory allergy. Ear, Nose, and Throat J. 1998;
77:960,962-4.
Question No. 2:
Are control measures designed to reduce or control
levels of cockroach allergens in houses effective?
Answer:
At present, there are no clear data on the effect
of eradication measures on cockroach allergens.
[LEVEL3]
151
ASthma
The effect of cockroach control measures on allergen
levels in houses has not been extensively studied; al
though a number of trials are under way.1 Both physical
and chemical procedures are used to control cockroach
populations in houses. These include the following:
•
•
Fastidious cleaning to reduce food supplies
Reducing access to food and water by:
- Removal of waste food
-Containment of surface water by reducing leakage
- Reducing condensation by improved ventilation1
• Restricting cockroach access by closing all
entry points through caulking and sealing cracks and
holes in the plasterwork and flooring.
• Using chemicals like diazinon, chlorpyrifos
and boric acid to control infestation
• Using bait stations containing hydramethylnon or avermectin which are generally effective in
reducing cockroach levels for two to three months2.
Professional extermination is needed to eliminate cock
roaches in multi-family dwellings because repopulation
can occur from other roach colonies found elsewhere
in the building.
References:
1. Custovic A, Simpson A, Chapman MD, Woodcock A.
Allergen avoidance in the treatment of asthma and atopic
disorders. Thorax. 1998;53:63-72.
2. Guidelines for the Diagnosis and Management of Asthma:
Expert Panel Report 2. Bethesda, MD: National institutes
of Health; National Heart, Lung, and Blood Institute 1997.
NIH Publication no. 97-4051A.
Animal Allergens
Question No. 1:
Can cat allergens cause asthma?
Answer:
Yes. Cats are a major source of allergen in the home
and and are capable of inducing symptoms in sensitive
patients [LEVEL 1].
Cat allergens are found in households with cats and
have been confirmed to cause asthma in studies using a
special cat challenge room.1 [LEVEL 1] The major cat
allergen, Fel d 1, is produced primarily in the sebaceous
glands and in the basal squamous epithelial cells of the
skin of cats. Very high levels of this allergen were also
demonstrated in cat anal secretions.2,3,4 Soft furnishings,
carpets and mattresses serve as reservoirs for the aller
gen. Individuals who have never had a cat may become
allergic by exposure to the allergen from contact with
cats belonging to others. Furthermore, Fel d 1 has been
detected in carpet dust of houses where cats have never
been present, suggesting it can be carried into cat-free
buildings on the clothing of people exposed to cats.5
152
CPM 9TH EDITION
Because of the small particle size (≤5 mm in diameter) of
these allergens, they can be detected in wall surfaces and
in the air of undisturbed rooms.5 This may explain why a
sensitized person may experience immediate symptoms
when entering a home with a cat, even without direct
exposure to the cat.
References:
1. de Blay F, Chapman MD, Platt-Mills TAE. Airborne cat
allergen (Fel d 1): environmental control with the cat in
situ. Am. Rev. Respir. Dis. 1991;143:1334-9.
2. Charpin C, Mata P, Charpin D, et al. Fel d 1 allergen
distribution in cat fur and skin. J. Allergy Clin Immunol.
1991;88:77-82.
3. Dabrowski AJ, Van Ber Brempt X. Soler M, et al. Cat skin
as an important source of Fel d 1 allergen. J. Allergy Clin
Immunol. 1990;86:462-5.
4. Domelas de Andrede A, Bimbaum J, Magalon C, et al. Fel d
1 levels in cat anal glands. Clin Exp Allergy. 1996;26:17880.
5. Bollinger ME, Eggleston PA, Flanagan E, et al. Cat antigen
in homes in and without cats may induce allergic symptoms.
J. Allergy Clin. Immunol. 1996;97: 904-16.
Question No. 2:
Can exposure to dog allergens also cause asthma?
Answer:
Yes, although obvious allergic reactions to dogs are less
common than those to cats. [LEVEL 2]
From preliminary results of studies, it appears that dog
allergens, like cat allergens, also become and remain
airborne. Thus, it is likely that the same rules apply to
dog allergen as to cat. However, most studies report
that children have fewer symptoms as a result of dog
allergens than cat allergens: in one study, one in ten
reacted to cat allergens, whereas only one in 100 reacted to dog allergens.1 This despite the fact that more
individuals own dogs than cats. However, intimacy of
exposure may be a factor − many dogs are kept outside
whereas cats more often go into the house and into the
bedroom of children. However, in areas where dogs are
kept in houses, they can become an important source of
allergens.2 [LEVEL 4]
Dog saliva and dog dander appear to be the main sources
of dog allergen (Can f 1). Dog allergen, like cat allergen,
can be detected in public places, including schools.3
Cross-reactivity between dog and cat allergens has been
demonstrated, suggesting the presence of common immunologic determinants.
References:
1. Murray AB, Ferguson AC, Morrison BJ. The frequency and
severity of cat allergen vs. dog allergen in atopic chilldren.
J. Allergy Clin Immunol 1983;72:145-9.
2. Ingram JM, Sporik R, Rose G, et al. Quantitative assessment of exposure to dog (Can f 1) and cat (Fel d 1)
allergens: relationship to sensitization and asthma among
children living in Los Alamos, NM. J. Allergy Clin. Immunol 1995;96:449-56.
CPM 9TH EDITION
3. MunirAKM, Einarson R, Shou C, et al. Allergens in school
dust I. The amount of the major cat (Fel d 1) and dog (Can
f 1) allergens in dust from Swedish schools is high enough
to probably cause perennial symptoms in most children
with asthma who are sensitized to cat and dog. J. Allergy
Clin. Immunol. 1993:91:1067-74.
Question No. 3:
Are measures to control cat or dog allergen levels
effective?
Answer:
There are no existing studies dealing with effectiveness
of control measures on cat or dog allergens.
The best way to reduce exposure to cat or dog allergen
is to remove the animal from the home. The clinical
benefit of control measures in person, who insist on
keeping their pets despite continued symptoms has not
yet been established. Airborne allergen levels increase
by approximately fivefold when the pet is in the room,
indicating that the immediate presence of a pet contributes to airborne allergen levels.1
The accepted control measures to control animal aller
gens are as follows:
1. Remove reservoirs such as carpets and sofas.
2. Keep the cat or dog outside as much as possible.
3. Use room air cleaners (e.g., High-efficiency particu
late air cleaner or HEPA), which can reduce allergens if the reservoirs are removed first.
4. Bathe the animal weekly. However, even aggressive washing can only remove about 40 to 70 % of
allergens.2,3
References:
1. Custovic A, Green R, Fletcher A, et al. Aerodynamic
properties of the major dog allergen, Can f 1: distribution
in homes, concentration and particle size of allergen in air.
Am. J. Respir. Crit. Care Med. 1997; 155:94-8.
2. Avner DB, Perzanowski MS, Platts-Mills TAE, Woodfolk JA. Evaluation of different techniques for washing
cats: quantitation of allergen removed from the cat and
the effect on airborne Fel d 1. J. Allergy Clin. Immunol.
1997;100:307-12.
3. Green R, Custovic A, Smith A, et al. Avoidance of dog
allergen Can f 1 with the dog in situ: washing the dog
and use of a HEPA air filter. J. Allergy Clin. Immunol.
1996;97:302.
Indoor and Outdoor Repiratory Irritants
Question No. 1:
Is there a relationship between outdoor air pollution
and asthma attacks?
Answer:
Yes, outdoor air pollution aggravates asthma. [LEVEL
2]
Several epidemiological studies have shown that of all
ASthma
outdoor pollutants, inhalable particulates ≤10 µm (PM10 )
in diameter are the single greatest hazard to asthma exacerbation.1,2 Likewise, the peak hourly nitrogen dioxide
(NO2) concentrations,3,4,5 increased ozone (03) and sulfur
dioxide (SO2) have individually6,7 or in combination,8
been reported to significantly increase emergency room
visit of asthmatics, 9,10,11,12,13-15[LEVEL 2]
Particulate matter (PM) exposure is difficult to achieve
in a controlled laboratory setting. However, controlled
studies on the effect of sulfuric acid show that asthma
tics are more “sensitive” than healthy subjects after
exposure.16 High SO2 concentration has been associated
with short-term increases in morbidity and mortality in
the general population during dramatic air population
episodes in the past.17 [LEVEL 3] Exposure to concen
trations of SO2 as low as 0.2 ppm appear to have a
significant effect in patients who are mouth-breathing or
undergoing heavy exercise. However, these effects are
short-lived and not increased by prolonged exposure.18
A combination of low concentration of SO2 and NO2__
often increased in heavy traffic-has been shown to enhance airway responsiveness to inhaled allergen.19,20
Although controlled clinical trials using ozone are equi
vocal,21 studies combining allergen challenges after
O3 exposure showed worsening of atopic asthma.22,23
[LEVEL 3]
Several studies have evaluated the relationship of lung
function and exposure to pollutants. In one study, healthy
and asthmatic patients were exposed for two hours to 0.40
ppm O3eand lung function changes were monitored.
Results showed that asthmatic patients have greater PEF
decrements and with enhanced reponses to methacholine
provocation challenge.24vOther studies showed greater
degree of airway inflammation in asthmatics exposed
to pollutants25 with higher levels of IL8 and proteins in
bronchoalveolar level (BAL) fluid even in the absence
of any PEF change.26-31 [LEVEL 3]
In summary, particulate matter exposure is associated
with decreased lung function, increased symptoms and
unscheduled visits to the emergency room. Exposure to
pollutants like SO2 causes dramatic bronchoconstriction
accompanied by shortness of breath and wheezing in
many subjects with asthma. Likewise, such exposure
is associated with many signs of asthma aggravation:
decreased lung function, airway inflammation, both
emergency department visits and hospital admissions,
and enhanced response to common aeroallergens. Thus,
asthmatics have been shown to be a sensitive population
relative to ozone and other air pollutants.
Further researches linking epidemiological, clinical and
toxicological approaches are required to better under
stand and characterize the risk of exposing asthmatics
to these pollutants. (See Table 4 on page 53)
References:
1. Choudhury AH, Gordain ME, Morris SS. Associations
between respiratory illness and PM10 air pollution. Arch.
153
ASthma
Environ Health. 1997;52:113-7.
2. Canadian Asthma Consensus Group. Provocative factors
in asthma in Canadian Asthma Consensus Report, 1999.
Can Med Assoc J. 1999;161:11 (Suppl): S8-S14.
3. Lipsett M, Hurley SB, Ostro B. Air pollution and emergency room visits for asthma in Santa Clara County,
California. Environ Health Perspect. 1997;105:216-22.
4. Pantazopoulou A, Katsouyanni K, Kourea-Kremastinou
J, Trichopoulos D. Short-term effects of air pollution on
hospital emergency outpatient visits and admissions in the
greater Athens. Greece area. Environ Res. 1995;69:31-6
5. Castellsague J, Sunyer J, Saez M, Anto JM. Short-term
association between air pollution and emergency room
visits for asthma in Barcelona. Thorax 1995; 50: 10516.
6. Romieu I, Meneses F, Sienra-Monge JJL, Huerta J, et al.
Effects of urban air pollutants on emergency room visits
for childhood asthma in Mexico City. Am J Epidemiol.
1995;141:546-53.
7. White MC, Etzel RA, Wilcox WD, Lloyd C. Exacerbations of childhood asthma and ozone pollution in Atlanta.
Environ Res. 1994;65:56-68.
8. Atkinson RW, Anderson HR. Strachan DP, et al. Shortterm associations between outdoor air pollution and visits
to accident and emergency departments in London for
respiratory complaints. Eur Respir J. 1999: 13:257-65.
9. Schwartz J. Slater D, Larson T, Pierson W, Koenig J.
Particulate air pollution and hospital emergency room
visits for asthma in Seattle. Am. J Respir. Crit. Care Med.
1993;147:826-31.
10. Gordian ME, Ozkaynak H, Xue J, et al. Particulate air
pollution and respiratory disease in Anchorage, Alaska.
Environ Health Perspect. 1996;104: 290-7.
11. Yang W, Jennison BL, Omaye ST. Air pollution and
asthma emergency room visits in Reno, Nevada. Inhal
Toxicol.1997;9:15-29.
12. Norris G, YoungPong SN. Koenig JQ, et al. An association
between fine particles and asthma emergency department
visit for children in Seattle. Environ Health Perspect
1999;107:489-93;
13. Peters A, Wichmann E, Tuch T, Heinrich J, Heyder J.
Respiratory effects are associated with the number of
ultrafine particles. Am. J. Respir. Crit. Care Med. 1997;
155:1376-83.
14. Timonen KL, Peldcanen J. Air Pollution and respiratory
health among children with asthmatic or cough symptoms. Am. J. Respir. Crit. Care Med. 1997:156: 546-52.
15. Vedal S. Petlau J, White R, Blair J. Acute effects of ambient inhalable particles in asthmatic and non-asthmatic
children. Am J. Respir. Crit. Care Med. 1998;157: 1-10.
16. Committee of the Environmental and Occupational Health
Assembly of the American Thoracic Society. Health effects of outdoor air pollution. Am J. Respir. Crit. Care Med
1996:153;3-50.
17. Bates DV, Baker-Anderson M, Sixto R. Asthma attacks
periodicity. A study of hospital emergency visits in Vancouver. Environ Res. 1990;51:51-70.
18. Pekkenan J, Timonen KL, Ruuskanen J, et al. Effects of
ultrafine and fine particles in urban air on peak expiratory
flow among children with asthmatic symptoms. Environ
Res 1997;74:24-33.
19. Rusznak C, Devalia JL, Davies RJ. Airway response of
asthmatic subjects to inhaled allegen after exposure to
pollutants. Thorax. 1996;51:1105-8.
20. Rossi OV, Kinnula VL, Tienari J, Huhti E. Association of
severe asthma attacks with weather, pollen and air pollutants. Thorax 1993;48:244-8.
21. Zhong NS. New insights into risk factors for asthma.
Respirology. 1996: 1: 159-66.
22. Hanley QS, Koenig JQ: Larson TV, et al. Response of
young asthmatic patients to inhaled sulfuric acid. Am. Rev.
154
CPM 9TH EDITION
Respir Dis 1992;145:326-31.
23. Koenig JQ, Laarson TV, Hanley QS, et al. Pulmonary function changes in children associated with fine particulate
matter. Environ Res. 1993;63:26-38.
24. Koren HS. Associations between criteria air pollutants and
asthma. Environ Health Perspect. 1995;103 (Suppl)6:23542.
25. Koenig JW, Pierson WE, Horike M, et al. Effects of SO2
plus NaCl aerosol combined with moderate exercise on
pulmonary function in asthmatic adolescents. Environ Res
1981;25:340-8.
26. Wardlaw AJ. The role of air pollution in asthma. Clin Exp
Allergy 1993;23:81-96.
27. Koren HS. Environmental risk factors in atopic asthma.
Int Arch Allergy Immunol 1997;113:65-8.
28. Molfino NA, Wright SC, Katz I, et al. Effect of low
concentrations of ozone on inhaled allergen responses in
asthmatic subjects. Lancet 1991; 338: 199-203.
29. Kreit JW, Gross KB, Moor TB, et al. Ozone-induced
changes in pulmonary function and bronchial responsiveness in asthmatics. J Appl Physio. 1989;66:217- 22.
30. Basha MA, Gross KB, Gwizdala CJ, et al. Bronchoalveolar
lavage neutrophilia in asthmatic and healthy volunteers
after controlled exposure to ozone and filtered purified
air. Chest. 1994;106:1757-65.
31. Scannel C, Chen L, Aris RM, et al. Greater ozone-induced
inflammatory responses in subjects with asthma. Am. J.
Respir. Crit. Care Med. 1996:154:24-9
32. Koenig J, Air pollution and asthma. J. Allery Clin. Immunol. 1999;104:717-22.
Question No. 2:
Does air pollution cause an increase in asthma
prevalence?
Answer:
There is no consistent evidence that common air pollu
tants are involved in the development of asthma.
Because genetics alone is unlikely to explain the increasing prevalence of asthma worldwide, it is very tempting
to attribute the epidemic to environmental factors suchas
indoor and outdoor air pollution1.
In many regions of the world, asthma prevalence has
increased just as the populations have become wester
nized.2,3 However, studies comparing asthma and allergy
prevalence between highly polluted Leipzig and clean
Munich in Germany showed no significant difference
between the two weternized cities.4,5,6,7 Air pollution
may aggravate existing asthma, but it is unlikely to be
responsible for the asthma epidemic. [level 3]
Various studies strongly suggest that air pollution can
modulate or enhance airway inflammation associated
with allergic and asthmatic diseases. There is now extensive evidence demonstrating adjuvant effects of air
pollutants on the formation of specific IgE antibodies
and cytokines in both animals and man.4,5,6,7
References:
1. Duhme H, Welland SK, Kell U. Epidemiological analyses of
the relationship between environmental pollution and asthma.
Toxicol Letters. 1998;28:102-3, 307-16.
2. Koren HS. Environmental risk factors in atopic asthma.
CPM 9TH EDITION
ASthma
Table 4. Relationship of Asthma End Points and Pollutant Exposures32
Asthma End Point PFT
BHR ED/Admissions
Symptoms/meds used
Inflammation
Allergen response^
Immune effects^^
SO2 ++
+/-
*
*
+/-
*
*
NO2
0
+
+
+
+/-
+
+
PM10
+
*
++
+
*
*
*
O3
++
++
++
+
++
+/+
* No published reports
^ Potentiation of allergen response by prior exposure to pollutants
^^ Immune system changes associated with air pollutant exposure
SO2 = sulfur dioxide
NO2 = nitrogen dioxide
PM10 = particulate matter ≤l0µm
O3 = ozone
Int Arch Allergy Immunol. 1997; 113:65-8.
3. Takafuji S, Suzuki S, Koizumi K, et al. Diesel exhaust
particulates inoculated by the intranasal route have an
adjuvant activity for IgE production in mice. J. Allergy
Clinl Immunol. 1987;79:639-45.
4. Fujimaki H, Saneyoshi K, Shiraishi P, et al. Inhalation of
diesel exhaust enhances antigen-specific IgE antibody production in mice. Toxicology. 1997;116:227-33.
5. Takano H, Yoshikawa T, Ichinose T, et al. Diesel exhaust
particles enhance antigen-induced airway inflammation
and local cytokine expression in mice. Am. J. Respir. Crit.
Care Med. 1997;121:165-78.
6. Diaz-Sanchez D, Dotson AR, Takenaka H, Saxon A. Diesel
exhaust particles induce local IgE production in vivo and
alter the pattern of IgE mRNA isoforms. J. Clin Invest.
1994;94:1417-25.
7. Diaz-Sanchez D, Tsien A, Casillas A, Dotson AR, Saxon
A. Enhanced nasal cytokine production in human beings
after in vivo challenge with diesel exhaust particles. J.
Allergy Clinl Immunol. 1996;98:114-23.
Recommendations
During periods of increased outdoor pollution,
asthmatics canminimize exposure by remaining
indoors or reducing outdoor physical activities or
exercise.
Bronchoconstriction resulting from controlled
exposure to air pollutants can be prevented by use
of an inhaled bronchodilator. However, continued
exposure even with the use of inhaled bronchodilator is unlikely to prevent the inflammatory effects
of pollution and may aggravate them by masking
symptoms.
Therefore, the primary management approach should
be preventing or reducing exposure.
Question No. 3:
Do anti-oxidants confer a protective effect on asth
matics exposed to air pollutants?
Answer:
Yes, initial studies show that anti-oxidants may offer
some benefit in asthmatic adults exposed to air pollu
tants [GRADE B].
Concentrations of antioxidant vitamins in the diet and in
the plasma are related to asthma status. Individuals with
asthma have been shown to have lower levels of serum
antioxidants such as vitamin C and E and β-carotene
compared to the general population.1-3 [LEVEL 3] In
studies evaluating the effect of dietary supplementation
with these vitamins on a subject's response to exposure
to ozone, it was shown that patients on vitamin treatment
exhibited a lesser BHR than placebo suggesting some
benefit in asthmatic adults exposed to air pollutants.4
References:
1. Troisi RJ, Wither WC, Trichopoulos D, et al. A prospective
study of diet and adult-onset asthma. Am. J. Respir. Crit.
Care Med. 1995;151:1401-8.
2. Schwartz J, Weiss ST. Relationship between vitamin
C intake and pulmonary function in the first National
Health and Nutrition Examination Survey. Am J Nutr.
1994;59:110-114.
3. Hatch GE. Asthma, inhaled oxidants and dietary antioxidants. Am J. Clin Nutr. 1995;61 (Suppl):S25-S30.
4. Canadian Asthma Consensus Group. Provocative factors
in asthma in Canadian Asthma Consensus Report, 1999.
Can Med Assoc J. 1999;161;11(Suppl):S8-S14.
More studies are needed before any recommendation
can be made on using antioxidants for their protective
effect on asthma.
155
ASthma
Question No. 4:
Can indoor air pollution trigger asthma exacer
bation?
Answer:
Yes, indoor air pollution, the most common of which is
tobacco smoke, has been shown to definitely increase
asthma exacerbation [LEVEL 1].
There is a significant body of evidence linking tobacco
smoke, an indoor pollutant, to asthma exacerbation.1-5
[LEVEL 1] Findings suggest that nitrogen dioxide at
concentrations encountered in the home environment
can potentiate the specific airway response of patients
with mild asthma to inhaled house dust mite allergen.6
Consensus from recent literature reviews and meta-ana
lyses reinforce previous conclusions of health effects
of environmental tobacco smoke (ETS) on children.7-10
Although a genetic etiology for asthma is assumed, the
development of asthma is considered to be dependent
on environmental factors, such as exposure to allergens
including ETS. This exposure may cause asthma onset
in children and adults and early non-allergenic wheezing
in infants and children. It also increases the frequency
and severity of symptoms among those with established
disease. 10,11,12
Environmental tobacco smoke exposure is thus an
accepted risk condition for pulmonary and other diseases.
References:
1. Martinez FD, Wright AL, Taussig IM, et al. Asthma and
wheezing in the first six years of life. N. Engl J Med.
1995;322:133-7.
2. Young S, Le Souef PJ, Geelhoed GC, et al. The influence of a history of asthma and parental smoking on
airway responsiveness in early infancy. N. Engl J Med.
1991;324:1168-73.
3. Samet JM, Lange P. Longitudinal studies of active and
passive smoking. Am. J. Respir. Crit. Care Med. 1996;154:
S257-S265.
4. Weitzman M, Gortmacher SL, Walker DK, et al. Maternal
smoking and childhood asthma. Pediatrics. 1990;85:50511.
5. Dezateux C, Stocks J, Dundas I, Fletcher ME. Impaired
airway function and wheezing in infancy: the influence of
maternal smoking and a genetic predisposition to asthma.
Am. J. Respir. Crit. Care Med. 1999;159:403-10.
6. Tunnicliffe, WS, Burge PS, Ayres JG. Effect of domestic concentrations of nitrogen dioxide on airway
responses to inhaled allergen in asthmatic patients. Lancet
1994;344:1733-6.
7. California Environmental Protection Agency. Health
effects of exposure to environmental tobacco smoke.
California Environmental Protection Agency, Office of
Environment Health Hazard Assessment. September
1997.
8. Scientific Committee on Tobacco and Health. Report of
the Scientific Committee on Tobacco and Health. 1988.
9. Cook DG, Strachan DP. Summary of effects of prenatal
smoking on the respiratory health of children and implications of research. Thorax. 1999;54:357-66.
10. Cook DG, Strachan DP. Background paper: Effects of
maternal and parental smoking on children's respiratory
156
CPM 9TH EDITION
health. International Consultation on Environmental Tobacco Smoke and Child Health. World Health Organization, 1999.
11. Coultas DB. Health effects of passive smoking. Passive
smoking and risk of adult asthma and COPD: an update.
Thorax. 1998;53:381-7.
More research is necessary to clarify the pathologic
mechanisms by which environmental tobacco smoke
causes or aggravates asthma.
Infections and Asthma Development
Question No. 1:
Is there an association between respiratory infections
and the development of asthma?
Answer:
Yes, there is emerging evidence that infections early in
life (i.e., in utero and in early infancy) have profound
influence on the development of asthma in later life.
[LEVEL 2]
Since asthma is an inflammatory disease,1 the main immunoglobulin implicated (IgE) and the kind of inflammatory cytokines predominating (IL-4, IL-5, IL-13)
point to a predominance of the T-helper lymphocyte-22
response.2 T-helper lymphocyte-21 response is further
characterized by increased production of IFN-γ and
Ipterlevel-12.3 It is now known that the intrauterine
milieu is skewed towards the TH2 phenotype. The most
vulnerable period for the switch from TH1 to TH2 is during pregancy and early infancy.4,5 Some viral infections
like the RSV6,7 and EBV8,9 favor the TH2 responses and
has been associated with increased allergen sensitization
in later life.10-13 Respiratory Syncitial virus infection
has been associated with increased Epstein Barr virus
in children regardless of asthma history.14,15,16
On the other hand, absence of the more common
infections (Mycobacterium tuberculosis,17 measles,18
Hepatitis A,19 other respiratory viruses20 and helminthic
infestations) during early childhood impairs the drive
to maturation of the TH1 pathway,20 causing a relative
increase in TH2. This phenomenon is believed responsible, at least in part, for the higher prevalence of asthma
in families with fewer siblings, in affluent societies, and
in the western, industrialized world. These conditions,
resulting in a cleaner environment, avert exposure to
and development of common childhood infections.21-22
However, in these same conditions. the prevalence of
asthma and other atopic diseases, which were considered
rare a few decades ago, appear to have doubled every
10-15 years, with the highest prevalence rates seen in
the industrialized western world.23
CPM 9TH EDITION
References:
Expert: Panel Report 2. Bethesda, MD: National Institutes
of Health; National Heart, Lung and Blood Institute 1997:
2. Holgate S. Mediator and cytokine mechanisms in asthma.
Thorax 1993;48:103-9.
3. Maggi E, Parronchi P, Manetti R, et al. Reciprocal regulatory role of IFN-γ and IL-4 on the in vitro development of
human TH1 and TH2 cells. J. Immunol 1992;148:21427.
4.Warner JA, Miles EA, Jones AC, Quint DC, Colwell BM,
Warner J. Is deficiency of interferon-γ production by allergen-triggered cord blood cells a predictor of atopic
eczema? Clin Exp Allergy. 1994;24:423-30.
5.Martinez FD, Stern DA, Wright AL, Holberg CJ, Taussig
LM, Halonen M. Association of interleukin-2 and interferon-γ production by blood mononuclear cells in infancy
with parenteral allergy skin tests and with subsequent development of atopy. J. Allergy Clin Immunol 1995;96:65260.
6. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B,
Björkstén B. Asthma and immunoglobulin E antibodies
after respiratory synctial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics.
1995;95:500-5.
7. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B,
Respiratory syncytial virus bronchiolitis in infancy is an
important risk factor for asthma and allergy at age 7. Am.
J. Respir. Crit. Care Med. 2000;161:1501-7.
8. Strannegård I-L, Strannegård Ö. Epstein-Barr virus antibodies in children with atopic disease. Intern Arch Allergy
Appl Immunol. 1981;64:314-9.
9. Rystedt I, Strannegård I-L, Strannegård Ö. Increased
serum levels of antibodies to Epstein-Barr virus in adults
with history of atopic dermatitis. Intern. Arch Allergy Appl
Immunol. 1984;75:179-83.
10. Grunberg K, Smits HH, Timmers MC, de Klerk EP, Dolhain
RJ, Dick EC, et al. Experimental rhinovirus 16 infection.
Effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am. J. Respir. Crit. Care Med.
1997;156:609-16.
11. Rager KJ, Langhand JO, Jacobs BL, Proud D, Marsh DG,
Imani F. Activation of antiviral protein kinase leads to
immunoglobulin E class switching in human B cells. J
Virology 1998;72:1171-6.
12. Terajima MN, Yamaya M, Sekizawa, Okinaga S, Suzuki T,
Yamada N, et al. Rhinovirus infection of primary cultures
of human tracheal epthelium: role of ICAM-1 and IL-1.
Am J. Physio 1997;273:749-59.
13. Johnston S, Johnston SL. Influence of viral and bacterial
infections on exacerbations and symptom severity in childhood asthma. Pediatr. Pulmonol. 1997;16 (suppl): 88-9.
14. Schwarze J, Hamelman E, Bradley KL, Takeda K, Gelfand
EW. Respiratory syncytial virus infection results in airway
hyperresponsesiveness and enhanced airway sensitization
to allergen. J. Clin. Invest. 1997; 100: 226-33.
15. Robinson PJ, Hegele RG, Schellenberg RR. Allergic sensitization increases airway reactivity in guinea pigs with
respiratory syncytial virus bronchiolitis. J. Allergy Clin
Immunol. 1997;100:492-8.
16. Cua-Lim F, Roa CC, Pagkatipunan R. Prevalence of adult
asthma and allergies in Malolos, Bulacan, Metro Manila,
Philippines. Presented as a poster study at the 3rd Asian
Pacific Congress of Allergology and Clinical Immunology,
PICC, Manila, Philippines. Dec 9-11, 1998.
17. Shirakawa T, Enomoto T, Shimazu S, Hopkin J. The inverse association between tuberculin responses and atopic
disorder. Science. 1997;275:77-9.
18. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell
AW, Goydiaby A. Measles and atopy in Guinea-Bissau.
Lancet 1996;347:1792-6.
ASthma
19. Matricardi PM, Rosmini F, Ferrigno L, et al. Cross sectional retrospective study of prevalence of atopy among
Italian military students with antibodies against hepatitis
A virus. Br Med J. 1998;314:999-1003.
20. Martinez FD. Role of viral infections in the inception
of asthma and allergies during childhood: could they be
protective? Thorax. 1994;49:1189-91.
21. Strachan DP, Harkins LS, Johnston ID, Anderson HR.
Childhood antecedents of allergic sensitization in young
British adults. J. Allergy Clin. Immunol. 1997; 99:6-12.
22. von Mutius E, Martinez F, Fritsch C, Nicolai T, Reitmeir P,
Theimann H. Skin test reactivity and number of siblings.
Br Med J. 1994;308:692-5.
23. International Study of Asthma and Allergies in Childhood
(ISAAC) Steering Committee. Worldwide variation in
prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:122532.
Question No. 2:
Is there an association between tuberculosis infections
and the development of asthma?
Answer:
Existing data show that asthma is less likely to occur in
tuberculin skin test (PPD) positive patients. [LEVEL 2]
The association of asthma and tuberculosis (TB) is
not as easy to explain. In a study among 867 Japanese
school children aged 12-13 years, asthmatic symptoms
were one half to one third less likely in positive tuber
culin responders as in negative responders. Remission
of atopic symptoms between the ages of 7 and 12 years
was 6-9 times more likely in positive tuberculin responders. In the investigation of this possible association, it
was established that the positive tuberculin responders
had significantly lower levels of the TH2 cytokines
IL-4, IL-10, and IL-13 and higher levels of the TH1 cytokine IFN-γ.1 Apparently, this ability to stimulate TH1
response suppresses TH2 sensitization which, in turn,
curbs the inflammatory cascade in asthma. Therefore,
asthmatic subjects may be tuberculin negative although
not necessarily uninfected since the skin test reaction
is just being naturally suppressed in the asthmatic TH2
phenotype.2,3
Aside from tuberculin reactivity, other indicators appear to prove the purported protection. In one study,
the asthma prevalence established with the ISAAC
project was correlated with the WHO data on smearpositive tuberculosis (TB) cases in countries where
TB information was deemed reliable. There were less
questionnaire-based asthma cases wherever active TB
prevalence was high.4 Furthermore, there was low
asthma occurrence among children in high TB prevalence areas which may indeed be indicative of asthma
protection from M. TB infection.
References:
1. Shirakawa T, Enomoto T, Shimazu S, Hopkin J. The inverse association between tuberculin responses and atopic
disorder. Science. 1997;275:77-9.
2. Strannegård I-L. Larsson LO, Wennergren GW, Stran
157
ASthma
negård Ö. Prevalence of allergy in children in relation
to prior BCG vaccination and infection with atypical
mycobacteria. Allergy 1998;53:249-54.
3. Yilmaz M, Bingol G, Altinas D, Kendirli SG. Correlation
between atopic diseases and tuberculin responses. Allergy.
2000;55:664-7.
4. Von Mutius, et al. International patterns of tuberculosis
and the prevalence of symptoms of asthma, rhinitis, and
eczema. Thorax. 2000;55:449-53.
Question No. 3:
Is there an association between respiratory infections
and acute exacerbations of asthma?
Answer:
Yes. Respiratory infections have been shown to trigger
asthma exacerbations. [LEVEL 1]
Respiratory infections are among the most common
triggers for asthma exacerbations.1-2 [LEVEL 1] It
seems that once asthma is established, re-exposure to
most infections tend to disturb the airway, inducing
more symptoms and, in many cases, frank exacerbation. Routine antibiotic use is not justified since most
infections are viral and self-limiting. Sputum purulence
may just reflect eosinophilia and does not by itself justify
antibiotic use.
References:
1. Nocholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. Br. Med J.
1993;307:982-6.
2. Busse WW, Lemanske RF Jr, Stark JM, Calhoun WJ. The role
of respiratory infections in asthma: In: Holgate ST, Austen
KF, Lichtenstein LM, Kay AB, eds. Asthma: Physiology,
Immunopharmacology and Treatment. London: Academic
Press 1993. pp. 345-53.
Chapter 4
Inhalational Devices
Question no. 1:
Is the inhalational route preferred over systemic ad
ministration of asthma medications?
Answer:
Yes, inhalational route is preferred over systemic administration [GRADE A].
The effects of nebulized and intravenous salbutamol in
severe and acute asthma were compared in two separate
studies. Both studies demonstrated better and faster
response rates in the nebulized group.1,2 [LEVEL 1]
Decreases in serum potassium were noted more often
in the intravenous treated group.1 However, there was
a higher incidence of tremors and palpitations in the
nebulized group, most likely due to the relatively higher
dose of salbutamol used in nebulization.2
Nebulized salbutamol was likewise compared with
subcutaneous epinephrine in children with acute at158
CPM 9TH EDITION
tacks.3 There were no differences noted in the clinical,
physiologic and pulmonary parameters measured in
both treatment arms. However, there were more reports
of nausea, vomiting, tremors, headaches, palpitations,
excitement and pallor in the subcutaneous group.
References:
1. Salmeron S, Brochard L, Real H, et al. Nebulized versus
intravenous salbutamol in hypercapneic acute asthma. Am.
J. Respir. Crit. Care Med. 1994;149: 1466-70.
2. Swedish Society of Chest Medicine. High dose inhaled
versus intravenous salbutamol combined with theophylline
in severe acute asthma. Eur Respir J. 1990; 3:163-70.
3. Becker AB, Nelson NA, Simons FER. Inhaled salbutamol
versus injected epinephrine in the treatment of acute
asthma in children. J Pediatr. 1983;162:465-9.
Question No. 2:
Is there a difference among the various inhalational
devices in terms of drug deposition, efficacy, safety and
promotion of compliance?
Answer:
There is no clear evidence that any one device is superior
over the other. Although lung deposition studies show
superiority of some inhaler devices, it is not clear whether
this translates to improved efficacy [LEVEL 2].
The pressurized metered dose inhaler (pMDI), when
used with optimal technique, delivers about 10-20% of
the nominal per puff dose to the targeted airways.1 In
normal patients, lung deposition with directly labeled
salbutamol can reach from 21.6 +/- 8.9% while patients
with reversible airflow obstruction achieve lung deposi
tion of 18.2 +/- 7.8%.2,3 [LEVEL 3]
Certain maneuvers appear to improve lung deposition. Lung deposition was 18.7% when inhaling from
residual volume and 33% when inhaling from 50% of
vital capacity.4 [LEVEL 5] Use of spacers increased
the amount of drug deposited in the airways in both
normal and asthmatic patients (12.4 +/- 3.5% and 19.0
+/- 8.9%, respectively) possibly because spacers act to
condition the aerosol, slowing the jet of medication and
allowing the propellant to evaporate. In another study
on mild to moderate asthmatics, use of a spacer device
increased lung deposition to 44.1 +/- 10.1%.5 [LEVEL
2] In comparison, single dose dry powder inhalers
(DPIs) show lung deposition between 9.1 and 12.4% 2,3.
Some DPIs like the Turbuhaler, deliver 20-30% of the
nominal dose in adults,5,6,7 whereas the Diskus delivers
about half of that to the lungs with about 1.28 fold difference.8 [LEVEL 2]
Regardless of the significant differences in lung deposi
tion among the inhaler devices, it is not clear whether
these differences are clinically important. For broncho
dilators, especially, only a very small amount of the drug
is needed to produce a useful clinical effect. In a Cochrane
Review on "Pressurized Metered Dose Inhalers versus
All other Handheld Inhalers Devices to Deliver β2-ago-
CPM 9TH EDITION
nists Bronchodilators for Non-acute asthma", results
show that there were no differences between devices
for most clinical outcomes.9 [LEVEL 1]
In any inhaler device used in the treatment of asthma,
systemic adverse events may be expected from the drug
being absorbed from the lung or from the gastrointestinal
tract. In a study on normal subjects treated with inhaled
beclomethasone, sytemic activity was greater using a
DPI (52%) than using a MDI with a large volume spacer
(28%).10 For the two commonly prescribed dry powder
inhalers, systemic bioavailability was higher for bude
sonide via Turbuhaler (39%) compared to fluticasone
via Diskus (13%), however, plasma cortisol levels
did not differ significantly between the two groups.
[LEVEL 2]
ASthma
A spacer device is recommended whenever the MDI is
used for severe asthma [GRADE A].
Three randomized, double-blind studies compared
the efficacy of salbutamol administered either by
nebulization (NEB) or by MDI with a spacer in adults
with moderate to severe acute asthmatic attacks.1,2,3 All
studies consistently demonstrated that NEB and MDI
are equally efficacious in improving FEV1, PEFR and
clinical symptoms. [LEVEL 1] However the NEB
group reported more headaches, palpitations, tremors3
and anxiety1. In another randomized open design trial,
the use of NEB, MDI and dry powder was evaluated in
acute severe asthma in adults. The three delivery systems
were found to improve FEV1 similarly. [LEVEL 1] No
evidence of cardiovascular adverse events were seen.4
References:
1. Newman SP. Aerosol deposition considerations in inhalational therapy. Chest 1985; 88 (Suppl);S152-S160.
2. Biddescombe MF, Melchor R, Mak VF, Short MG, Mak
SG. Lung deposition patterns of directly labeled salbutamol
in normal subjects and inpatients with reversible airflow
obstruction. Thorax. 1993;48:506-11.
3. Zainudin BM, Biddescombe M, Tolfree SE, Short M, Spiro
SG. Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurized
metered dose inhaler, as a dry powder and as a nebulized
solution. Thorax. 1990;45:469-73.
4. Kohler D, Fleischer W, Matthys H. New method for easy
labelling of β2-agonist in the metered dose inhaler with
Technetium99 Respiration. 1988;53:65-73.
5.Hirst PH, Bacon RE, Pitcaim GR, Silvasti UK. A comparison of the lung deposition of budesonide from Easyhaler,
Turbuhaler, and pMDI plus spacer in asthmatic patients.
Respir. Med. 2001;95:720-7.
6.Everard ML. Drug delivery from Turbuhaler dry powder
inhaler to children with cystic fibrosis. Am. J. Respir. Crit.
Care Med 1996;153:a70.
7.Thorrson L et al. Lung deposition of budesonide from
Turbuhaler is twice that from a pressurized metered dose
inhaler. Eur. Respir. J. 1994;7:1839-44.
8.Lipworth BJ, Clark DJ. Comparative lung delivery of salbutamol given Turbuhaler and Diskus dry powder inhaler
devices. Eur. J. Clin. Pharmacol. 1997;53:47-9.
9. Ram FSF, Brocklebank DM, White J, Wright JP, Jones
PW. Pressurized metered dose inhalers versus all other
handheld inhaler devices to deliver β2-agonists broncho
dilators for non-acute asthma (Cochrane Review). The
Cochrane Library 1, 2002. Oxford.
10. Trescoli C, Ward MJ. Systemic activity of inhaled and
swallowed beclomethasone dipropionate and the effect of
different inhaler devices. Postgrad. Med. J. 1998;74:6757.
Two studies involving children compared the effects
of NEB and MDI in mild5 and severe6 acute asthma.
In both studies, FEV1 was shown to improve with both
devices. However the improvement in FEV1 was higher
in the severe attack group using the MDI. [LEVEL 2]
The NEB group had higher heart rates, while the MDI
group reported more dryness of mouth, throat irritation
and more coughing. Despite these side effects, most of
the children preferred MDI over the NEB because of
its shorter administration time.
Question No. 3:
Is wet nebulization better than other inhalational
delivery devices in the acute care setting?
Chapter 5
Answer:
No. Wet nebulization is not any better than other inhalational delivery devices in the acute care setting. In fact,
the use of a metered-dose ihaler (MDI) with or without a
chamber (valve spacer device) is preferred over the use of
a wet nebulizer for patients with mild to moderate asthma.
References:
1. Rodrigo C, Rodrigo G. Salbutamol treatment of acute
severe asthma in the ED: MDI vs. hand-held nebulizer.
Am. J. Emerg. Med. 1998;16(7).
2. Colacone, Afilalo, Wolkove. A comparison of salbutamol
administration by metered-dose inhaler and holding chamber or wet nebulizer in acute asthma. Chest 1993;104:83541.
3. Mandelberg A, Chen E, Noviski N, Priel I. Nebulized
wet aerosol treatment in ED − is it essential? Comparison
with large spacer device for metered dose inhaler. Chest
1997;112:1501-5.
4. Raimondi C, Schottlender J, Lombardi D, Molfino N.
Treatment of acute severe asthma with inhaled albuterol
delivered via jet nebulizer, metered dose inhaler with
spacer, or dry powder. Chest 1997;112:24-8.
5. Schub S, Johnson DW, Stephen D. Comparison of salbutamol by metered dose inhaler with spacer versus a
nebulizer in children with mild acute asthma. J. Pediatr.
1999;135:22-7.
6. Fuglsang G, Pederson S. Comparison of nebuhaler and
nebulizer treatment of acute severe asthma in children
Eur. J. Respir. Dis. 1986;69:109-13.
Acute Care
Question No. 1:
What is the ideal first line therapy for asthma exac
erbations?
Answer:
Inhaled β2-agonists, due to their rapid onset of action,
are recommended as first line therapy in the management
159
ASthma
of acute asthma [GRADE A].
Inhaled short-acting β2-agonists are the drugs of choice
for the initial management of acute exacerbations of
asthma. They are effective bronchodilators [LEVEL
1] and have the fewest side effects. The minimum dose
of short-acting β2-agonists that will effectively control
asthma symptoms should be used2 and they should be
used on an as-needed (not regular) basis. [LEVEL 2]
References:
of Health; National Heart, Lung, and Blood Institute 1997.
2. The British guidelines on asthma management: 1995
review and position statement. Thorax 1997; 52 (Suppl
1):S1-S21.
Question No. 2:
Is nebulization better than MDI in the delivery of
short-acting β2-agonists during acute asthma exac
erbations?
Answer:
No, there is no difference between nebulized and MDIadministered β2-agonist concentrations in the lungs
[GRADE A].
In certain studies using salbutamol, doses are calculated on the basis of the percentage of the drug that
reaches the lower airway. These studies show that in
patients with severe asthma, bronchodilation achieved
was equivalent regardless of whether β2-agonist was
administered by either MDI-spacer or nebulization.1,2,3,4,5
[LEVEL 2] However, the groups given nebulization
showed greater side effects most likely due to increased
systemic absorption and higher plasma levels. Hence,
the nebulization route should only be used if the patient
cannot adequately perform the metered-dose inhalation
technique.
References:
1. Rodrigo C, Rodrigo G. Salbutamol treatment of acute
severe asthma in the ED: MDI vs. hand-held nebulizer.
Am J. Emerg. Med. 1998;16(7).
2. Raimondi C, Schottlender J, Lombardi D, Molfino N. Treatment of acute severe asthma with inhaled albuterol delivered
via jet nebulizer, metered dose inhaler with spacer, or dry
powder. Chest 1997;112:24-8.
3. Mandelberg A, Chen E, Noviski N, Priel I. Nebulized
wet aerosol treatment in ED - is it essential? Comparison
with large spacer device for metered dose inhaler. Chest
1997;112:1501-5.
4. Giannini D, di Franco A, Bacci E, et al. The protective
effect of salbutamol inhaled using different devices on
metacholine bronchoconstriction. Chest 2000; 117;131923.
5. Hindle M, Newton D, Chrystyn H. Dry powder inha
lers are bioequivalent to metered-dose inhalers. Chest
1995;107;629-33.
160
CPM 9TH EDITION
Question No. 3:
Does systemically administered β2-agonists have a role
in acute asthma exacerbations?
Answer:
No, there is no evidence to support the use of intravenously administered β2-agonists in acute asthma
exacerbations [GRADE A].
A meta-analysis addressing the issue on the advantages
using intravenous (IV) β2-agonists in acute asthma exacerbations was recently published by Travers et al. In this
review, 15 randomized clinical trials spanning a period
of 25 years involving 584 patients were analyzed. The
authors concluded that the use of IV β2-agonists, either
as an adjunct to, or a replacement of, inhaled bronchodilator therapy appears to offer no clinical benefit in
acute asthma. [LEVEL 1]
Other issues, however were not addressed in this metaanalysis are:
1. Benefit of IV therapy in ventilated patients
2. Efficacy in the pediatric population since there were
very few pediatric clinical trials identified
3. The efficacy of IV β2-agonists in patients who are
unable to use inhaled β2-agonists
4. The administration of β2-agonists via subcutaneous
route
Reference:
1. Travers A, Jones AP, Kelly K, Barker SJ, Camargo CA,
Rowe BH. The intravenous β2-agonists for acute asthma
in emergency department. The Cochrane Database of
Systematic Reviews. Volume 2001 (Issue 3).
Question No. 4:
Should intravenous aminophylline be used as first line
drug for acute asthma?
Answer:
No, intravenous aminophylline should not be used as
a first line for the treatment of acute asthma. [GRADE
A]
Intravenous aminophylline offers little benefit over
β2-agonist in the treatment of acute asthma.1 In a
study assessing the role of aminophylline in adults,
44 asthmatics were initially treated with nebulized
β2-agonist, then randomized to receive either an infusion of aminophylline or placebo if their peak flow
rates did not improve to more than 40% predicted.2 For
both groups, nebulized β2-agonist was continued and
intravenous methylprednisolone was started. There was
no clinical benefit observed in the aminophylline group
over the placebo group. Furthermore, higher incidence
of side effects was noted in the aminophylline group.
[LEVEL 2]
Systematic reviews evaluating randomized controlled
trials of aminophylline compared to placebo in the acute
treatment of adults3,4 and children5,6 clearly demonstrate
CPM 9TH EDITION
a lack of benefit in major outcomes such as pulmonary
functions and admission rates.[LEVEL 1] These studies
also identified excessive side effects which outweighed
the benefits of aminophylline in this setting.
Currently, aminophylline can only be used as an option for patients where all other modalities had failed
(β2-agonists, corticosteroids, ipratropium bromide,
magnesium, oxygen, IV salbutamol, etc.) and even then
should be used cautiously.7,8
References:
1. Littenberg B. Aminophylline treatment in severe, acute
asthma. A meta-analysis. J. Am. Med. Assoc. 1988;
259:1678-84.
2. Murphy DG, McDermott MF, Rydman RJ, Sloan EP, Zalenski RJ. Aminophylline in the treatment of acute asthma
when β2-adrenergics and steroids are provided. Arch Intern
Med 1993;153:1784-8.
3. Beveridge R, Grunfeld A, Hodder R, Verbeek P. Guidelines
for the emergency management of asthma in adults. Can
Med Assoc J. 1996;155:25-37.
4. Coleridge J, Cameron P, Epstein J, Teichtahl H. Intravenous aminophylline confers no benefit in acute asthma
treated with intravenous steroids and inhaled bronchodilators. Aust N. Z. J. Med. 1993;23:348-54.
5. Yung M, South M. Rsandomized controlled trial of
aminophylline for severe acute asthma. Arch. Dis. Child.
1998;79:405-10.
6. Goodman D, Littenberg B, O' Connor G, Brooks J. Theophylline in acute childhood asthma: a meta-analysis of its
efficacy. Pediatr Pulmol. 1996;21:211-8.
7. Rossing TH, et al. Emergency therapy of asthma comparison of the acute effects of parenteral and inhaled
sympathomimetics and infused aminophylline. Am. Rev.
Respir. Dis. 1980;122:365-71.
8. Murphy DG, McDermott MF, Rydman RJ, Sloan EP,
Zalenski RJ. Aminophylline in treatment of acute asthma
when β2-agonist and steroid are provided. Arch Intern Med.
1993;153:1784-8.
Question No. 5:
Should systemic steroids be used in acute exacerba
tions of asthma?
Answer:
Yes. The use of short course systemic steroids has been
shown to shorten duration of attacks, prevent relapse in
the outpatient treatment of asthma exacerbations and
reduce subsequent hospital admissions [GRADE A].
A meta-analysis of studies on systemic steroids clearly
shows the benefit of systemic steroids in patients with
asthma exacerbation.1,2,3 [LEVEL 1] This review suggests that the early administration of corticosteroids
may reduce rates of admissions to the hospital. The
treatment appears to be most effective in patients who
have severe asthma and who have not received inhaled
corticosteroids during their initial presentation.
Use of corticosteroids in acute asthma is effective not
only in reducing hospital admission rates, but also in
improving pulmonary function, and reducing relapses
of asthma.4 Since it is difficult to predict which patients
will improve spontaneously, corticosteroids should be
offered to every patient who presents with an acute
ASthma
exacerbation of asthma.
References:
1. Rowe B, Keller J, Oxman A. Steroid use in the emergency
department treatment of asthma exacerbation: a meta-analysis. Am. J. Emerg. Med 1992;10:301-10.
2. Fanta SB, et al. Glucocorticoids in acute asthma: a clinical
controlled trial. Am J. Med. 1983;74:845-51.
3. Fiel SB, et al. Efficacy of short-term corticosteroid therapy
in outpatient treatment of acute bronchial asthma. Am. J.
Med. 1983;75:259-62.
4. Chapman KR, et al. Effect of a short-course of prednisone
in the prevention of early relapse after the emergency room
treatment of acute asthma. N. Engl. J. Med. 1991;324:78894.
Question No. 6:
In the treatment of acute exacerbations, are oral ste
roids as effective as parenteral steroids?
Answer:
Yes, oral steroids are just as effective as parenteral
steroids [GRADE A].
The onset of effect in pulmonary function occurs within
three hours and reaches a peak effect within 8 to 12 hours
following a single dose of oral prednisolone.1 Following
intravenous prednisolone, the effect on pulmonary function can be measured after 60 minutes, with maximal
improvement occurring in about 5 hours. However,
comparative studies have not shown a significant benefit
of IV over oral administration in the initial treatment of
severe asthma. In fact, systematic reviews show that oral
steroids are just as effective as IV steroids in controlling
acute asthma.2,3,4 Based on these findings, it is recommended that corticosteroids be administered early and
by mouth; intravenous treatment should be reserved for
those who cannot tolerate food intake.
References:
1. Chung KF, Wiggins J, Collins J. Corticosteroids In: Weiss,
EB, Stein M. (eds). Bronchial Asthma− Mechanisms and
Therapeutics, 3rd edition. Little Brown, Boston 1993. pp
800-817.
2. Rowe B, Keller J, Oxman A. Steroid use in the emergency
department treatment of asthma exacerbation: a meta-analysis. Am J. Emerg. Med. 1992;10:301-10.
3. Fanta SB, et al. Glucocorticoids in acute asthma: a clinical
controlled trial. Am. J. Med. 1983;74:845-51.
4. Fiel SB, et al. Efficacy of short-term corticosteroid therapy
in outpatient treatment of acute bronchial asthma. Am. J.
Med. 1983;75:259-62.
Question No. 7:
What is the effective dose of corticosteroids for acute
asthma?
Answer:
The recommended dosage is hydrocortisone 50 mg fourtimes-a-day for 48 hours, followed by oral prednisone.
[GRADE A]
Twelve controlled clinical trials examined the dose-response
effect of corticosteroids. Of these, only 2 studies were
161
ASthma
CPM 9TH EDITION
able to show a difference between doses.1 [LEVEL 1]
acute asthma attacks [GRADE A].
Generally, the literature does not support the use of
high dose corticosteroids in acute asthma. Hydrocortisone 50 mg four-times-a-day for 48 hours, followed
by oral prednisone, was as effective as 200 mg or 500
mg of hydrocortisone followed by high dose prednisone.2,3 The effective dose of oral prednisolone was
established to be between 30-50 mg daily.3 Furthermore,
the use of high doses of steroids are associated with
increased adverse effects, such as mood disturbance
and myopathy.3
A pooled analysis of three randomized double-blinded
clinical trials conducted in the United States, Canada,
and New Zealand involving 1,064 patients (18-55 yrs),
clearly demonstrated that the addition of ipratropium to
salbutamol in the treatment of acute asthma produces
a small improvement in lung function, and reduces the
risk of the need for additional treatment, subsequent
asthma exacerbations, and hospitalizations.1
References:
1. Engel T, Hering JH. Glucocorticosteroid therapy in
acute severe asthma - a critical review. Eur. Respir. J.
1991;4:881-8.
2. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroid in
acute severe asthma: effectiveness of low doses. Thorax
1992;47:584-7.
3. Webb JR. Dose response of patients to oral corticoste
roid treatment of exacerbation of asthma. Br. Med. J.
1986;292:1045-7.
Question No. 8:
What is the recommended dose interval for oral
steroids?
Answer:
The recommended dose interval of oral steroids is every
12 hours. [GRADE A]
Since the duration of action of corticosteroids on lung
function in unstable asthma is 9 hrs, oral steroids should
be given every 12 hours.1,2 One study suggests a decline
in the efficacy of steroids over 7-12 hours, so fourtimes-a-day dosing is suggested until the FEV1/PEFR is
50-60% of predicted, when the dose may be decreased
and given twice a day.3
References:
1. Ellul-Micallef R, Johansson SA. Acute dose response
studies in bronchial asthma with a new corticosteroid,
budesonide. Br. J. Clin. Pharmaco 1983;15:419-22.
2. Beam WR, Weiner DE, Martin RJ. Timing of prednisone
and alterations of airways inflammation in nocturnal
asthma. Am. Rev. Respir. Dis. 1992;146:1524-30.
3. Kelly, Murphy. Corticosteroids for acute severe asthma.
Ann. Pharmaco. 1991;25:72.
Question No. 9:
What is the role of ipratropium bromide in the ma
nagement of acute asthma?
Answer:
The use of ipratropium bromide alone for acute asthma
has been shown to be inferior to β2-agonists in terms of
bronchodilating properties. The addition of nebulized
ipratropium bromide to salbutamol, however, further
improves the FEV1 or PEFR in the initial treatment of
162
A meta-analysis of ten randomized, placebo-controlled,
double blinded trials involving 1,377 patients (>18 yrs)
showed a modest but statistically significant improvement in airway obstruction (improvement of FEV1 by
100 mL or a PEFR improvement by 31.5 L/min) among
patients who were given a combination of ipratropium
bromide plus salbutamol; (either in metered dose or wet
nebulization). However, the clinical significance of this
improvement remains unclear. It is interesting to note
that none of the trials analyzed reported serious adverse
effects attributable to either the combination therapy or
the single-therapy regimen.2 [LEVEL 1]
A smaller randomized, double-blinded clinical trial involving 180 patients compared the effect of salbutamol
plus placebo with ipratropium bromide plus salbutamol
at higher doses, using metered dose inhaler and spacers
at 10-minute intervals for three hours (24 puffs or 2880
µg of salbutamol and 504 µg of ipratropium bromide
each hour). The results of this study showed that there
may be substantial therapeutic benefit from the addition
of ipratropium bromide to salbutamol administered in
high doses through MDI plus spacer, particularly in
patients with FEV1 less than 30% and with long duration of symptoms before presentation at the Emergency
Department.3 [LEVEL 2]
References:
1. Lanes SF et al. The effect of adding ipratropium bromide
to salbutamol in the treatment of acute asthma; a pooled
analysis of three trials, Chest 1998 Aug; 114(2):365-72.
2. Stoodley RG, Aaron SD, Dales RE. The role of ipratropium
bromide in the emergency management of acute asthma
exacerbation: a meta-analysis of randomized clinical trials.
Ann. Emerg. Med. 1999;34:8-18.
3. Rodrigo GJ, Rodrigo C. First-line therapy for adult patients
with acute asthma receiving a multiple-dose protocol of
ipratropium bromide plus salbutamol in the emergency department. Am. J. Respir. Crit. Care Med. 2000;161:1862-8.
Further studies are needed to determine if the initial
use of combined ipratropium bromide and a β2-agonist will cause significant clinical improvement in
terms of patient's symptom relief, duration of stay in
the Emergency Department (ED), and the probability
of hospitalization.
CPM 9TH EDITION
Chapter 6
Chronic Management of Asthma
Controller Medications
Question No. 1:
Are inhaled corticosteroids effective in the chronic
management of asthma?
Answer:
Yes. Inhaled corticosteroids (ICS) are the mainstay
therapy for persistent asthma [GRADE A].
Long-term treatment with inhaled corticosteroids suppresses the disease by affecting the underlying airway
inflammation. Several studies demonstrate that inhaled
corticosteroids are effective in reducing symptoms and
exacerbations, improving lung function, and decreasing the need for bronchodilator rescue therapy.1,2 A
reduction of airway inflammation, manifested both by
airway histology findings and improved airway hyperres
ponsiveness (AHR), has also been documented.3,4,5,6
[LEVEL 1]
The outcome parameter responding most rapidly to
the initiation of inhaled corticosteroids is symptom
relief. The PEF values improve more gradually, while
improvements in AHR may continue over many months
or even years.1,3,7
References:
1. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen
S, Lehtonen K, Nikander K, Persson T, Reinikainen K,
Selroos O, et al. Comparison of a β2-agonist, terbutaline,
with an inhaled corticosteroid, budesonide, in newly detected asthma. N. Engl. J. Med. 1991;325:388-92.
2. Busse, WW. What role for the inhaled steroids in chronic
asthma? Chest 1993;104:1565-71.
3. Laitinen LA, Laitinen A, Haahtela T. A comparative study
of the effects of an inhaled corticosteroid, budesonide,
and a β2-agonist, terbutaline, on airway inflammation in
newly diagnosed asthma: a randomized, double blind,
parallel-group controlled trial. J. Allergy Clin. Immunol.
1992;90:32-42.
4. Jeffrey PK, Godfrey RW, Adelroth E, Nelson F, Rogers A.
Johansson SA. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. Am Rev. Respir. Dis. 1992;145:890-9.
5. Wilson JW, Djukanovic R, Howarth PH, Holgate ST. Inhaled beclomethasone dipropionate downregulates airway
lymphocyte activation in atopic asthma. Am J Respir Crit
Care Med 1994;149:86-90.
6. Djukanovic R, Wilson JW, Britten KM, Wilson SJ,
Walls AF, Roche WR, Howarth PH, Holgate ST. Effect
of an inhaled corticosteroid on airway inflammation and
symptoms in asthma. Am Rev. Respir. Dis 1992;145:66974.
S, Lehtonen K, Nikander K, Persson T, Selroos O, Sovijarvi A. Effects of reducing or discontinuing inhaled
budesonide in patients with mild asthma. N Engl J. Med.
1994;331:700-5.
ASthma
Question No. 2:
Does early intervention with inhaled corticosteroids
result in a better outcome?
Answer:
Yes. Anti-inflammatory therapy, specifically inhaled corticosteroids when started early in the course of asthma,
diminishes the adverse effects of airway inflammation
[GRADE A].
Long standing uncontrolled asthma is associated
with lower levels of lung function, greater airway
hyperreactivity, more symptoms and greater use of
β2-agonists.1 Lung function in uncontrolled asthma
deteriorates progressively over time and leads to irreversible obstruction in 80% of elderly patients.2 The
decrease in FEV1 among asthmatics is 38 mL/year,
compared with 22 mL/year in non-asthmatics. Delay
in initiating therapy with inhaled steroids for as little
as two years, is associated with a blunted improvement
in lung function (FEV1) when compared with patients
treated with inhaled corticosteroids one to two years
earlier.3 Patients with symptoms of asthma for less than
two years prior to initiation of inhaled corticosteroids
had higher mean FEV1 and PEF values than those
who had symptoms for a longer period of time prior
to initiation of inhaled corticosteroid therapy.4 These
studies suggest that inhaled corticosteroid therapy, in
addition to suppressing the disease, may also modify
the disease outcome if prescribed early enough and given
long enough.3,5,6 [LEVEL 1]
References:
1. Agertoft L, Pedersen S. Effects of long-term treatment with
an inhaled corticosteroid on growth and pulmonary function
in asthmatic children. Respir. Med. 1994;88:373-81.
2. Lange P, Parner J, Vestibo J, Schnohr P, Jensen G.A 15-year
follow-up of ventilatory function in adults with asthma.
N. Engl J. Med. 1998;101:720-5.
S, Lehtonen K, Nikander K, Persson T, Selroos O, Sovijarvi A. Effects of reducing or discontinuing inhaled
budesonide in patients with mild asthma. N Engl J. Med.
1994;331:700-5.
4. Selroos O, Pietinalho A, Loofros AB, Riska H. Effect of
early versus late intervention with inhaled corticosteroids
in asthma. Chest 1995;108:1228-34.
S, Lehtonen K, Nikander K, Persson T, Reinikainen K,
Selroos O, et al. Comparison of a β2-agonist, terbutaline
with an inhaled corticosteroid, budesonide, in newly
detected asthma. N Engl J. Med 1991;325:388-92.
6. Laitinen LA, Laitinen A, Haahtela T. A comparative study
of the effects of an inhaled corticosteroid, budesonide,
and a β2-agonist, terbutaline, on airway inflammation
in newly diagnosed asthma: a randomized, double blind
parallel-group controlled trial. J. Allergy Clin. Immunol.
1992;90:32-42.
163
ASthma
Question No. 3:
Are inhaled steroids safe in the chronic management
of asthma?
Answer:
Yes, inhaled steroids are relatively safe. At low to mode
rate doses, inhaled steroids do not frequently exhibit
clinically important side effects and provide asthmatics
a good risk-benefit profile [GRADE A].
The occurrence and magnitude of adrenal suppression is
the most extensively studied systemic effect of inhaled
corticosteroids. However, even if moderate and high
doses of exogenous corticosteroids affect the hypothalamic-pituitary-adrenal (HPA) axis, the resulting adrenal
suppression does not appear to be clinically important,
as there were no cases of adrenal crisis reported in
adults using only inhaled corticosteroids. [LEVEL 3] In
children, only two such cases have been reported, each
patient having received 400 and 1000 µg of budesonide
for several years.1
In patients reporting any bony abnormality from inhaled
steroid use, a causal link between the abnormality
found and inhaled therapy is often impossible to prove.2
Many such patients would have previously received
short- or long-term therapy with oral steroids, which
in turn would likely to have effects on bone turnover
with resultant structural abnormalities. Even in studies
involving patients who have never received exogenous
steroids, the bone mineral density (BMD) results are
conflicting. Moreover, severe asthma may in itself affect
BMD through its effect on the lifestyle of the patient
(e.g. less exercise, different dietary habits).
Data on the causal relationship between ICS use and
development of cataracts and glaucoma also show
conflicting results. Currently available data suggest that
the risk of developing posterior subcapsular cataract
is not increased in patients being treated with inhaled
corticosteroids alone, even when high doses (up to as
mean dose of 1,500 µg/day) were used for a mean of nine
years of treatment.3 A more recent epidemiologic study
conducted in Canada suggested that patients aged 66 and
older receiving high-dose inhaled corticosteroids (1,500
µg/day) continuously for at least three months have an
increased risk of glaucoma (odds ratio 1.4, CI 1.1-3.0).4
[LEVEL 3] This observation needs further assessment
in controlled, preferably prospective studies.
Thinning skins and easy bruisability are unwanted effects that occur in a dose-dependent fashion with inhaled
corticosteroids. It appears to have a higher prevalence in
older female patients.5,6 The effects are due to a reduction
in extracellular ground substance in the dermis possibly
because of reduced dermal fibroblast activity. The effects
are very rarely seen when total daily doses of inhaled
corticosteroid are less than 1,000 µg. [LEVEL 3]
164
CPM 9TH EDITION
Oral candidiasis, or thrush, has been reported in up to
5% of adult patients receiving inhaled corticosteroids.
When it occurs this can be easily managed by nystatin
mouthwash. The risk of occurrence can be greatly reduced by mouth rinsing with water immediately after
inhalation, or with the use of a spacer device (with a
MDI) or Turbuhaler.7
Dysphonia, or nonspecific throat symptoms are reported
to occur in up to 58% of patients taking inhaled corticosteroids via MDI.8 These effects were not diminished
by the use of spacer devices. However, in studies using
the Turbuhaler, the prevalence of this local side effect
appears to be lower,9 probably owing to the different position of the vocal cords during the inhalation process.
References:
1. Wong J, Black P. Acute adrenal insufficiency associated
with high dose inhaled steroids. Br. Med. J. 1992;304:1415.
2. Toogood JH, Sorva R, Puolijoki H. Review of the effects
of inhaled steroid therapy on bone. Int J Risk Saf Med
1994;5:1-14.
3. Toogood JH, Markov AE, Baskerville J, Dyson C. Association of ocular cataracts with inhaled and oral steroid
therapy during long-term treatment of asthma. J. Allergy
Clin. Immunol. 1993;91:571-9.
4. Garbe EJ, LeLorier J, Boivin J-F, Suissa S. Inhaled and
nasal glucocorticoids and the risk of ocular hypertension
or open-angle glaucoma. J. Am. Med. Assoc. 1997;337:814.
5. Mak VH, Melchor R, Spiro SG. Easy bruising as a side effect of inhaled corticosteroids. Eur Respir. J. 1992;5:106874.
6. Roy A, Leblanc C, Paquette L, Ghezzo H, Cote J, Cartier A,
Malo JL. Skin bruising in asthmatic subjects treated with
high doses of inhaled steroids: frequency and association
with adrenal function. Eur Respir. J 1996;9:226-31.
7. Boulet LP. Summary of recommendations from the Canadian Asthma Consensus Report. Can. Med. Assoc J. 1999;
161(11):S1-S12.
8. Williamson IJ, Matusiewicz SP, Brown PH, Greening AP,
Cromptom GK. Frequency of voice problems and cough in
patients using pressurized aerosol inhaled steroid preparations. Eur Respir. J. 1995;8:590-7.
9. Selroos O, Backman R, Forsen KO, Lofross AB, Niemisto
M, Pietinalho A, Aikas C, Riska H. Local side effects
during 4-year treatment with inhaled corticosteroids: a
comparison between pressurized metered-dose inhalers
and turbuhaler. Allergy 1994; 49:888-90.
Question No. 4:
Does the addition of long-acting bronchodilator to
inhaled corticosteroid produce better control of asthma
than corticosteroid alone?
Answer:
Yes, combining a long-acting inhaled β2-agonist like
salmeterol or formoterol with inhaled corticosteroids
leads to greater improvement in the control of symptoms and lung function among patients with persistent
asthma [GRADE A].
This recommendation is based upon the results of two
landmark placebo-controlled clinical studies. Greening
CPM 9TH EDITION
et. al. compared the effect of adding 50 µg of salmeterol
with doubling the steroid dose in asthmatics who remain
symptomatic despite maintenance treatment with low
dose inhaled beclomethasone dipropionate (BDP) at
400 µg. This study showed that the increase in mean
morning PEF was greater when salmeterol was added
than when BDP dose was doubled.1 [LEVEL1] Wool
cock et al performed a similar study on asthmatics using
higher doses of BDP. Compared to doubling the dose
of BDP, the addition of salmeterol to moderate doses of
BDP improved lung function and increased the number
of symptom-free days.2 [LEVEL 1] These two studies
clearly demonstrate that regular, long-acting β2-agonist
therapy improves lung function in patients already on
inhaled glucocorticoids.
Subsequent studies3,4 strengthen further the conclusion
that, in patients not ideally controlled on moderate
doses of inhaled steroids, the best clinical decision is
to add a long-acting β2-agonist. However, fears have
been raised about the effects of regular treatment with
long-acting β2-agonists on tolerance or its ability to
mask an increase in airway inflammation because of
the lower doses of inhaled corticosteroids used. This
concern was addressed adequately in the Formoterol and
Corticosteroid Establishing Therapy (FACET) study.5
The FACET study has shown that inhaled formoterol
and budesonide have independent effects on asthma
exacerbation rates and that formoterol improves lung
function. Furthermore, these effects were maintained
over the entire one-year study period with no adverse
safety implications. Regular treatment with formoterol
combined with budesonide did not cause any long-term
loss of control of asthma. Previous studies did show that
there were no signs of worsening of disease or tolerance
to the effects of long-acting β2-agonist (LABA) with
regard to any clinical or functional variable examined.6-9
[LEVEL 1]
References:
1. Greening AP, Ind PW, Northfield M, Shaw G. Added
salmeterol versus higher dose corticosteroid in asthma
patients with symptoms on existing inhaled corticosteroid.
Lancet 1994;334:219-24.
2. Woolcock A, Lundback B, Ringdal N, Jacques L. Comparison on addition of salmeterol to inhaled steroids with
doubling the dose of inhaled steroids. Am J. Respir. Crit.
Care Med. 1996;153:1481-8.
3. Ind PW, Dal Negro R, Colman N, et al. Inhaled fluticasone propionate and salmeterol in moderate adult asthma
I: Lung function and symptoms (abstract). Am J. Respir.
Crit. Care Med. 1998;157(Pt 2) Suppl; A416.
4. Ind PW, Dal Negro R, Colman N, et al. Inhaled fluticasone
propionate and salmeterol in moderate adult asthma II:
Exacerbations (abstract). Am J. Respir. Crit. Care Med.
1998; 157 (Pt 2) Suppl; A415.
5. Pauwels RA, Claes-Goran L, Postma DA, Tattersfield
AE, O'Byrne P, Barnes PJ, Ulman A. Effect of inhaled
formoterol and budesonide on exacerbations of asthma.
N. Engl. J. Med. 1997;337:1405-11.
6. Kalrea S, Swystun VA, Bhagat R, Cockroft DW. Inhaled
ASthma
corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest
1996;109;953-6.
7. O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma. N.
Engl. J. Med. 1992;327:1204-8.
8. Cockroft DW, Swystun VA, Bhagat R. Interaction of
inhaled β2-agonist and inhaled corticosteroid on airway
responsiveness to allergen and methacholine. Am J. Respir.
Crit. Care Med. 1995;152:1485-9.
9. Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF.
Regular formoterol treatment in mild asthma: effect on
bronchial responsiveness during and after treatment. Am
J. Respir. Crit. Care Med. 1995; 152:1170-4.
Question No. 5:
Is there a role for fixed dose combination therapy
(long-acting β2-agonist and inhaled corticosteroids)
in the management of persistent asthma?
Answer:
Yes, recent studies suggest that additional clinical benefit
can be achieved with fixed dose combination therapy of
LABA and ICS [GRADE A].
Numerous researches, all randomized, double-blind,
placebo-controlled and parallel group design compared the effects of the fixed combination therapy of
salmeterol and fluticasone to either steroid alone (either
BDP, budesonide or fluticasone), salmeterol alone and
placebo. These studies unequivocally demonstrated that
addition of an inhaled LABA to the ICS treatment improves all aspects of asthma control.1,2,3,4 [LEVEL 1]
The additional clinical benefit derived from the fixedcombination therapy results not only from the LABA-glucocorticoid interaction but also from the steroid-induced
transcription of β2-adrenoceptor gene with the resultant
increased synthesis of the β2-receptor protein. This interaction between the LABA and the ICS increased the
efficacy of both drugs. Fixed dose combination therapy
has likewise been found to be beneficial in terms of other
aspects of asthma management such as cost of treatment3
and patient compliance.5,6,7,8,9 [LEVEL 2]
References:
1. Kavuru, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment
of asthma: a randomized, double-blind placebo-controlled
trial. J Allergy Clin Immunol 2000; 105:1108-16.
2. Lundback B, et al. Cost-effectiveness of salmeterol/fluticasone propionate combination product 50/250 µg twice
daily and budesonide 800 µg twice daily in the treatment
of adults and adolescents with asthma. Respir. Med.
2000;94:724-32.
3. Jenkins C, et al. Salmeterol/fluticasone propionate combination therapy 50/250 µg twice daily is more effective
than budesonide 800 µg twice daily in treating moderate
to severe asthma. Respir. Med. 2000; 94:715-23.
4. Shapiro G, et al. American Thoracic Society. Combined
salmeterol 50 µg and fluticasone propionate 250 µg in the
diskus device for the treatment of asthma. Am J. Respir.
Crit. Care Med. 2000;161:527-634.
165
ASthma
5. van den Berg NJ, et al. Salmeterol/fluticasone propionate
(50/100 µg) in combination in a diskus inhaler (Seretide) is
effective and safe in children with asthma. Pediatr Pulmol.
2000;30:97-105.
6. Bateman ED, et al. Salmeterol/fluticasone combination
inhaler - a new effective and well-tolerated treatment for
asthma. Clin Drug Invest 1998;16(3):193-201.
7. Chapman K, et al. Salmeterol and fluticasone propionate
(50/250 µg) administered via combination diskus inhaler:
as effective when given via separate diskus inhalers. Can
Respir J. 1999; 6(1):45-51.
8. Aubier M, et al. Salmeterol/fluticasone propionate (50/500
µg) in combination in a diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma.
Respir Med 1999;93:876-84.
9. Chrystyn H. The diskus inhaler: a review of its pharmaceutical and clinical performance. Clin. Drug Invest.
1999;18(4):287-96.
Question No. 6:
Can oral steroids be used as alternative controller to
the combination of inhaled corticosteroids and longacting β2-agonist in persistent asthma?
Answer:
Although prednisolone 7.5 to 12 mg/day is as efficacious
as inhaled steroid (800-2000 µg/day), no study has been
made on how oral steroids compare to the ICS plus
LABA combination in controlling persistent asthma.
Daily doses of prednisolone 7.5-10 mg/day are equivalent to moderate to high doses of inhaled corticosteroids.
On the other hand, alternate-day doses of oral steroids
and doses of less than 5 mg/day appear to be less effective than low to moderate doses of inhaled steroids. No
published information about the long-term side effects
of oral steroids in asthma is available, thus, if there is
no alternative to oral steroids, the lowest effective dose
(which appears to be 7.5 mg/day) should be given.1
[LEVEL 2]
Reference:
1. Mash B, Bheekie A, Jones PW. Inhaled versus oral steroids for adults with chronic asthma (Review) Cochrane
Database of Systemic Reviews. Vol 2000 (issue 3).
A well-designed study should be conducted to determine how oral steroids alone compare with combined ICS with LABA in controlling the symptoms
and improving the lung function of patients with
persistent asthma.
Question No. 7:
Does theophylline have a role in the management of
chronic asthma?
Answer:
Yes, theophylline has a role in the management of
166
CPM 9TH EDITION
chronic asthma, but because of its low bronchodilating
effect and potential for significant adverse effects, it
should not be used as first line therapy [GRADE B].
Theophylline is a commonly prescribed bronchodilator
therapy, preferred by some physicians because of the
oral administration and relatively low cost.
Recent studies indicate that theophylline, when added
to a medium dose or low dose of inhaled steroids
(Budesonide (BUD) 800 µg/day or BPD 400 µg/day),
was more effective in controlling asthma than doubling
the inhaled steroid dose.1,2 [LEVEL 3] Theophylline
was also found to be useful for the control of nocturnal
asthma because it improved airflow during the early
hours of the morning and reduced bronchial hyperreactivity.3,4 It was effective when given as a nocturnal
slow-release (SR) preparation in patients with nocturnal
asthma and when wheezing is not responsive to inhaled
long-acting β2-agonists. [LEVEL 2]
Recent evidence shows that theophylline improves lung
function at serum levels below the accepted therapeutic
range (<10 mg/L) in patients with moderate asthma who
are already on high dose inhaled steroids.5,6 [LEVEL
3] Furthermore, withdrawal of theophylline from an
asthma regimen results in an increase in asthmatic
symptoms and a need for higher dose of oral steroids.7
In one study, theophylline was found to be as effective
as beclomethasone even when serum theophylline concentrations were lower than traditional levels of normal
therapeutic range for bronchodilation.8
Theophylline was also found to exhibit anti-inflammatory effects. In patients with atopic asthma given
an allergen challenge, theophylline appeared to inhibit
the late response to allergen and cause a reduction in
bronchial mucosal eosinophils.9 [LEVEL 3]
Common adverse effects of theophylline include nausea,
vomiting, and other gastrointestinal symptoms. Cardiopulmonary effects include tachycardia, arrhythmias, and
occasionally, stimulation of respiratory center. Appropriate dosing and monitoring can generally avoid these.
A general approach is to aim for a steady state serum
concentration of between 5-15 µg/mL. Previous studies
have shown that theophylline levels of 8.7 µg/mL were
achieved in patients given slow-release theophylline in
a dose of 500-750 mg/day.1
Doxofylline is a newer xanthine derivative with claims
of equivalent bronchodilating property and less side effects.11,12 However, there is very little available evidence
to support this. Data to support its anti-inflammatory
effects is likewise lacking.
References:
1. Evans DJ, Tylor DA, Zetterstrom O, et al. A comparison of
low-dose inhaled budesonide plus theophylline and highdose inhaled budesonide for moderate asthma. N. Engl J.
Med 1997;337:1412-8.
CPM 9TH EDITION
2. Ukena D, Harnest U, Sakalauskas R, et al. Comparison of
addition of theophylline to inhaled steroid with doubling
of the dose of inhaled steroid in asthma. Eur Respir J.
1997;10:2754-60.
3. Milgrom H, Barnhart A, Gaddy J, Bush W. The effect of a
24-hour sustained theophylline (Uniphyl) on diurnal variations in airway responsiveness (abstract). J. Allergy Clin.
Immunol 1990;85:144.
4. Bush RK. Nocturnal asthma: mechanism and the role
of theophylline in treatment. Postgrad Med J. 1991; 67
(Suppl):S20-S24.
5. Kidney J, Dominguez M, Taylor PM, et al. Immunomo
dulation by theophylline in asthma. Demonstration by
withdrawal of therapy. Am J. Respir. Crit. Care Med
1995;151:1907-14.
6. Nassif EG, Weinberger M, Thompson R, Huntley W. The
value of maintenance theophylline in steroid-dependent
asthma. N. Engl J. Med 1981;304:71-5.
7. Brenner M, Berkowitz R, Marshall N, Strunk RC. Need for
theophylline in severe steroid-requiring asthmatic. Clin.
Allergy 1988;18:143-50.
8. Chung KF. Theophylline in asthma - evidence for disease
modifying properties. Clin. Exp. Allergy 1996;26:22-7.
9. Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose theophylline in atopic asthma. Lancet
1994;343:1006-8.
10. Ernst P, Fitzgerald JM, Spier S. Canadian Asthma Con
sensus Conference Summary of recommendations. Can.
Respir. J. 1996;3(2):89-100.
11. Dini FL, Cogo R. Doxofylline: a new generation xanthine
bronchodilator devoid of major cardiovascular adverse effects. Curr Med Res Opin 2001;16(4);258-68.
12. Gross E. Doxofylline: drug profile and review of clinical
studies. Eur Rev. Med. Pharm. Sci. 1988:10:1-16.
Question No. 8:
What is the role of anti-leukotrienes in asthma treat
ment?
Answer:
Anti-leukotrienes (Anti-LTs) or leukotriene-receptor antagonists (LTRAs) may be given as a controller drug for
mild persistent asthma whenever inhaled corticosteroid
(ICS) are not in use. [GRADE A]
For moderate to severe persistent asthma, they may be
used as an add-on therapy. [GRADE B]
Studies comparing anti-LTs and ICS consistently show
the latter to be the more potent controller.1,2 [LEVEL
2] However, there were some non-ICS-responders who
showed significant improvement with anti-LTs. Furthermore, some patients clearly preferred anti-LTs over ICS
despite the greater improvement of lung function associated with the steroid.3 The oral formulation and the
positive feedback of symptom relief argue for the use of
the anti-LTs as first-line controller therapy. Therefore,
under selected circumstances, particularly when inhaled
corticosteroids are not available or the patient refuses
to take ICS, the anti-LTs would be suitable first-line or
substitute controllers. [LEVEL 4]
Among patients already on low or high dose inhaled
steroids and who are still symptomatic, the addition
ASthma
of anti-LTs provides for additional control. Several
studies show that asthma symptoms and lung function
improved, and that frequency of exacerbations were
significantly reduced. Furthermore, the use of anti-LT
can facilitate dose reduction of the maintenance inhaled
and/or oral steroids.9,10,11 [LEVEL 2]
5-8
References:
1. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral
montelukast, inhaled beclomethasone, and placebo for
chronic asthma: a randomized controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern. Med
1999;130:487-95.
2. Laitinen LA, Naya IP, Binks S, Harris A. Comparative
efficacy of zafirlukast and low dose steroids in asthmatics
on prn β2-agonists. Eur Respir J. 1997; 10:419S.
3. Ringdal N, Whitney JG, Summerton L. A comparison of
patient preference for treatment with oral zafirlukast or
inhaled beclomethasone. Eur Respir J. 1997; 10:437S.
4. Reiss TF, Chervinsky P, Edwards T, Dockhorn R, Nayak A,
Hess J et al. Montelukast (MK-0476), a CysLT1 receptor
antagonist, improves asthma outcomes over a three-month
period. Am J. Respir. Crit. Care Med 1997.
5. Dahlén B, Nizankowska E, Szczeklik A, Zetterström O,
Bochenek G, Kumlin M et al. Benefits from adding the
5-lipoxygenase inhibitor zileuton to conventional therapy
in aspirin-intolerant asthmatics. Am J. Respir. Crit. Care
Med 1998;157:1187-94.
6. Dahlén SE, Malmström K, Kuna P, Nizankowska E,
Kowalski M, Stevenson D, et al. Improvement of asthma
in aspirin-intolerant patients by montelukast (MK-0476),
a potent and specific CysLT1 receptor antagonist: correlations with patient's baseline characteristics. Eur Respir J
1997;10:419.
7. Virchow JC, Hassall SM, Summerton L, Harris A. Improved asthma control over 6 weeks with Accolate (zafirlukast) in patients on high-dose inhaled corticosteroids.
J. Invest. Med. 1997;10:286A.
8. Israel E, Cohn J, Dubé L, Drazen JM and the Zileuton
Clinical Trial Group. Effect of treatment with zileuton, a
5-lipoxygenase inhibitor in patients with asthma. J. Am.
Med. Assoc. 1996;275:931-6.
9. Tamaoki J, Kondo M, Sakai N, Nakata J, Takemura H, Nagai A, et al. Leukotriene antagonist prevents exacerbation
of asthma during reduction of high-dose inhaled corticosteroid. Am J. Respir. Crit. Care Med. 1997;155:1235-40.
10. Bateman ED, et al. A multicentre study to assess the
steroid-sparing potential of Accolate (zafirlukast; 20 mg
b.d.) Allergy 1995; 50 (Suppl 26): Abs P-0709.
Question No. 9:
Are anti-leukotrienes comparable with the currently
available add-on controllers?
Answer:
Anti-LTs have less bronchodilating effect and symptom
relief compared to inhaled long acting bronchodila
tors1 [LEVEL 1] but have similar effects compared
to theophylline. [LEVEL 4]. However, anti-LTs have
greater anti-inflammatory activity over both LABA and
theophylline. [LEVEL 2]
The addition of either anti-LTs or LABA to inhaled
steroids as maintenance therapy has resulted in less
167
ASthma
asthma symptoms, better quality of life and fewer exacer
bations.1,2-4,5,6 [LEVEL 1] In a study comparing montelukast and salmeterol as add-on therapy in subjects
on concurrent ICS, there was no difference in asthma
exacerbation and adverse reaction rates. Before and after
within group analysis, nonetheless, showed that both
treatments are equally effective.7 [LEVEL 3]
In a double blind randomized study involving 197 patients with mild exercise-induced bronchospasm (EIB),
wherein 25% of the subjects were on concurrent ICS,
salmeterol protection waned significantly more than
montelukast by the 4th and 8th week.7 In contrast, a study
by Busse on 289 adult subjects with mild to moderate
asthma, 80% of whom were on concurrent ICS, showed
that, when compared to zafirlukast, salmeterol produced
significantly greater improvement in A.M. and P.M.
PEFR, less diurnal PEFR variability, fewer symptoms,
and less prn use of short-acting β2-agonist (SABA).5
[LEVEL 3]
Based on these head-on comparative studies, LABA
is the preferred drug over anti-LTs in the majority of
asthmatics still symptomatic despite use of ICS. Some
patients, particularly those with EIB and those in whom
inhaler compliance is not assured, may respond better to
anti-LTs. Anti-LTs should be considered if patients on
both ICS and LABA are still not controlled.
Since anti-leukotrienes appear to modulate leukotriene
activity whose production is not decreased by ICS, it
naturally poses as a more attractive anti-inflammatory
agent than LABA or theophylline. The bronchodilator
effects seen with Zileuton, a leukotriene synthesis modifier, were greater than that reported with theophylline
given on top of ICS.8 No other head-on comparison of
these two class of compounds as add-on therapy has
been done.
References:
1. Busse W. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J. Allergy Clin. Immunol.
1999;103:1075-80.
2. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a
once-daily leukotriene receptor antagonist, in the treatment
of chronic asthma: a multicenter, randomized, double-blind
trial. Montelukast Clinical Research Study Group. Arch
Intern. Med 1998; 158: 1213-20.
3. Dahlén B, Nizankowska E, Szczeklik A, Zetterström O,
Bochenek G, Kumlin M et al. Benefits from adding the
5-lipoxygenase inhibitor zileuton to conventional therapy
in aspirin-intolerant asthmatics. Am J. Respir. Crit. Care
Med. 1998;157:1187-94.
4. Dahlén SE, Malmström K, Kuna P, Nizankowska E,
Kowalski M, Stevenson D et al. Improvement of asthma
in aspirin-intolerant patients by montelukast (MK-0476),
a potent and specific CysLT1 receptor antagonist: correlations with patient's baseline characteristics. Eur Respir J.
1997;10:419.
5. Virchow JC, Hassall SM, Summerton L, Harris A. Improved asthma control over 6 weeks with Accolate (zafirlukast) in patients with high-dose inhaled corticosteroids.
168
CPM 9TH EDITION
J. Invest Med. 1997;10:286A.
6. Villaran C, O'Neill S, Helbling A, et al. Montelukast compared to salmeterol in the treatment of exercise-induced
asthma (EIA). Eur Respir. J. 1998; 12 (Suppl): 361S.
7. Evans DJ, Taylor DA, Zetterstrom O, Chug KF,
O'Connor BJ, Barnes PJ. A comparison of low-dose
inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N. Engl. J. Med
1997;337:1412-8.
8. Schwartz HJ, Petty T, Dube LM, Swanson LJ, Lancaster
JF. A randomized controlled trial comparing zileuton
with theophylline in moderate asthma. Arch Intern Med
1998;158:141-8.
Question No. 10:
How safe are the anti-leukotrienes?
Answer:
Anti-leukotrienes (anti-LTs) are safe drugs even for
prolonged use [GRADE A].
The Antileukotriene Working Group has clearly established the safety of anti-LTs even when given for
prolonged periods of time.1 [LEVEL 1] An analysis
of four 13-week RCTs of similar methodology assessing efficacy and safety of anti-LTs, showed that of the
1484 asthmatics, 560 or 64% in the zafirlukast group
and 391 (65%) in the placebo group developed adverse
effects.2 In one of these studies, extended by Grossman
to 39 more weeks, the most common adverse events
noted were pharyngitis (zafirlukast and placebo 24.2%)
and headache (zafirlukast, 13.0%; placebo, 10.9%).3,4
A similar study assessing safety and tolerability of
montelukast reported the same frequency of adverse
reactions.5 [LEVEL 1]
Anti-LTs should be used with caution among patients
with liver disease, although more recent studies failed to
implicate direct hepatotoxicity with leukotriene receptor
antagonist use. Churg-Strauss syndrome, a rare severe
eosinophilic granulomatous lung disease, has been reported to be associated with anti-LT use (1:20,000 asthma
cases), noted particularly during the period of oral steroid
tapering.6,7,8,9 It was proposed that this situation may be
due to the unmasking, rather than causation of ChurgStrauss syndrome. The syndrome may have mistakenly
diagnosed as asthma and initially controlled with oral
steroids. Once the oral steroid dose has decreased during
tapering, then the syndrome resurfaced.9-11
References:
1. Spector SL. Safety of antileukotriene agents in asthma
management. AntiLeukotriene Working Group. Ann Allergy Asthma Immunol. 2001;86(Suppl):18-23.
2. Tashkin DP, Nathan RA, Howland WC, et al. An evaluation
of zafirlukast in the treatment of asthma with exploratory
subset analyses. J. Allergy Clin. Immunol 1999;103:24654.
3. Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter
study. Clin Therap. 1997;19:675-90.
4. Grossman J, et al. Long-term safety and efficacy of zaf-
CPM 9TH EDITION
irlukast in the treatment of asthma interim results of an
open-label extension trial. Ann Allergy Asthma Immunol
1999;82:361-9.
5. Knoor B. Matz J, Bernstein JA, et al. Montelukast for
chronic asthma in 6-to 14-year-old children: a randomized
double-blind trial. J. Am. Med Assoc. 1998; 279:1181-6.
6.Weschler ME, Garpestad E, Flier SR, et al. Pulmonary
infiltrates, eosinophilia, and cardiomyopathy following
corticosteroid withdrawal in patients receiving zafirlukast.
J. Am. Med Assoc. 1998;279:455-7.
7.Knoell DL, Lucas J, Allen JN. Churg-Strauss syndrome
associated with zafirlukast. Chest 1998;114:332-4.
8.Franco J, Artes MJ. Pulmonary eosinophilia associated
with montelukast. Thorax 1999;54:558-60.
9.Weschler ME, Finn D, Gunawardena D, et al. ChurgStrauss syndrome in patient receiving montelukast as
treatment for asthma. Chest 2000;117:708-13.
10. Churg A, Brallas M, Cronin SR, Churg J. Formes frustes
of Churg-Strauss syndrome. Chest 1995;108:320-3.
11. Churg A, Churg J. Steroids and Churg-Strauss syndrome.
Lancet 1998;352:32-3.
Question No. 11:
What is the recommended dose for anti-leukotrienes
in asthma?
Answer:
Below are the recommended initial adult dosages of the
available anti-LTs in the Philippine market:
Montelukast: 10 mg (5 - 10 mg) H.S., P.O.
Zafirlukast: 20 mg (range: 20 - 80) b.i.d. (one hour
before or two hours after a meal) P.O.
In both preparations, higher dosages have been used,
but only modest additional improvements of asthma
parameters were seen.1,2 The effective dose is continued
up to 3 months after which, the anti-LT can be stopped
if asthma control is good. [LEVEL 4]
References:
1. Noonan MJ, Chervinsky P, Brandon M, et al. Montelukast,
a potent cysteinyl leukotriene antagonist, causes dose
related improvements in chronic asthma. Eur Respir J. In
press.
2. Altman. A placebo-controlled, dose-ranging study of
montelukast, a cysteinyl leukotriene-receptor antagonist.
J. Allergy Clin. Immunol. 1998;102:50-6.
Reliever Medications
Question No. 1:
Are inhaled short-acting β2-agonists administered reg
ularly safe and effective for maintenance therapy?
Answer:
No, inhaled short-acting β2-agonists (SABA) administered regularly is neither safe nor effective as maintenance therapy. Regular use of SABA has been shown
to increase hyperresponsiveness, significantly decrease
asthma control, cause deterioration in the objective
measures of pulmonary function, and increase mortality. Therefore, inhaled SABA should only be used on
an 'as-needed' basis [GRADE A].
ASthma
A 26-week, randomized, multi-center, double-blind
placebo-controlled trial conducted by the National Institute of Health in patients with mild asthma, compared
effects of regularly scheduled salbutamol with as-needed
dosing.1 There were no deleterious nor beneficial effects
derived from the regular use of inhaled salbutamol beyond those derived from the use of the drug on as-needed
basis. [LEVEL 1] Lower values in the evening peak
flow and short-term bronchodilator response to inhaled
salbutamol were noted in the regularly scheduled group,
but these were judged to be not clinically significant.
During a withdrawal period in the study, there was no
deterioration in lung function observed in either group.
In one of the treatment groups, an increase in airway
hyperresponsiveness was observed after two weeks
of regular therapy. The study concluded that inhaled
salbutamol should be prescribed for patients with mild
asthma on an 'as-needed' basis.
Similar studies done by Sears2 and Cockroft,3 also
showed that regular four-times-a-day treatment with
SABA is not more beneficial than its use on a prn basis.
Although regular use of SABA showed a consistent
trend toward more symptoms, reduced lung function and
increased airway responsiveness, the differences for all
outcomes except airway hyperresponsiveness, did not
achieve significant levels.3 [LEVEL 1]
The more potent SABA, like fenoterol, seem to have
more adverse effects when taken regularly. Several
studies demonstrated clear evidence that regular use
of fenoterol was associated with increased morbidity
and mortality due to increased severity of asthma.4,5,6,7
In New Zealand, the use of high-dose fenoterol was
associated with a second epidemic of asthma mortality
during the late 1970s. Case control studies subsequently
confirmed that fenoterol use was a significant predictor
of mortality independent of asthma severity.7 Other studies further demonstrated that the higher risk associated
with fenoterol was attributed solely to the use of higher
doses,8,9 and that regular use of fenoterol resulted in
poorer asthma control, compared with as-needed use.10,11
The decline in the use of fenoterol in New Zealand in
1990 led to reduction in both asthma mortality and hospitalizations for severe asthma. These findings suggested
that the excess mortality was related to severe asthma
exacerbated by fenoterol use.10,11,12 A meta-analysis of
epidemiological studies concluded that the apparent association between β2-agonist use and increased mortality
applied only to nebulized therapy.13 [LEVEL 1]
References:
1. Guidelines for the Diagnosis and Management of Asthma.
National Asthma Education, and Prevention Program:
of Health; National Heart, Lung, and Blood Institute 1997,
2. Sears MR, Taylor DR. The β 2-agonist controversy.
Observations, explanations and relationships to asthma
epidemiology. Drug Safety 1994;11:259-83.
169
ASthma
3. Cockroft DW, McParland CP, Britto SA, et al. Regular
inhaled salbutamol and airway responsiveness to allergen.
Lancet 1993;342:833-7.
4. Canadian Asthma Consensus Report. Can Med Assoc J
1999;161(11 Suppl):S28-S30.
5. Cockroft DW, O'Byrne PM, Swystun VA, Bhagat R.
Regular use of inhaled salbutamol and the allergen-induced late asthmatic response. J. Allergy Clin. Immunol.
1995;96:44-9.
6. Inman MD, O'Byrne PM. The effect of regular inhaled
albuterol on exercise-induced bronchoconstriction. Am.
J. Respir. Crit. Care Med. 1996;153-65-9.
7. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol
and death from asthma in New Zealand, 1981-1983: case
control study. Lancet 1989;1:917-22.
8. Spitzer WO, Suissa S, Ernst P, et al. The use of β2-agonists
and the risk of death and near death from asthma. N. Engl.
J. Med. 1992;326:501-6.
9. Suissa S, Ernst P, Boivin J-F, Horwitz RI, Habbick B,
Cockroft D, et al. A cohort analysis of excess mortality in
asthma and the use of inhaled β2-agonists. Am. J. Respir.
Crit. Care Med 1994;149:604-10.
10. Sears MR, Taylor DR, Print CG. Regular inhaled β2-agonist treatment in bronchial asthma. Lancet 1990; 336:13916.
11. Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled
β2-agonist in asthma: effects on exacerbations and lung
function. Thorax 1993;48:134-8.
12. Pearce N, Beasley R, Crane J, et al. End of New Zealand
asthma mortality epidemic. Lancet 1995;345: 41-4.
13. Mullen M, Mullen B, Carey M. The association between
β2-agonist use and death from asthma. A meta-analytic
integration of case-control studies. J. Am. Med Assoc
1993;270:1842-5.
Question No. 2:
Is there a role for long acting β2-adrenergic agonists
as rescue medication?
Answer:
Yes, long-acting β2-agonists with rapid onset of action
may be used as rescue medication [GRADE B].
Of the two inhaled LABA available, formoterol has
a more rapid onset of action, and its role as rescue
medication has been investigated extensively. Studies
have shown that it relieves bronchoconstriction as rapidly as salbutamol1 and as effectively as terbutaline.2,3,4
[LEVEL 2]
A study by Ind comparing the clinical efficacy and safety
of terbutaline and formoterol used as rescue medications3 showed that both drug were similarly effective.
The probability of not having a severe exacerbation was
similar for both groups and the difference was not statistically significant. For both groups, the mean number
of rescue inhalations used was similar. In another study
by Tattersfield et al, patients who used formoterol as
rescue medication had 38% fewer severe exacerbations
per patient than those who used terbutaline.4
Furthermore, as-needed formoterol use significantly
increased the time to first severe exacerbation over
a period of 12 weeks compared with terbutaline.
[LEVEL 2]
170
CPM 9TH EDITION
The safety of 'as-needed' formoterol was also evaluated
and compared to that of terbutaline. These studies show
that formoterol, when used as rescue medication, was as
safe and well tolerated as terbutaline. No relevant diffe
rences were noted between treatments in terms of adverse
events, ECG changes, serum potassium concentrations, or
other potential systemic side effects. Moreover, no tolerance to the bronchodilating effect was observed.
Another study evaluated the initial effects of treatment
with formoterol in children over 12-16 years using an
open, randomized, and parallel-group design.5 This
study likewise show that, in children, treatment with
formoterol was as well tolerated as treatment with
terbutaline.
References:
1. Politiek MJ, Boorsma M, Aalbers R. Comparison of
formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J.
1999;13:988-92.
2. Malolepszy J, Boszormeny Nagy G, Brander R., Larson P.
Formoterol 90 µg via Turbuhaler was safe in patients with
acute bronchoconstriction. Eur Respir J. 1998:12 (Suppl
28):323s.
3. Ind P, Borszormenyi Nagy G, Pietinalho A, Shiner R, et
al. The safety of formoterol and terbutaline given on demand via Turbuhaler on top of formoterol bid in patients
with moderate asthma. Eur Respir J. 1999;14 (Suppl
30):341s.
4. Tattersfield A, Lofdahl C, Postma D, et al. On demand
treatment: Comparison of formoterol and terbutaline in
moderate asthma. Am. J. Respir. Crit Care Med 1999;159:
A636.
5. Behling B, Matthys H. Comparison of efficacy and safe
ty of formoterol with terbutaline in children with mild to
moderate asthma. Eur Respir J. 1999;14(Suppl 30):43s.
Recommendation
Although limited evidence exists on the usefulness of
LABA as rescue medication, its role as such should
always be with caution. More controlled studies
along this line will validate its role.
Other Treatment/Medication
Question No.1:
Can allergen-specific immunotherapy be used in the
management of asthma?
Answer:
Yes, numerous studies have shown that allergen specific
immunotherapy can be used in the management of
asthma [GRADE A].
Several double-blind, placebo-controlled studies have
been conducted on the efficacy of specific immunotherapy, using various allergens such as house dust
mites, pollens, cat and dog dander. These studies show
that specific immunotherapy may result in a significant
CPM 9TH EDITION
decrease in asthma medication consumption and improvement in symptom scores and FEV1.
Likewise, there is decreased skin and bronchial sensitivi
ty to the allergen among patients undergoing immunotherapy. Some of the most significant improvements
were seen in the studies involving dust mite allergens.
However, many trials involving cat, dog, cockroach and
pollens have also shown significant results.1-10 [LEVEL
1] A meta-analysis of randomized controlled trials on
immunotherapy clearly demonstrated symptomatic im
provement with immunotherapy (odds ratio of 2.7, 95%
CI: 1.7 to 4.4); medication reduction with house dust
mite immunotherapy (odds ratio of 4.2, 95% CI: 2.2 to
7.9) and reduction in bronchial hyperreactivity (odds
ratio of 13.7, 95% CI 3.8 to 50).7 [LEVEL 1]
References:
1. Olsen OT, et al. A one-year, placebo-controlled, doubleblind house dust mite immunotherapy study on asthmatic
adults. Allergy 1997;52:853-9.
2. Jacobsen L et al. Immunotherapy with partially purified
and standardized tree pollen extracts. IV. Results from
long term (six-year) follow up. Allergy 1997; 52:914.
3. Hirsch T, et al. Double-blind placebo-controlled study of
sublingual immunotherapy with house dust mite extract
(D. pt.) in children. Pediatr Allergy Immunol. 1997;8:217.
4. Tari MG, et al. Immunotherapy with an alum-adsorbed parietaria pollen allergoid: a two-year double-blind placebo
controlled study. Allergy 1997;52:65-74.
5. Dolz I, et al. A double-blind placebo-controlled study
of immunotherapy with grass pollen extract alutard
subcutaneous during a three-year period with initial rush
immunotherapy. Allergy 1996;51:489-500.
6. Platts-Mills T. Immunotherapy in the treatment of asthma.
UpToDate May 3, 1999; vol 7, no.2.
7. Abramson M, et al. Is allergen immunotherapy effective in
asthma? A meta-analysis of randomized controlled trials.
8. Haugaard L, et al. Immunotherapy in patients allergic
to cat and dog dander. I. Clinical results. Allergy 1992;
47:249-54.
Question No. 2:
Is immunotherapy safe?
Answer:
Yes, immunotherapy is a relatively safe treatment modality [GRADE A].
Most studies did not reveal any significant harmful
effects from immunotherapy.1-4 [LEVEL 1] A metaanalysis done in 1995 revealed systemic reactions in
32% (95% CI) of patients receiving immunotherapy as
compared with 18% of patients receiving placebo.3 It is
strongly advised that patient selection be strict, and that a
specialist perform this procedure in a clinic setting, with
emergency drugs on hand. Patients undergoing immunotherapy should be observed for up to two hours after
the procedure, as this is the time when the most serious
complications (e.g. anaphylaxis) may occur. Patients
ASthma
with unstable or steroid dependent asthma are usually
at an increased risk for severe reactions and therefore
should be excluded from receiving immunotherapy.
References:
1. Giovane AL, et al. A three-year double blind placebo
controlled study with specific immunotherapy to dermatophagoides: evidence of safety and efficacy in pediatric
patients. Clin Exp. Allergy. 1994:24:53-9.
2. Alvarez Cuesta E et al. Monoclonal antibody-standardized cat extract immunotherapy: risk benefit effects from
a double blind placebo study. J. Allergy Clin. Immunol.
1994;93:556-66.
3. Abramson M et al. Is allergen immunotherapy effective in
asthma? A meta-analysis of randomized controlled trials.
4. Fish JE, Peters SP. Asthma: clinical presentation and management. In: Fishman AP, Elias JA, Fishman JA, Grippi
MA, Kaiser LR, Senior RM, (eds) Fishman's Pulmonary
Diseases and Disorders. 3rd edition. New York: McGrawHill; 1998. p.766.
Recommendation
Referral to a specialist for specific allergen immunotherapy should be considered when avoidance
measures are not possible and appropriate medication
fails to control symptoms of allergic asthma.
Question No. 3:
What is the role of cromones in the management of
chronic asthma?
Answer:
Cromones may be used in young asthmatics and in
those with atopy, nocturnal and exercise-induced asthma
[grade a].
Both cromolyn sodium and nedocromil sodium may
be used in the management of asthma particularly in
children, in atopic young adults, and in patients with
nocturnal asthma and exercise-induced bronchoconstriction. The main hindrances to its efficacy are the
frequent daily dosing (up to four-times-a-day) as well
as the unpleasant taste.
Several studies have compared the efficacy of cromolyn
sodium and nedocromil sodium to placebo, inhaled
short-and long-acting β2-agonists, inhaled steroids,
oral theophylline, and against each other. Most studies comparing these drugs with placebo have revealed
statistically significant improvements in all indexes of
asthma symptoms including quality of life, pulmonary
function measures and bronchodilator use.1-9 [LEVEL
1] When compared to inhaled SABA, cromolyn sodium
and nedocromil sodium showed improved efficacy in patients with atopy.5,6 [LEVEL 2] Long-acting β2-agonist
like salmeterol, however, showed greater improvement
in most pulmonary parameters when compared to the cro
171
ASthma
mones.4 Studies involving theophylline and cromolyn
sodium and nedocromil sodium showed that efficacy
of these drugs are comparable as far as improvement
in asthma symptoms and lung function are concerned.2
[LEVEL 1] However, more significant side effects were
noted with the theophylline group.2
In studies comparing these drugs with inhaled steroids,
it was demonstrated, that although there was improvement in symptoms and lung function in patients on
cromolyn sodium and nedocromil sodium, the use of
inhaled steroids was far more efficacious.5 [LEVEL 1]
Furthermore, the more frequent daily dosing of these
drugs as against the twice daily dosing of steroids may
contribute to lower patient compliance and, therefore,
less efficacy.5
Between the two available cromones, studies have
shown that nedocromil sodium is more effective than
cromolyn sodium in improving asthma symptoms and
pulmonary function tests in adults.2,8,10 [LEVEL 2]
References:
1. Manaker S, Tietze KJ, Wittbrodt ET. Pulmonary pharmacotherapy. In: Fishman AP, Elias JA, Fishman JA, Grippi
Diseases and Disorders. 3rd edition. New York: McGrawHill; 1998. p. 2654-5.
2. Schwartz HJ, et al. A comparative study of the clinical
efficacy of nedocromil sodium and placebo. How does
cromolyn sodium compare as an active control treatment?
Chest 1998;109:945-52.
3. Marin JM, et al. Effects of nedocromil sodium in steroidresistant asthma: a randomized controlled trial. J. Allergy
Clin. Immunol. 1996;97:602-10.
4. Bousquest J, et al. Comparison of salmeterol with disodium
cromoglycate in the treatment of adult asthma. Ann. Allergy Asthma Immunol. 1996;76:189-94.
5. Faurschou P, et al. Comparison between sodium cromogly
cate MDI and beclomethasone dipropionate MDI in the
treatment of adult patients with mild to moderate bronchial
asthma. A double blind, double-dummy randomized parallel group study. Allergy 1994;49:659-63.
6. Fink JN, et al. A double-blind study of the efficacy of
nedocromil sodium in the management of asthma in pa
tients using high doses of bronchodilators. J. Allergy Clin.
Immunol. 1994;94:473-81.
7. De Jong JW, et al. Nedocromil sodium versus albuterol in
the management of allergic asthma. Am. J. Respir. Crit.
Care Med 1994;149:91-7.
8. Jones PW. Quality of life, symptoms and pulmonary
function in asthma: long-term treatment with nedocromil
sodium examined in a controlled-multi-center trial. Nedocromil Sodium Quality of Life Study Group. Eur. Respir.
J. 1994;7:55-62.
9. Clancy L, et al. Treatment of nocturnal asthma with ne
docromil sodium. Thorax 1994;49:1225-7.
10. Lal S, et al. Nedocromil sodium is more effective than
cromolyn sodium for the treatment of chronic reversible
airway disease. Chest 1993;104:438-74.
172
CPM 9TH EDITION
Recommendation
The use of cromones should be limited to patients
who are unwilling or unable to include inhaled steroids in their asthma regimen.
Question No. 4:
Do antihistamines have a role in the management of
chronic asthma?
Answer:
The role of antihistamines is limited to providing relief
of allergic symptoms in some asthmatics. [GRADE
B]
Some patients with both atopy and asthma may benefit
from antihistamines. Several studies, however, have
shown that these drugs may be more useful for allergic
rhinitis rather than bronchial asthma as there is no decrease in bronchial responsiveness to methacholine after
antihistamine treatment.1,4,5,6,7,8,9,10 [LEVEL 2]
Other studies also show that although antihistamines
may help inhibit the early asthma response, they have
no effect on the late asthma response.1,2,8,9,10 [LEVEL 2]
Studies involving the use of ketotifen and terfenadine
have shown improvement in symptomatology of allergic asthmatics compared to placebo, but only after 2-4
weeks of continuous use.8,9 [LEVEL 2] These drugs,
therefore, are inferior when compared to long acting
β2-agonists and steroids in both the relief and control
of asthma symptoms.2,7
References:
1.Twentyman OP, et al. The effect of H1 receptor blockade
on the development of early and late-phase broncho
constriction and increased bronchial responsiveness
in allergen-induced asthma. J. Allergy Clin. Immunol.
1993;91:1169-78.
2.Muir JF. Salmeterol versus slow-release theophylline
combined with ketotifen in nocturnal asthma: a multicen
ter trial. French Multicenter Study Group. Eur Respir. J.
1992;10:1197-2000.
3.Tamaoki J, et al. Effect of azelastine on sulphur dioxide induced impairment of ciliary motility in airway epithelium.
Thorax 1993;48:542-6.
4. Nieber K, et al. Effect of azelastine on substance P content
in bronchoalveolar and nasal lavage fluids of patients with
allergic asthma. Clin Exp. Allergy 1993; 23:69-71.
5.Balzano Gallo, et al. Effect of azelastine on the seasonal
increase in non-specific bronchial responsiveness to
methacholine in pollen allergic patients. A randomized
double-blind placebo-controlled, crossover study. Clin
Exp. Allergy 1992;22:371-7.
6.Turco A, et al. Transcutaneous O2 and CO2 monitoring of
bronchial responsiveness in FEV1 non-responder asthmatics during ketotifen and placebo treatment. Respiration
1993:60:144-8.
7.Manaker S, Tietze KJ, Wittbrodt ET. Pulmonary pharmacotherapy. In: Fishman AP, Elias JA, Fishman JA, Grippi
Diseases and Disorders. 3rd edition. New York: McGrawHill; 1998 p. 2654.
8.Hoshino, et al. Effects of ketotifen on symptoms and on
CPM 9TH EDITION
bronchial mucosa in patients with atopic asthma. Allergy
1997;52:814-20.
9.Tasaka T, et al. The Japanese perspective: effects of ter
fenadine in bronchial asthma: in vitro and in vivo research.
Ann Allergy 1993;71:312-6.
10.Cockroft DW, et al. Allergen-induced increase in airway
responsiveness is not inhibited by acute treatment with
ketotifen or clemastine. Ann Allergy 1992; 68:245-50.
Management Strategy for Chronic Asthma
Question No. 1:
What is the recommended treatment of chronic
asthma?
Answer:
The management of chronic stable asthma depends on
the level of severity of the condition. [GRADE A]
In the chronic management: of persistent asthma, controller medications which have been invariably used
are: inhaled corticosteroids, long acting β2-agonists,
leukotriene antagonists, theophylline and oral steroids. Anti-inflammatory therapy, specifically inhaled
corticosteroids, has been most effective in achieving
asthma control in these patients. In contrast, intermittent
asthma is not considered an indication for continuous
use of ICS. The mainstay reliever medication, however,
remains to be a SABA, which is recommended for use
on a prn basis for all levels of severity. Table 5 shows
the recommended severity-based therapy for chronic
asthma.
The introduction of the fixed single inhaler combination
ICS plus LABA represents a major advance in asthma
treatment since the first edition of the Philippine Consensus Report on Asthma. These fixed-combination
inhalers are effective across the whole spectrum of persistent asthma, from mild to severe persistent disease.1-7
[LEVEL 1] Furthermore, many patients with severe
persistent asthma who used to require maintenance oral
steroids can be kept under control with the ICS plus
LABA single inhaler alone.8,9
With the combination inhaler, a significant proportion of mild to moderate persistent asthmatics can be
symptom free with even half the ICS dosages previously
required.1,5,10-12 The salutary effects of the combination
inhaler are thought to be due to the complementary
actions of the component drugs acting on the same
site of the airways.13-16 Their availability through more
user-friendly gadgets and their twice-a-day dosing have
contributed to improving patient compliance. Furthermore, since lower corticosteroid doses were found to
be just as effective in combination with a LABA when
compared with previously utilized moderate to higher
doses, this has somewhat allayed fears of systemic
side effects. Also, the reduced daily drug cost of the
combination preparations when compared with the two
components taken separately is also likely to enhance
patient adherence.17-19
The broad efficacy of combination inhalers makes the
ASthma
strategy of micro-staging of asthma severity unnecessary. [LEVEL 4] As such, the severity levels of mild
persistent and moderate persistent asthma may be
lumped together into one category. This revolutionary
approach to managing mild and moderate persistent
asthma as a single asthma category has gained relevance
in the light of recent findings on the underutilization of
ICS noted in the asthma survey results conducted in the
Philippines. A sub-analysis of the data on the Asthma
Insights and Reality in Asia-Pacific (AIRIAP) study
clearly indicates the low usage of ICS is the reason why
a big proportion of Filipino asthmatic patients continue
to suffer from persistent symptoms.20 A device, which
delivers both ICS plus LABA, therefore, is bound
to be more acceptable for a greater majority of these
patients, especially since ICS itself does not produce
the immediate relief experienced with bronchodilators.
Better compliance and fewer defaults are, therefore,
expected. Continued use of anti-inflammatory medications correlates with better asthma control. With the
array of doses available for the combination inhalers,
their early use in mild persistent asthma patients is not
at all disadvantageous and greatly simplifies the management approach.
For the more severe persistent cases, the combination
ICS plus LABA in a single inhaler would also be just as
effective. However since the functional airway compromise may be more marked in these patients, significant
improvement in symptomatology and lung function may
take effect only after a few days. Prudence, therefore
dictates that these patients be given a course of oral steroids at the start of treatment in moderate to high doses
which can then be subsequently tapered to a level that
would maintain the asthma under control.
References:
1. Condemi JJ, Goldstein S, Karlberg C et al. The addition of
salmeterol to fluticasone propionate versus increasing the
dose of fluticasone propionate in patients with persistent
asthma. Salmeterol Study Group. Ann Allergy Asthma
Immunol 1999;88:383-9.
2. Shrewberry S, Pyke S, Britton M. Meta-analysis of
increased dose of inhaled steroid or addition of salmete
rol in symptomatic asthma. (MIASMA) Br. Med J.
2000;320:1368-73.
3. Ind PW, Dal Negro R, Colman N et al. Inhaled fluticasone
propionate and salmeterol in moderate adult asthma: Lung
Function and symptoms (abstract) Am J. Respir Crit Care
Med 1998;157 (Pt 2) Suppl;A416.
4. Jenkins C et al. Salmeterol/fluticasone propionate com
bination therapy 50/250 µg twice daily is more effective
than budesonide 800 µg twice daily in treating moderate
to severe asthma. Respir Med 2000;94:715-23.
5. Kips JC, O'Connor BJ, Inman MD, Svenson D, Pauwels
RA, O'Byrn PM. A long-term study of anti-inflammatory
effect of low-dose budesonide plus formoterol versus
high-dose budesonide in asthma. Am J. Respir Crit Care
Med. 2000;161:996-1001.
6. van Noord JA, Schreurs AJM, Mol SJM, Mulden PGH.
Addition of salmeterol versus doubling the dose of flu
ticasone propionate in patients with mild to moderate
asthma. Thorax 1999;54:207-212.
7. Ringdal N, Chuchalin AG, Chovan L et al. A comparison of
Advair/Seretide (salmeterol 50 µg/fluticasone propionate
173
ASthma
250 µg bid) with formoterol 12 µg + budesonide 800 µg
bid in moderate-severe asthma (abstract) Am J. Respir Crit
Care Med 2000;161(3):A196.
8. Aubier M et al. Salmeterol/fluticasone propionate (50/500
µg) combination in a discus inhaler (Seretide) is effective
and safe in the treatment of steroid-dependent asthma.
Respir Med 1999;93:876-84.
9. Nielson LP, Pedersen B, Faurschou P et al. Salmeterol
reduces the need for inhaled corticosteroid in steroiddependent asthma. Respir Med 1999;93(12):863-8.
10. Johansson G, Melvor RA, Purelio FDA et al. Salmeterol/
fluticasone propionate combination dry powder inhaler
50/100 µg bid) is more effective than budesonide (400
µg bid) in mild to moderate asthma (abstract no. p. 162)
Eur Respir J. 1998; 12 Suppl 29:20s.
11. Greening PA, Ind PW, Northfield M, Shaw G. Added
salmeterol versus higher dose of corticosteroid in asthma
patients with symptoms on existing inhaled corticosteroids.
Lancet 1994;334:219-24.
12. Woolcock A, Lundback B, Ringdal N, Jacques L. Comparison on addition of salmeterol to inhaled steroid with
doubling the dose of inhaled steroids. Am J. Respir Crit
Care Med 1996;153:1481-8.
13. Chung KF. The complementary role of glucocorticoids
and long-acting β2 adrenergic agonist. Allergy 1998;53
Supplement 42:7-13.
14. Jack D. The use of inhaled β2 adrenergic bronchodilators
and anti-inflammatory steroids in asthma. J. Pharmaco.
Med 1996;6(1-6):5-16.
15. Spencer CM, Jarvis B. Salmeterol/fluticasone propionate
combination. Drugs 1999, Jun;57:933-40.
16. Markham A, Jarvis B. Inhaled salmeterol/fluticasone
propionate combination: a review of its use in persistent
asthma. Drugs 2000 Nov 60(5):1207:33.
17. Lundback B. et al. Cost-effectiveness of salmeterol/flu
ticasone propionate combination product 50/250 µg
twice daily and budesonide 800 µg twice daily in the
treatment of adults and adolescents with asthma. Respir
Med 2000;94:724-32.
18. Pieters WR. Lundback B. Johansson G et al. Cost-effectiveness analyses of salmeterol/fluticasone propionate
combination product and fluticasone in patients with
asthma II: Study methodologies Pharmacoeconomics
1999;16 Suppl 2:9-14.
19. Palmqvist M, Price MJ, Sondhi S. Cost-effectiveness
analysis of salmeterol/fluticasone propionate combination
50/250 µg vs fluticasone propionate 250 µg in adults and
adolescents with asthma IV: results. Pharmacoeconomics
1999; 16(Suppl) 2:23-8.
20. Lai CKW on behalf of AIRIAP Steering committee.
Clinical Management of asthma in Asia-Pacific in 2000:
the asthma insights and reality in Asia-Pacific (AIRIAP)
Study. Eur Respir J. 2001;18:441s.
Chapter 7
Patient Education
Question No. 1:
Does patient education have a role in asthma man
agement?
Answer:
Yes, patient education is considered by many national
and international consensus guidelines as a key and essential component of successful asthma management.
[GRADE A]
Asthma, although a chronic condition, is also a highly
174
CPM 9TH EDITION
variable and episodic condition. Current management
approaches require asthmatics and their families to effectively carry out complex and multiple pharmacologic
regimes. Asthmatics, therefore, should possess the basic
knowledge and understanding of the mechanisms of action of the different drug prescriptions, the mastery of
inhaler techniques, and the ability to adhere to prolonged
and maintained drug therapy, even during asymptomatic
periods. In addition, the asthmatic and his or her caregiver must have the capability to recognize early warning signs of an acute (especially severe) exacerbation,
make rapid decisions about symptom severity, institute
rational self-medication, and determine when to seek
medical advice. Finally, that he or she must be prepared
to make lifestyle changes and institute environmental
control strategies.
Patient education is thought to be the mechanism through
which patients can learn to successfully accomplish
these tasks. Education is considered to be necessary "to
help patients gain the motivation, skills and confidence
to control their asthma."1,2,3,4 [LEVEL 1]
References:
1. Guidelines for the Diagnosis and Management of Asthma.
National Asthma Education, and Prevention Program.
Expert Panel Report 2: Bethesda, MD: National Institutes
of Health; National Heart, Lung, and Blood Institute 1997,
NIH Publication 97-4015A.
2. International Consensus Report on Diagnosis and Management of Asthma. National Asthma Education and
Prevention Program. Bethesda, MD: National Institutes of
Health; National Heart, Lung, and Blood Institute 1995,
NIH Publication 95-3659.
3. Canadian Asthma Consensus Report. Can. Med Assoc J.
1999; 161(11 Suppl):S15-S19.
4. Philippine College of Chest Physicians Council on Asthma.
Philippine Consensus Report on Asthma Diagnosis and
Management 1996, 55-60.
Question No. 2:
Does asthma patient education improve health care
outcomes?
Answer:
Yes, well-designed asthma patient education programs
reduce the frequency of asthma morbidity indices
over a wide range of patient populations. [LEVEL 1]
Formal asthma education programs, aside from improving symptom control, can likewise enhance self-care
behavior. [LEVEL 2].
A systematic review of 22 randomized controlled trials
recently compared the effects of asthma self-management education programs coupled with regular practitioner review with the usual care in adult patients.1
Self-management education was found to significantly
reduce hospitalizations, emergency room visits, unsche
duled visits to the doctor, days off work or school, and
nocturnal asthma. However, measures of lung function
were not significantly changed. [LEVEL 1] Interventions for educating children who have attended the
CPM 9TH EDITION
ASthma
Question No. 3:
Which educational strategies and methods have
been found to be effective in influencing clinical
outcomes?
emergency room for an asthma exacerbation have found
similar improvement in disease outcomes.2 [LEVEL
1] A recent review by the Education and Delivery of
Care Working Group at the first World Asthma Meeting
reinforced these findings.3
Answer:
Educational strategies that focus on individuals or small
groups employing multiple interactive educational
methods, and incorporating self-management skills
transfer, self-monitoring modalities, and regular practitioner review have been found to be effective. However,
strategies that are limited to the transfer of information
about asthma, its causes and its treatment have not been
shown to improve health outcomes [GRADE A].
A local study conducted at the Philippine General Hospital compared adult asthmatics enrolled at an existing
asthma self-management program and an enriched
education program with a control group who received
usual care.4 The study showed that at three months postintervention, patients who were enrolled in either formal
education programs showed significant improvement in
different facets of asthma self-efficacy, including level
of confidence in performing self-care behavior, decision-making, communication, knowledge of preventive
medication and symptom management. Compared with
the control group, these patients also demonstrated significant change toward correct inhaler technique.
A recent review showed that published asthma educational programs for adults vary widely in terms of
general and educational objectives, teaching techniques,
tools, content, assigned trainers, duration of intervention
and number of sessions. Thus, this precludes replication
and reduces the possibility of identifying the most effec
tive components.1 Nevertheless, a systematic review
of 11 randomized controlled trials of variable quality
showed that limited asthma education (information
only) among patients aged 16 years and above did not
reduce hospitalization for asthma and had no effect on
doctor visits, lung function and medication use.2 The
effects of these education programs on asthma symptoms were variable. There was no reduction in days lost
from normal activity. [LEVEL 1] Moreover, programs
relying primarily on providing books or videotapes
to asthma patients were successful only in improving
knowledge.3,4 [LEVEL 1]
References:
1. Gibson PG, Coughlan J, Wilson AJ, et al. Self-manage
ment education and regular practitioner review for adults
with asthma. Cochrane Database Systematic Review
2000;37(2):CD001117.
2. Haby MM, Waters E, Robertson CF, et al. Interventions for
educating children who have attended the emergency room
for asthma. In: The Cochrane Library, 1, 2001. Oxford:
Update Software.
3. Partridge MR, Hill SR. Enhancing care for people with
asthma: the role of communication, education, training and
self-management. 1998 World Asthma Meeting. Education and Delivery of Care Working Group. Eur Respir J.
2000;16:333-48.
4. Tuazon J, et al. Comparative study of two adult asthma
education programs in enhancing self-care behavior and
symptom control. Doctoral dissertation, UP Manila College
of Public Health, 1999.
Very few studies have addressed the optimal method for
educational intervention. As described in the previous
Table 6.1 Treatment based on Asthma Severity*
Severity
Recommended Treatment
Daily controller medica
tions
Intermittent
None needed
Mild to Moderate Per ICS + LABA combination as
sistent
single inhaler
Severe Persistent
Alternative controller
Oral steroids + ICS + LABA
combination as single inhaler
+ any of the ff:
- SR theophylline
- Antileukotriene
- Oral SR β2-agonist
Reliever medications
SABA as needed
ICS high dose or ICS
regular dose plus any of
the ff:
- SR theophylline
- Antileukotriene
- Oral SR β2-agonist
SABA as needed
SABA as needed
* Available in the Philippines
175
ASthma
section, programs that focus on asthma self-management
skills and are coupled with regular practitioner review,
rather than usual care, improve morbidity indices. Subanalyses of these clinical trials showed that those that
involved individualized written asthma action plans
showed greater reduction in hospitalization than those
that did not.5 [LEVEL 1]
Asthma education should ideally begin in the physician's
office and this can be effective only in the presence of
appropriate asthma therapy.6 [LEVEL 3] With regards to
the comparison between educational programs focused
on individuals versus those using small groups, there
appeared to be few differences in outcomes, although
small-group teaching resulted in a slight decrease in
frequency of exacerbations, possibly because of the
influence of peer support.6,7 [level 2]
As to the issue of PEF self-monitoring, this practice
may be useful in some patients, particularly those who
are poor perceivers of airflow obstruction. Patient selfmonitoring may be effective using either measurement
of PEF or monitoring of symptoms.8,9,10 [LEVEL 1]
References:
1. Sudre P. Jacquemet S, et al. Objectives, methods and
content of patient education programmes for adults with
asthma: systematic review of studies published between
1979 and 1998. Thorax 1999;54:681-7.
2. Gibson PG, Coughlan J, et al. Limited (information only)
patient education programs for adults with asthma. In: The
Cochrane Library, 4, 1999. Oxford: Update Software.
3. Hilton S, Sibbald B, et al. Controlled evaluation of the effects of patient education on asthma morbidity in general
practice. Lancet 1986;1:26.
4. Jenkinson F, Davidson J, et al. Comparisons of effects of
a self-management booklet and audiocassette for patients
with asthma. Br Med J. 1988;297:267-70.
5. Gibson PG, Coughlan J, Wilson AJ, et al. Self-manage
ment education and regular practitioner review for adults
with asthma. Cochrane Database Syst Rev 2000; 37(2):
CD001117.
6. Canadian Asthma Consensus Report. Can Med. Assoc J.
1999;161(11 Suppl):S15-S19.
7. Wilson SR. Individual versus group education: is one
better? Patient Educ. Couns 1997;32(1 Suppl):S67-S75.
8. Ignacio-Garcia JM, Gonzales-Santos P. Asthma selfmanagement education program by home monitoring
of peak exploratory flow. Am J. Respir Crit Care Med
1995;151:353-9.
9. Jones KP, et al. Peak-flow based asthma self-management:
a randomized controlled study in general practice. Thorax
1995;50:851-7.
10. Cowie RL, Revitt SG, et al. The effect of a peak-flow
based action plan in the prevention of acute exacerbations
of asthma. Chest 1997;112:1534-8.
11. Wilson SR. Patient Education. The 3rd Triennial World
Asthma Meeting Syllabus. Chicago, July 15, 2001.
176
CPM 9TH EDITION
Recommendation
Patient education is a key and essential component
of successful asthma management. Education is a
necessary tool not only as means to acquire knowledge about the condition but also to help patients
gain the motivation, skills and confidence to control
their asthma.
Well-designed asthma education programs have been
shown to be effective in reducing asthma morbidity
indices over a wide range of patient population.
Chapter 8
Special Considerations
Exercise-Induced Asthma (EIA)
Question no. 1:
What is the mechanism of exercise-induced asthma
(EIA)?
Answer:
The heat exchange theory is currently one of the top
theories for bronchoconstriction associated with exercise (EIA).1,2,3,4,5,6,7 [LEVEL 2]
During exercise, the humidification and heating function of the nose is bypassed and cold air reaches the
airways, which in turn produces bronchial spasm. This
theory also suggests that the cold air may produce a
humoral effect or a nerve reaction in the small airways
that leads to bronchospasm.8 Neurohumoral transmitters
like leukotrienes have also been implicated in mediating
a portion of the airway narrowing.9,10
Leukotrienes have been found to play a role in airway
refractoriness with repeated bouts of exercise. They may
act through release of inhibitory prostaglandins or by
inhibiting other mediator release. [LEVEL 3]
References:
1. Wells RE, Walker JEC, Hecklen RB. Effects of cold air on
respiratory airflow resistance in patients with respiratory
tract disease. N. Engl. J. Med. 1960; 263: 268-73.
2. Strauss RH, McFadden ER, Ingram RH, Deal EC, Jaeger JJ. Influence of heat and humidity on the airway
obstruction induced by exercise asthma. J. Clin. Invest
1978;61:433-40.
3. Deal EC, McFadden ER, Ingram RH, et al. Role of respiratory heat exchange in production of exercise-induced
asthma. J. Appl Physio. 1979;46:467-75.
4. Anderson SD, Schoeffel RE, Follet R, Perry CP, Daviskas
E, Kendall M. Sensitivity to heat and water loss at rest
during exercise in asthmatic patients. Eur J. Respir. Dis.
1982;63:459-71.
5. Anderson SD, Schoeffer RE, Black JL, et al. Airway
cooling as the stimulus to exercise-induced asthma: reevaluation. Eur J. Respir. Dis. 1985;67:20-30.
6. McDonald J, Nelson J, Lenner K, McLane M, McFadden EJ. Effects of the combination of skin cooling and
CPM 9TH EDITION
hyperpnea of frigid air in asthmatic and normal subjects.
J. Appl Physio. 1997;82:453-9.
7.Banner AS, Chausow A, Green J. The tussive effect of
hyperpnea with cold air. Am Rev Respir Dis 1985; 131:3627.
8.McFadden ER Jr. Exercise-induced airway obstruction.
Clin Chest Med 1995;16:671-82.
9.Israel E, Dermarkarian R, Rosenberg MA, et al. The effects
of a 5-lipoxygenase inhibitor on asthma induced by cold,
dry air. N Engl J Med 1990;323:1740-4.
10. Manning PJ, Watson RM, Margolskee DJ, et al. Inhibition
of exercise-induced bronchoconstriction by MK-571, a
potent leukotriene D4-receptor antagonist. N Engl J Med
1990;323:1736-9.
Question No. 2:
How is exercise-induced asthma controlled?
Answer:
Exercise-induced asthma may be controlled through
non-pharmacological or pharmacological means.
[GRADE B]
Non-pharmacologic treatment entails avoiding incle
ment atmospheres and choosing a sport that is less likely
to induce an asthmatic attack. A third strategy would be
by inducing the known refractory period a few times
earlier in the day of competition so that at the time of
exercise competition, the neurohumoral transmitters
are exhausted.1
Pharmacological treatment methods can be divided into
primary and secondary methods. The primary pharmacological agents given by inhalation are the β2-agonists,
which will prevent exercise-induced bronchospasm in
more than 80% of asthmatics. The most common are the
rapid-acting, short-duration β2-agonists like salbutamol
and terbutaline.2,3 The next most common are the rapidonset, long duration formoterol and the slower-onset,
long-duration β2-agonist salmeterol.4,5,6 [LEVEL 2]
Secondary of adjunctive treatment would be the use of
agents for long-term control of asthma like inhaled corticosteroids7 cromolyn8 and antileukotrienes.9 [level
3] The role of theophylline and anticholinergic agents
are not clearly defined.
References:
1. Cummiskey, J, Exercise-induced Asthma: An overview.
Am J. Med. Sci. 2001:322:200-3.
2. Vilsvik J, Schaaning J, Stahl E, Holthe S. Comparison
between Bricanyl Turbuhaler and Ventolin metered dose
inhaler in the treatment of exercise-induced asthma in
adults. Ann Allergy 1991:67:315-8.
3. Andersen SD, Seale JP, Rozea P, et al. Inhaled and oral
salbutamol in exercise-induced asthma. Am Rev Respir
Dis 1976;114:493-500.
4. McAlpine LG, Thomson NC. Prophylaxis of exercise-induced asthma, a long-acting β2-adrenergic agonist. Respir
Med 1990;84:293-5.
5. Konig P, Hordvik NL, Serby CW. Fenoterol and exercise-
ASthma
6.
7.
8.
9.
induced asthma. Effect of dose on efficacy and duration
of action. Chest 1984;85:462-4.
Nelson JA, Strauss L, Skowronski M, et al. Effect of longterm salmeterol treatment on exercise-induced asthma. N
Engl J Med 1998;339:141-6.
Konig P, Jaffe P, Godfrey S. Effects of corticosteroids
on exercise-induced asthma. J Allergy Clin Immunol
1974;54:14-9.
Tullet WM, Tan KM, Wall RT, Patel KR. Dose-response
effect of sodium cromoglycate pressurized aerosol in
exercise-induced asthma. Thorax 1985;40:41-4.
Leff JA, Busse WW, Pearlman D, et al. Montelukast, a
leukotriene-receptor antagonist, for the treatment of mild
asthma and exercise induced bronchoconstriction. N Engl
J Med 1998;339:147-52.
Food Allergy
Question No. 1:
Is there an association between food allergy and
asthma exacerbations?
Answer:
Yes, the association between food allergy and asthma
has now been clearly established. [Grade B]
There is evidence that respiratory responses, including
bronchoconstriction and increased airway hyperrespon
siveness, have been demonstrated in individuals
following positive food challenges.1 However, foodinduced asthma in adults is actually not very common,
with an incidence of only 2-8.5%.2-3 The clinical correlation of food allergy with asthma is much higher in
children at 17%.4 [level 2]
Multiple food allergy is generally uncommon. In infants
and children, the majority of allergic reactions are due
to milk, eggs, soy, peanuts and wheat5-6, while in adults,
the most common food allergens are peanuts, tree nuts,
fish, shellfish, and eggs.7-8 [level 2]
Sulfite-containing foods have been shown to cause bronchospasm and severe asthmatic attacks in sensitive asthmatic patients, although the mechanism by which sulfate
agents worsen asthma is unknown.9-12 The relationship
between monosodium glutamate (MSG) and asthma is
more controversial with several groups reporting both
association and non-association.13-17 [level 3] The
mechanism by which MSG produces asthma attaks is
not well understood. There is conflicting evidence as
to whether MSG exacerbates or induces asthma or if it
alters airway reactivity. Tartrazine (FD & C Yellow No.
5) and other dyes commonly used for artificial coloring
of food, drink, pills and tablets have been reported to
cause urticaria and asthmatic symptoms in a few sensitive patients.18-19 [level 3]
Asthma exacerbated by food allergy should be suspected
in the following circumstances:
• If asthma started early in life, especially if associated
177
ASthma
with atopic dermatitis
• If asthma associated with a current or past history
of food allergies or atopic dermatitis
• If wheezing after specific foods has been noted
• If asthma poorly controlled even with appropriate
medications and aeroallergen avoidance.
Food-induced asthma may present acutely, occurring
within minutes to one hour of food ingestion, manifesting initially with itchy watery eyes and nose, and itchiness in the mouth. This may later on progress to deep,
repetitive coughing, shortness of breath, and wheezing.
Acute attacks of asthma may be severe and occasionally progress to systemic anaphylaxis and even death.
Respiratory reactions from food allergens may also be
subtle, at times presenting only with cough, chronic
asthma, or increased BHR.20
The diagnosis of food allergy is dependent on adequate
history and physical examination, skin testing or in vitro
antigen-specific IgE tests, results of an appropriated
exclusion diet and blinded provocation when this may
be performed safely.
Food-induced asthma is confirmed if food challenge
reveals wheezing, a significant drop in FEV1, or a
positive methacholine challenge on the test day but
not on the placebo day.21 Elimination of the suspected
food is often tried as part of a diagnostic approach.
If symptoms resolve, confirmation by food challenge
is recommended, except in cases wherein the patient
has a convincing history of systemic anaphylaxis to a
specific food.
Following identification of allergenic food, strict elimination of that food is the only treatment proven effective
to prevent reactions. The use of oral desensitization,
prophylactic medications, or immunotherapy has not
yet been demonstrated in well-designed studies to have
clear efficacy in the management of food allergies.1
[level 2]
References:
1. Rumsaeng V, Metcalfe DD. Asthma and food allergy. Nutr
Rev. 1998;56:S153-S60.
2. Bock SA, Atkins FM. Patterns of food hypersensitivity
during sixteen years of double-blind, placebo-controlled
food challenges (DBPCFC). J Pediatr 1990; 117:561-7.
3. Onorato J, Merland N, Terral C, et al. Placebo-controlled
double-blind food challenge in asthma. J Allergy Clin
Immunol 1986;78:1139-46.
4. James JM, Bernhisel-Broadbent J, Sampson HA. Respiratory reactions provoked by double-blind food challenges
in children. Am J. Respir Crit Care Med 1994; 49:59-64.
5. Burks AW, Mallory SB, Williams LW, et al. Atopic der
matitis: clinical relevance of food hypersensitivity reactions. J. Pediatr. 1988;113:447-51.
6. Burks AW, Sampson HA. Food allergies in children. Curr
Prob Pediatr 1993;23:230-52.
7. Metcalfe DD. Allergic gastrointestinal diseases. In: Rich
RR, Fleisher TA, Schwartz BD, et al. (eds) Clinical
Immunology: Principles and Practice. 1995, St. Louis:
Mosby-Year Book, 966-75.
8. Rumsaeng V, Metcalfe DD. Food allergy. Semin Gastrointest Dis 1996;7:134-43.
178
CPM 9TH EDITION
9. Koepke JW, Christopher KL, Chai H, et al. Dose-dependent bronchospasm from sulfites in isoetharine. JAMA
1984;251;2982-3.
10. Taylor SL, Bush RK, Selner JC, et al. Sensitivity to sul
fited foods among sulfite-sensitive subjects with asthma.
J. Allergy Clin Immunol 1988;81:1159-67.
11. Freedman BJ. Sulphur dioxide in foods and beverages: its
use as a preservative and its effect on asthma. Br J. Dis.
Chest 1980;74:128-34.
12. Delohery J, Simmul R, Castle WD, et al. The relationship
of inhaled sulfur dioxide reactivity to ingested metabisulfite sensitivity in patients with asthma. Am. Rev. Respir.
Dis. 1984;130:1027-32.
13. Allen DH, Delohery J, Baker G. Monosodium L-gluta
mate-induced asthma. J Allergy Clin Immunol 1987;
80:530-7.
14. Germano P, Cohen SG, Hahn B, et al. An evaluation of
clinical reactions to monosodium glutamate (MSG) in
asthmatics using a blinded, placebo-controlled challenge.
J. Allergy Clin Immunol 1991:87:177.
15. Germano P, Cohen S. Hibbard V, et al. Assessment of bron
chial hyperreactivity by methacholine challenge (MTC) in
asthmatics before and after monosodium glutamate (MSG)
administration. J. Allergy Clin Immunol 1993;91:340.
16. Schwartzstein RM, Kelleher M, Weinberger SE, et al. Airway
effects of monosodium glutamate in subjects with chronic
stable asthma. J. Asthma 1987;24:167-72.
17. Moneret-Vautrin DA. Monosodium glutamate-induced
asthma: study of the potential risk of 30 asthmatics and
review of the literature. Allergy Immunol 1987; 19:2935.
18. Virchow C, Szezeklik A, Bianco S, et al. Intolerance to
tartrazine in aspirin-induced asthma: results of a multi
center study. Respiration 1988;53:20-3.
19. Stevenson DD, Simon RA, Lumry WR, et al. Adverse
reactions to tartrazine. J. Allergy Clin Immunol 1986;
78:182-91.
20. Bousquet J. Mechanisms in adverse reactions to food. The
lung. Allergy 1995;50:52-5.
21. Hodge L, Yan KY, Loblay RL. Assessment of food che
mical intolerance in adult asthmatic subjects. Thorax
1996;51:805-9.
Asthma and Gastroesophageal Reflux Disease
Question No. 1:
What is the relationship between asthma and gastro
esophageal reflux disease (GERD)?
Answer:
Like asthma and sinusitis, GERD and asthma frequently
coexist, but there have been no convincing evidence
confirming the role of GERD in triggering or aggravating asthma. [GRADE C]
A relationship between GERD and asthma was first
documented in the late 1960s when asthma patients
were reported to be "cured" of asthma following surgery
for hiatal hernia and/or GERD. Additional research
has continued to show that reflux may cause or trigger
asthma symptoms.1,2,3,4 [LEVEL 3]
There were two accepted mechanisms for the role of
GERD in asthma. The first hypothesis states that the
stimulation of esophageal mucosal receptors produces
vagally mediated bronchospasm. Prolonged reflux clea
rance time often causes symptomatic esophageal disease
CPM 9TH EDITION
and esophagitis, consequently increasing the sensitivity of esophageal receptors to refluxed material. Once
stimulated, the receptors transmit a signal that results in
constriction of the bronchioles. The second hypothesis
is the micro- or macro-aspiration of gastric contents
into the lungs, especially in the supine position of sleep,
causing a chemical pneumonitis. More recent research,
however, has suggested that although aspiration does
occur on rare occasions, it is unlikely to be the primary
reason for reflux-triggered asthma.5
More recently, a third mechanism being proposed is
heightened bronchial reactivity secondary to esophageal
reflux.5 In one study of 105 consecutive asthmatics, the
degree of methacholine reactivity correlated with the
number of episodes of reflux during 24-hour esophageal
pH monitoring.6 [LEVEL 3] Furthermore, nocturnal
esophageal acid events are associated with lower respiratory resistance.7
References:
1. Barish CF, Wu WC, Castell DO. Respiratory complications of gastroesophageal reflux. Arch Intern Med
1985;145:1882-8.
2. Nelson HS. Is gastroesophageal reflux worsening your
patient's asthma? J. Respir. Dis. 1990;11:827-44.
3. Simpson WG. Gastroesophageal reflux disease and asthma.
Arch Intern Med 1995;155:798-803.
4. Mansfield LE, Hameister HH, Spaulding MS, et al. The
role of the vagus nerve in airway narrowing caused by
intraesophageal hydrochloric acid provocation and esophageal distention. Ann Allergy 1981;47:431.
5. Harding SM, Sontag SJ. Asthma and gastroesophageal
reflux. Am J. Gastroentro. 2000;95:S23.
6. Vincent D, Cohen-Jonathan AM, Leport J, et al. Gastroesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur. Respir. J. 1997; 10:225.
7. Cuttitta G, Cibella F, Visconti A, et al. Spontaneous
gastroesophageal reflux and airway patency during the
night in adult asthmatics. Am. J. Respir. Crit. Care Med.
2000;161:177.
Asthma and the Menstrual Cycle
Question No. 1:
Does menstrual cycle affect the course of asthma?
Answer:
No direct correlation exist between the airway hyperres
ponsiveness in asthma and hormonal changes in the
menstrual cycle [GRADE C]
Premenstrual asthma (PMA) is a phenomenon first des
cribed by Frank in 1931, as a symptom of "premenstrual
tension."1 Large-scale longitudinal studies have not yet
been undertaken to adequately address just how prevalent the condition is. Several small studies, however,
seem to suggest that 30-40% of female asthmatics
experience a premenstrual worsening of symptoms but
these were retrospective and based on patient-recorded
recollections of subjective data without any objective
finding of increased asthma severity.2,3,4 [LEVEL 4]
ASthma
Modest reductions in peak flow rate at the time of
menstruation for affected women compared to unaffected women were noted, but these were not usually
associated with clinical deterioration.3,5
Two small prospective uncontrolled studies on the
influence of menstrual cycle on airway responsiveness
reported no significant difference on FEV1 or medication use before or after the menstrual period. Asthma
control, however, deteriorated just prior to and during
menses.6,7 [level 4] A small prospective cohort study
by Pauli et al in 1989 showed significant worsening of
asthma symptoms, slight decline of peak expiratory
flow rates but no deterioration in spirometric values
showing airway responsiveness among asthmatics du
ring menses.8 A larger prospective analysis of data from
182 nonpregnant asthmatic women presenting to the
emergency room for acute asthma reported that nearly
half of all exacerbations occurred during the period
from two days before until four days after the onset of
menses.9 [level 5]
The weight of evidence seems to suggest that there is
at least a subset of female patients with asthma who
develop morbidity in conjunction with their menstrual
cycle. A study by Shames showed that this distinct subset
of women are the older asthmatics with more severe
disease and longer duration of symptoms.10
References:
1. Frank RT. The hormonal causes of premenstrual tension.
Arch Neuro. Psych. 1931;26;1053.
2. Rees L. An etiological study of premenstrual asthma. J.
Psycho. Res. 1963;7:191-7.
3. Gibbs CJ, Coutts H, et al. Premenstrual exacerbation of
asthma. Thorax 1984;39:833-6.
4. Eliasson O, Scherzer HH, et al. Morbidity in asthma in
relation to the menstrual cycle. J. Allergy Clin. Immunol
1986;77:87-94.
5. Hanley SP. Asthma variation with menstruation. Br. J. Dis.
Chest 1981;75:306-8.
6. Juniper EF, Kline PA, et al. Airway responsiveness to
methacholine during the natural menstrual cycle and
the effect of oral contraceptives. Am. Rev. Respir. Dis.
1987;135:1039-42.
7. Weinmenn GG, Zacur H, et al. Airway responsiveness to
methacholine during the normal menstrual cycle. J. Allergy
Clin. Immunol. 1987;79:634-8.
8. Pauli BD, Reid RL, et al. Influence of the menstrual cycle
on airway function in asthmatic and normal subjects. Am.
Rev. Respir. Dis 1989;140:358-62.
9. Skobeloff EM, et al. The effect of menstrual cycle in
asthma presentations in the emergency department. Arch
Intern Med 1996;156:1837-40.
10. Shames RS, Heilbron DC, et al. Clinical difference among
women with and without self-reported perimenstrual
asthma. Ann Allergy Asthma Immunol 1998;81:65-72
Question No. 2:
Why does worsening of asthma occur in these patients
during menstruation?
Answer:
The precise cause of worsening of asthma during mens
truation is thought to be related to changing levels of
179
ASthma
progesterone or prostaglandins. Current studies, however, presently do not show any definite correlation
between airway responsiveness and the absolute levels
of these substances [GRADE C].
Progesterone levels fall in the days before menstruation
and it has a relaxant effect on airway smooth muscle
contractility. Thus, this may lead to cyclic changes in
airway responsiveness in women prone to perimenstrual exacerbation of asthma.1 Progesterone-induced
hyperventilation may further influence asthma leading
to symptomatic deterioration and dyspnea.2 Although
an increase in asthma symptoms and a decrease in peak
expiratory flow rates have been demonstrated in the
luteal phase of the menstrual cycle, there seems to be
no deterioration in airway reactivity.3 It must be emphasized, however, that there is no real relationship between
airway function and absolute levels of progesterone.
Prostaglandins have previously been reported to have
bronchoconstrictive effects; endogenous prostaglandin
synthesis, however, has not been shown to correlate with
occurrence of premenstrual asthma.4
The lack of definitive evidence for either progesterone
or prostaglandin mediation has led to several other
theories that are under investigation.5 These theories
are as follows:
• "Allergy" to endogenous hormones
• Psychological changes associated with the premens
trual syndrome
• Progesterone potentiation of an unidentified bronchodilator
• Progesterone-mediated loss of microvascular integrity with subsequent edema leak
• Dynamic fluctuations of estrogen levels after sustained but static elevation
• Increase in mucus secretions that may accompany
menstruation
Further clarification of and investigation into these
mechanisms need to be undertaken to provide more information and insight into the pathogenesis of the effect
of asthma on the menstrual cycle or vice versa.
References:
1. Boggess KA, Williamson HO, et al. Influence of the menstrual cycle on systemic disease. Obst. Gyne. Clin. N. Am.
1990;17:321-42.
2. Moore LG, McCullough RE, et al. Increased HVR in
pregnancy: relationship to hormonal and metabolic challenges. J. Appl. Physio. 1987;62:158-63.
3. Pauli BD, Reid RL, et al. Influence of menstrual cycle on
airway function in asthmatic and normal subjects. Am Rev
Respir Dis 1989;140:358-62.
4. Eliasson O, Densmore MJ, et al. The effect of sodium meclofenamate in premenstrual asthma: a controlled clinical
trial. J Allergy Clin Immunol 1987;79:909-18.
5. Case AM, Reid RL. Effects of menstrual cycle on medical
disorders. Arch Intern Med 1998;158:1405-12.
180
CPM 9TH EDITION
Question No. 3:
Does treatment of premenstrual asthma differ from the
usual treatment of asthma exacerbations?
Answer:
No, the treatment options include the usual medications
for asthma. Intramuscular progesterone, however, may
be effective in women with severe, refractory peri
menstrual asthma. [grade c]
Treatment of perimenstrual asthma entails the usual
asthma medications, namely: β2-agonists, anticholi
nergics, and corticosteroids. Intramuscular progesterone
was shown to be more effective in women with severe,
refractory premenstrual asthma, eliminating the decrease
in peak flow rate, as well as reducing total corticosteroid
requirement.1 [level 4]
The use of danazol, intramuscular medroxyprogesterone
acetate or gonadotropin-releasing hormone agonists to
suppress menstrual cyclicity remains a promising area
of investigation.
Reference:
1. Beynon HLC, Garbett ND. Severe premenstrual exacer
bations of asthma: effect of intramuscular progesterone.
Lancet 1988:2:370-2.
Occupational Asthma
Question No. 1:
Is occupational asthma a common condition?
Answer:
Although occupational asthma is the most common
occupational lung disease in developed countries,1,2,3
very few prevalence data has been published for many
developing countries including the Philippines.
Occupational exposures have been estimated to cause
5-15% of adult-onset asthma.4,5,6 The prevalence of occupational asthma due to agents with high molecular
weight is generally less than 5% while prevalence due
to low molecular weight agents is 5-10%.7
References:
1. Meredith S, Nordman H. Occupational asthma: measures
of frequency from four countries. Thorax 1996; 51:43540.
2. Toran, K. Self-reported rate of occupational asthma in
Sweden 1990-92. Occup Environ Med 1996;53:757-61.
3. Provencher S, Labreche FP, DeGuire L. Physician based
surveillance system for occupational respiratory diseases,
the experience of PROPULSE, Quebec, Canada. Occup
Environ Med 1997;54:272-6.
4. Kogevinas M, Anto JM, Soriano A, et al. The risk of asthma
attributable to occupational exposures. A population-based
study in Spain. Spanish Group of European Asthma Study.
Am. J. Respir. Crit. Care Med 1996;154:137-43.
5. Blanc PD, Casternas M, Smith S, Yelin E. Occupational
asthma in a community-based survey of adult asthma.
Chest 1996;109 (Suppl1): S56-S78.
6. Fishwick D, Pearce N, D'Sousa W, et al. Occupational
asthma in New Zealanders: a population based study.
CPM 9TH EDITION
Occup Environ Med 1997;54:301-6.
7. Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI.
Asthma in the workplace. New York, Marcell Dekker Inc.
1993.
Question No. 2:
When should you suspect occupational asthma?
Answer:
An occupational cause should be considered for all new
cases of asthma in adults.1 [grade d]
A detailed occupational history of past and current exposure to possible causal agents in the workplace, work
processes and specific job duties should be obtained. A
history of asthma beginning during a working lifetime
should lead to consideration of occupational asthma.
The classic history is one of a worker whose asthma
is worse at work, with improvement during weekends
or holidays. However, this pattern may often be absent
because symptoms are also usually present outside the
workplace, being triggered by exposure to irritants, such
as cold air, fumes or exercise.
Questionnaires, although sensitive and essential in the
assessment, are not specific tools. In a study on workers
suspected to have occupational asthma, the predictive
value of a positive questionnaire was 63% and a negative
questionnaire was better at 83%. Another study showed
that clinical history has a high sensitivity of 96% but a
low specificity of 25% for the diagnosis of occupational
asthma.2 [level 4]
References:
1. Cartier A. Occupational asthma: what have we learned? J.
Allergy Clin. Immunol 1998;102 (Suppl 5):S90-S95.
2. Malo JL, Ghezzo H, L'Archeveque J, et al. Is the clinical
history a satisfactory means of diagnosing occupational
asthma? Am Rev Respir Dis 1991;143:528-32.
Question No. 3:
What is the approach to the patient suspected of having occupational asthma?
Answer:
As opposed to other occupational lung diseases like
pneumoconiosis in which the diagnosis is based only
on exposure history and chest x-ray abnormalities, occupational asthma needs to be confirmed by objective
means.1 [grade d]
The first step following history and physical examination is to confirm objectively that the patient has
asthma. Spirometry before and after bronchodilator
therapy should be assessed within 24 hours of typical
workplace exposure or at a time when symptoms are
present. If spirometry is normal, then bronchoprovocation using either methacholine or histamine should
be performed to determine the presence or absence of
airways hyperresponsiveness. A normal methacholine
response in a symptomatic patient who is still working,
ASthma
rules out occupational asthma.
Once the diagnosis of asthma is objectively confirmed
by pulmonary function tests, the next step is to assess objectively the relationship of asthma to work. This could
be done by challenge testing with the specific suspected
agent or by serial monitoring of PEF for a period at work
and a similar period away from work.2,3 Sensitivity and
specificity of PEF monitoring in confirming occupational asthma are 81% and 74%, respectively.4 Combining
PEF monitoring with serial assessments of bronchial
responsiveness using histamine or methacholine can
provide further objective evidence.5 When the above
results are inconclusive, serial spirometry performed
throughout the work shift is advisable.
Early referral and rapid access to a specialist and a
specialized center where investigations can be arranged
is needed because the diagnosis is often difficult to establish in those who have left work and cannot or will
not return. [grade a]
References:
1. Cartier A. Occupational asthma: what have we learned?
J. Allergy Clinl Immunol 1998; 102 (Supplement 5): S90S95.
2. Chan-Yeung M. Assessment of asthma in the workplace.
American College of Chest Physicians Consensus Statement. Chest 1995;108:1084-117.
3. Burge PS. Single and serial measurements of lung function
in the diagnosis of occupational asthma. Eur J. Respir. Dis.
1982;63 (Suppl 123):47-59.
4. Perrin B, Lagier F, L'Archeveque J, et al. Occupational
asthma: validity of monitoring of peak expiratory flow
rates and non-allergic bronchial responsiveness as
compared to specific inhalation challenge. Eur Respir J.
1992;5:40-8.
5. Moscato G, Godnic-Cvar J, Maestrelli P. Statement on
self-monitoring of PEF in the investigation of occupational
asthma. Subcommittee on Occupational Allergy of European Academy of Allergy and Clinical Immunology. J.
Allergy Clin. Immunol 1995;96:295-301.
6. Lerover C, Perfetti L, Trudeau C, et al. Comparison of PEF
and FEV1 monitoring with specific inhalation challenge in
the diagnosis of occupational asthma. Am. J. Respir. Crit.
Care Med 1997;155 (Part2): A137.
Question No. 4:
How should patients with occupational asthma be
managed?
Answer:
The ideal treatment is the permanent removal of patients
with occupational asthma from exposure to the causal
agent. [GRADE A]
During the period of diagnostic investigations and following diagnosis, the patient should have appropriate
treatment for asthma, consistent with recent asthma
guidelines.
Unfortunately, studies indicate that the majority of
patients with occupational asthma are left with some
degree of permanent lung function impairment.1 Over
181
ASthma
60% of subjects fail to recover even after removal from
exposure. The best prognosis is seen among those with
early diagnosis, early removal from further exposure
to the sensitizer, and in those with milder asthma at the
time of diagnosis.2,3
The patient with occupational asthma should be considered to represent a 'sentinel event' in the workplace.
Consideration should be given to the possibility of
occupational asthma in other exposure workers, and appropriate measures should be taken to reduce the risk of
further exposure to the offending agent. [grade a]
References:
1. Balkissoon R, Newman L. Occupational Asthma. Med
scape Respiratory Care 1999;3(6).
2. Malo JL, Cartier A, Ghezzo H, et al. Patterns of improvement on spirometry, bronchial hyperresponsiveness and
specific IgE antibody levels after cessation of exposure in
occupational asthma caused by snow-crab processing. Am
Rev Respir Dis 1988;138:807-12.
3. Lemiere, C, Cartier A, Dolovich J, et al. Outcome of
specific bronchial responsiveness to occupational agents
after removal from exposure. Am. J. Respir. Crit. Care
Med 1996;154:329-33.
Asthma and Pregnancy
Question No. 1:
Does the course of asthma change during preg
nancy?
Answer:
Asthma may remain unchanged, become worse, or
improve during pregnancy. [LEVEL 2]
Approximately 4% of pregnancies are complicated by
bronchial asthma. The true prevalence may be even
higher; at least 10% of the population appears to have
nonspecific airway hyperreactivity, a hallmark of asth
ma.1 The course of asthma during pregnancy is variable;
it may remain unchanged, become worse or improve
during pregnancy. In a prospective study by SteinusAarniala et al, 42% of pregnant asthmatics required
more medications, 40% were managed with the same
medications before pregnancy and 18% actually needed
less medications.2 [level 1]
As a rule, women with more severe asthma prior to preg
nancy are likely to deteriorate during pregnancy. The
factors most likely contributing to worsening asthma
during pregnancy include upper respiratory tract infections and patient non-compliance with medical regimen.3 [level 2] The peak of exacerbations appears
between the 24th-36th weeks age of gestation (AOG).
Asthma generally remains quiescent during labor and
delivery in about 90% of pregnant women. Whatever
the course of asthma may be during pregnancy, changes
generally revert to pre-pregnancy level of severity
within 3 months post-partum.4
182
CPM 9TH EDITION
References:
1. National Heart, Lung and Blood Institute. Management of
asthma during pregnancy. NIH Publication No. 93-3279,
September 1993.
2. Steinus-Aarniala B, et al. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988; 43:12-8.
3. Gluck JC, Gluck P. The effects of pregnancy on asthma:
a prospective study. Ann Allergy 1976;37 (3):164-8.
4. Schatz M, et al. The course of asthma during pregnancy,
post-partum and with successive pregnancies: a prospective study. J. Allergy Clin Immunol 1988; 81(3):509-17.
Question No. 2:
How does maternal asthma affect pregnancy out
come?
Answer:
When asthma is properly controlled, pregnant women
with asthma can maintain a normal pregnancy with
little or no increased risk to themselves or their fetuses.
[GRADE B]
Uncontrolled asthma during pregnancy has been proven
to produce serious maternal and fetal complications.
Both mother and child are at risk if asthma is not well
managed during pregnancy. Severe persistent asthma
has been related to the development of maternal complications like pre-eclampsia, maternal hypertension,
hyperemesis gravidarum, uterine vaginal hemorrhage,
toxemia, placenta previa, and induced complicated
labors.1,2,3 Fetal complications include increased risk
of perinatal mortality, intrauterine growth retardation,
preterm birth, low birth weight, and neonatal hypoxia.2
[level 2]
Studies in which asthma was actively controlled did not
show any difference in the overall incidence of adverse
fetal outcomes among infants of asthmatic women and
non-asthmatic women.4,5 [level 2] A study involving severe asthma reported that pregnant women with
poorly controlled asthma requiring hospital admission
gave birth to infants who weighed significantly less than
babies whose mothers' asthma is well controlled.6 Severe
asthma requiring emergency therapy or corticosteroid
seem to be associated with an increased incidence of
perinatal complications like pre-eclampsia, low-birth
weight infants, perinatal mortality, preterm births and
hyperbilirubinemia. However, these associations did not
reach statistical significance.4,7
References:
1. Alexander S, Dodds L, Armson BA. Perinatal outcomes
in women with asthma during pregnancy. Obstet Gyne.
1998;92:435-40.
2. Demissie K, Breckenridge MB, Rhaods GG. Infant and
maternal outcomes in the pregnancies of asthmatic women.
Obstet Gyne Survey 1999;54:355-6.
3. Tan KS, Thomson NC. Asthma in pregnancy. Am J Med
2000;109(9):727-33.
4. Schatz M, Zeiger RS, Hoffman CP, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am. J. Respir. Crit. Care Med
CPM 9TH EDITION
1995;15:1170-4.
5. Perlow JH, Montgomery D. Severity of asthma and perinatal outcomes. Obstet Gyne 1992;167:193-7.
6. Greenberger PA, Petterson R. The outcome of pregnancy
complicated by severe asthma. Allergy Proc. 1988;9:53943.
7. Schatz M. The safety of asthma and allergy medications during pregnancy. Can J. Allergy Clin. Immunol.
1998;3:242-54.
Question No. 3:
Are asthma medications safe to use during preg
nancy?
Answer:
Most asthma medications are safe to use during pregnancy. [GRADE B]
The use of inhaled β2-agonist, theophylline, cromolyn,
antihistaminics and inhaled steroids are not associated
with major congenital malformations when used at
anytime during gestation, including the first trimester.1
[level 3] In a review of ten studies on asthmatic
women during the first trimester of pregnancy, only
three met the relevant quality criteria.1,2,3 There was no
significant increase in the rate of congenital malformations with any of the exposures.4 [level 2]
Because few safety studies on medication use during
pregnancy are available, the US Food and Drug Administration (FDA) has published pregnancy risk categories
for drugs. (See Table 6) All commonly used asthma
medications fall under safety categories B and C. This
system was developed from animal exposure data and
epidemiologic data from population studies.5
For mild intermittent asthma and acute exacerbations in
all asthmatic patients, inhaled short-acting β2-agonists
is the preferred treatment. These agents have not been
shown to have any adverse effects on pregnancy outcomes or teratogenic effects on the fetus.1 Use of oral
and parenteral β2-agonists should be avoided because
of lack of safety data, the increased risk of side effects
(e.g. tremor), and the potential to inhibit delivery.
Inhaled corticosteroids are the 'gold standard' for
controlling all forms of persistent asthma. [level
1] These agents have been shown to decrease asthma
exacerbations and mortality and improve overall quality
of life. The 2000 position paper of the American College
of Obstetricians and Gynecologist and the American
College of Allergy, Asthma and Immunology states,
"it would not be unreasonable to continue a different
inhaled corticosteroid in a patient well-controlled by
that drug prior to pregnancy."6
Long-acting β2-agonists, salmeterol and formoterol are
the preferred adjunctive therapy to inhaled corticoste
roids for managing moderate to severe persistent asthma.
[level 1] Although no adequate or well-controlled human data are available on salmeterol and formoterol use
during pregnancy, there are also no reports of congenital
ASthma
defects. Use of an inhaled long-acting β2-agonist with an
inhaled corticosteroid appears to be acceptable during
pregnancy, especially if the patient has taken such agents
without problems before the pregnancy.7
Long-term safety data are available for inhaled cromolyn and it is a feasible option for use during pregnancy
especially if there is a concern about prescribing inhaled
corticosteroids.8 The leukotriene receptor antagonists,
zafirlukast and montelukast sodium are classified as
FDA category B because no human or animal teratogenic effects have been seen with agents. Use of oral
corticosteroids during pregnancy poses some risk.9
Theophylline has not been shown to have teratogenic
effects during pregnancy although its use has radically
decreased because of possible toxicity with elevated
serum levels and because of the development of newer,
safer agents. When used during pregnancy, clearance of
the agent decreases, therefore dosing should be carefully
watched and adjusted. Theophylline crosses the placenta
and the newborn may have jitterness, increased heart
rate and even vomiting at birth.5
Nebulized ipratropium can be used for acute asthma not
responding well to inhaled β2-agonist. Ipratropium bromide is an inhaled anticholinergic agent that is used as an
adjunctive therapy to short-acting β2-agonists for acute
asthma exacerbations. Animal data have not demonstrated
any birth defects, but human data are lacking.10
Omalizumab, an IgG monoclonal antibody directed
against IgE, was recently approved in the United States
for use in moderate to severe allergic asthma that has
not responded to moderate to high doses of inhaled
corticosteroids. The FDA gave this agent a pregnancy
category B rating because no teratogenic effects were
seen in animal studies. In clinical studies with omalizu
mab before FDA approval, several women became
pregnant and delivered normal infants. Because of the
newness of this agent, caution should be exercised when
prescribing during pregnancy.11
References:
1. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma
and allergy medications during pregnancy. J Allergy Clin
Immunol 1997;100:301-6.
2. Schatz M, et al. The course of asthma during pregnancy,
postpartum and with successive pregnancies: a prospective
study. J Allergy Clin Immunol 1988; 81:509-17.
3. Rydhstroem KG. Congenital malformations after use
of inhaled budesonide in early pregnancy. Obstet Gyne
1999;93:392-5.
4. Jadad A, Sigouin C, et al. Risk of congenital malformations associated with treatment of asthma during early
pregnancy. Lancet 2000;355:119.
5. Blaiss, MS, Managing asthma during pregnancy: the
whys and hows of aggressive control. Postgrad Med
2004;115(5):55-64.
6. The use of newer asthma and allergy medications during
pregnancy. The American College of Obstetricians and
Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy
Asthma Immunol 2000;84(5):475-80.
7. Blaiss, MS, Management of rhinitis and asthma in preg-
183
ASthma
nancy. Ann Allergy Asthma Immunol 2003; 90 (6 Suppl
3):16-22.
8. Scatz M. The efficacy and safety of asthma medications
during pregnancy. Semin Perinatol 2001; 25(3):145-52.
9. Spector SL; Antileukotriene Working Group. Safety of
antileukotriene agents in asthma management. Ann Allergy
Asthma Immunol 2001;86(6 Suppl 1):18-23.
10. Liccardi G, Cazzola M, Canonica GW, et al. General strategy for the management of asthma in pregnancy. Respir.
Med 2003;97(7):778-89.
11. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE
recombinant humanized monoclonal antibody for the treatment of severe allergic asthma. J. Allergy Clin Immunol
2001;108(2):164-90.
Question No. 4:
Are steroids associated with increased risk of perinatal
complications?
Answer:
Inhaled corticosteroids have no effect on pregnancy out
come and do not increase the risk to the fetus. [grade
b] However, the use of oral steroids for severe asthma
during pregnancy may be associated with increased
perinatal complications.
Review of literature on human studies do not show
any evidence of teratogenicity with the use of inhaled
corticosteroids during pregnancy. The most published
information is on beclomethasone, and it does not appear to have any adverse effect on pregnancy outcome
and does not increase the risk to the fetus.1,2,3 Likewise,
a study with more than 2000 patients did not show an
increased rate of congenital malformations with the use
of inhaled budesonide.4 [level 2]
Among 293,948 births identified from 1995 to 1998
derived from the Swedish Medical Birth register, pregnancy outcomes were compared for mothers reporting
asthma medication usage with those for women who
reported no usage. Researchers found that 2,968 mothers
who reported use of inhaled budesonide during early
pregnancy gave birth to infants of normal gestational
age, birth weight, and length; there was no increase in
rate of stillbirths or multiple births.5 Because of this data,
budesonide has been assigned a safety category B rating
by the FDA. At present, all other inhaled corticosteroids
are category C.
On the other hand, oral steroids have been associated with
risk for pre-eclampsia in several studies.4,6,7 Whether or
not this link represents a drug effect or is a marker of
severity cannot be ascertained. [level 2] The use
of oral steroids during the first trimester has also been
associated with oral cleft palate deformities.8 [level
2] and prednisone treatment throughout the pregnancy
is associated with lower birth weights.9 The benefit of
using oral steroids, when indicated however, far outweighs the risk of uncontrolled asthma to the mother
and fetus.10
184
CPM 9TH EDITION
References:
1. Schatz M. The safety of asthma and allergy medications during pregnancy. Can J. Allergy Clin Immunol.
1998;3:242-54.
2. Fitzsimmons R, Greenberger PA, Patterson R. Outcome of
pregnancy in women requiring corticosteroids for severe
asthma. J. Allergy Clin Immunol 1986;78:349-53.
3. Greenberger PA, Patterson R. Beclomethasone dipro
pionate for severe asthma during pregnancy. Ann Intern
Med 1983;98:578-90.
4. Schatz M, Petitti D, Chilinger L, et al. The safety of asthma
and allergy medications during pregnancy. J. Allergy Clin
Immunol 1997;100:301-6.
5. Norjavaara E, de Verdier MG, Normal pregnancy outcomes
in a population-based study including 2,968 pregnant
women exposed to budesonide. J. Allergy Clin Immunol
2003;111(4):736-42.
6. Hornby PJ, Abrahams TP. Pulmonary physiology. Clin Ob
Gyne 1996;39:17-35.
7. Steinus-Aarniala B, et al. The effects of pregnancy on asthma:
a prospective study. Ann Allergy 1976;37: 164-8.
8. Alexander S, Dodds L, Armson BA. Perinatal outcomes
in women with asthma during pregnancy. Obst Gyne
1998;92:435-40.
9. Rodriguez-Pinilla E, Martinez-Friaz ML. Corticosteroids
during pregnancy and oral clefts: a case control study.
Teratology 1998;58:2-5.
10. Reinisch JM, Simon NG, et al. Perinatal exposure to prednisone in humans and animal retards intrauterine growth.
Science 1978;202:436-8.
Asthma and Surgery
Question No. 1:
Are patients with asthma undergoing surgery at
greater risk for peri-operative complications?
Answer:
No, the risk of peri-operative complications in patients
with asthma undergoing surgery is low. [grade b]
Generally, the risk of peri-operative complications in
patients with asthma undergoing surgery is low.1,2,3
[level 2] Warner et al reviewed the records of 706
diagnosed asthmatics who had at least one surgical
procedure involving a general anesthetic or central
neuroaxis block.1 The frequency of perioperative bronchospasm and laryngospasm was low in his cohort of
patients with asthma. The frequency of complications
was increased in older patients and in those with active
asthma. The frequency of complications did not depend
on the severity of asthma symptoms or the chronic use
of bronchodilators before operation.
A computer-aided study of 136,929 patients by Olsson in
1987 found the incidence of intraoperative bronchospasm
to be 0.80% in 3,210 patients with asthma versus 0.16%
in those patients without asthma.5 Bronchospasm during
anesthesia occured in only one out of 634 anesthetics or
1.7 per 1000 patients. This author concluded that there
was the likelihood of increased incidence of intraoperative complications (bronchospasm) in the presence of
pre-existing airway obstruction, particularly in the face
of airway instrumentation. [level 4]
CPM 9TH EDITION
References:
1. Warner DO, Warner MA, Barnes RD, et al. Perioperative
respiratory complications in patients with asthma. Anesthesiology 1996;85:460-7.
2. Shnider SM, Papper EM. Anesthesia for the asthmatic
patient. Anesthesiology 1961;22:886-92.
3. Gold MI, Helrich M. A study of the complications related to anesthesia in asthmatic patients. Anesth Analg
1963;42:283-93.
4. Pien LC, Grammer LC, Patterson R. Minimal complications in a surgical population with severe asthma receiving prophylactic corticosteroids. J Allergy Clin Immunol
1988;82:696-700.
5. Olsson GL. Bronchospasm during anesthesia. A computeraided study of 136,929 patients. Acta Anaesthesiol Scand
1987;31:244-52.
Question No. 2:
Are steroid-controlled asthmatics at risk for developing
peri-operative complications?
Answer:
No, there is no increased risk for peri-operative complications in steroid-controlled asthma. [grade b]
The use of pre-operative steroids to control asthma does
not put the asthmatic at greater risk for peri-operative
complications.1-5 [level 2] Prior to surgery, patients
should be free of wheezing, with a peak flow greater
than 80 percent of the predicted personal best value.2
To achieve this goal, the patient may need oral corticosteroids (60 mg of prednisone daily or the equivalent).
Kabalin et al4 studied the effect of pre-operative steroids
on the incidence of postoperative bronchospasm, infection, clinical evidence of adrenocortical insufficiency
and death among 71 asthmatics who underwent 89
surgical procedures. Of the complications monitored,
intra-operative wheezing developed in only one patient;
three patients (4.5%) developed mild post-operative
bronchospasm. The incidence of infection was not statistically different between two surgical groups that were
compared and there was no evidence of adrenocortical
insufficiency. One death was related to a neurosurgical
intra-operative complication. Therefore, a short-course
of peri-operative corticosteroids does not appear to increase the incidence of infection or other post-operative
complications in patients with asthma.3,4,5 [level 3]
References:
1. Smetana, GW. Current concepts: preoperative pulmonary evaluation (Review Article). N. Engl. J. Med.
1999;340:937-44.
2. Guidelines for the Diagnosis and Management of
Asthma. National Heart, Lung, and Blood Institute.
National Asthma Education Program, Expert Panel Report. X. Special considerations. J. Allergy Clin Immunol
1991;88(Suppl):523-34.
3. Pien LC, Grammer LC, Patterson R. Minimal complications in a surgical population with severe asthma receiving prophylactic corticosteroids. J. Allergy Clin Immunol
1988;82:595-700.
4. Kabalin CS, Yarnold PR, Grammer LC. Low complication
rate of corticosteroids-treated asthmatics undergoing surgi-
ASthma
Table 6. US FDA Pregnancy Risk Categories for
Asthma Medications
Agent
Bronchodilators
Albuterol
Salmeterol
Formoterol
Ipratropium bromide
Respiratory inhalants
Cromolyn sodium
Nedocromil sodium
Leukotriene agents
Zafirlukast
Montelukast
Inhaled corticosteroids
Budesonide
Beclomethasone dipropionate
Fluticasone propionate
Triamcinolone acetate
Flunisolide
Fluticasone/salmeterol
Oral corticosteroids
Theophylline
Risk Category
Omalizumab
C
C
C
B
B
B
B
B
B
C
C
C
C
C
C
C
B
Risk Categories:
A - Adequate studies in pregnant women have not demonstrated a
risk to the fetus in the first trimester of pregnancy and there is
no evidence of risk in later trimesters.
B - Animal studies have not demonstrated a risk to the fetus, but
there are no adequate studies in pregnant women or Animal
studies have shown an adverse effect, but adequate studies in
pregnant women have not demonstrated a risk to the fetus in
the first trimester of pregnancy, and there is no evidence of risk
in later trimesters.
C - Animal studies have shown adverse effects on the fetus, but
there are no adequate studies in humans; the benefits from the
use of the drug in pregnant women may be acceptable despite
its potential risks; or there are no animal reproduction studies
and no adequate studies in humans.
D - There is no evidence of human fetal risk, but the potential
benefits from the use of the drug in pregnant women may be
acceptable despite its potential risks.
X - Studies in animals or humans demonstrate fetal abnormalities,
or adverse reaction reports indicate evidence of fetal risk. The
risk of use in pregnant women clearly outweighs any possible
benefits.
cal procedures. Arch Intern Med 1995; 155:1379-84.
5. Warner DO, Warner MA, Barnes RD, et al. Perioperative
respiratory complications in patients with asthma. Anesthesiology 1996;85:460-7.
Asthma and Upper Airway Disease
Question No. 1:
Is there a relationship between asthma and rhinitis
established?
Answer:
No, there is no established relationship between asthma
and rhinitis, however, they commonly occur as co-morbidities. [grade b]
The concept of "one airway, one disease"1 was proposed
in the late 1990s because of several common factors
noted between asthma and rhinitis: common epidemiologic, pathologic, and physiologic characteristics and a
common therapeutic approach.2-5
185
ASthma
A study which utilized a standard questionnaire in 478
patients demonstrated that rhinitis is nearly a universal
phenomenon in patients with allergic asthma, occurring
in 99% of adults and 93% of adolescents.6 [level 4]
Conversely, asthma has also been shown to affect up
to 38% of patients with allergic rhinitis which is substantially higher than the 3-5% prevalence noted in the
general population.7 Even nonallergic rhinitis was also
found to be associated with asthma.8,9,10 [level 3]
Allergic rhinitis often precedes or occurs at the same
time as asthma. However, although atopic subjects commonly have coexisting asthma and rhinitis, rhinitis alone
does appear to be a risk factor for asthma.11 Settipane
et al noted that in a 23-year follow up study of 690
college freshmen without asthma, those who reported
nasal symptoms in 1961 developed asthma three times
more often (10.5%) than individuals without rhinitis
(3.6%).12-13 [level 3]
Although it appears that patients with rhinitis are more
likely to develop asthma, it has not been possible to predict which patients are at greatest risk. Patients with allergic rhinitis and no clinical evidence of asthma have been
shown to frequently exhibit bronchial hyperresponsive
ness to methacholine. This has given rise to the postulate
that BHR may represent an intermediate phase between
nasal allergy and symptomatic asthma. However, largescale prospective studies are needed to confirm these
findings. It has also not been proven that the presence
of rhinitis is related with asthma severity although a few
studies suggest that such an occurrence is also related to
higher use of anti-asthma medications.14-15
In patients with both asthma and allergy, it has been
suggested that treating rhinitis adequately will improve
asthma symptoms and lung function. Two small trials
show that prevention of seasonal nasal inflammation
with topical steroids reduced subsequent exacerbations
of allergic asthma.16-17 However, there were no published
well-controlled, large-scale clinical trials thus far to
quantify the effect of treatment of nasal disease on
asthma symptoms and lung function. [level 3]
References:
1. Grossman J. One airway, one disease. Chest 1997; 111
(suppl 2):11S-6S.
2. Rowe-Jones JM. The link between the nose and lung, perennial rhinitis and asthma: is it the same disease? Allergy
1997;52:20-8.
3. Vignola Am, Chanez P, Godard P, Bousquet J. Relationships between rhinitis and asthma. Allergy 1998; 53:8339.
4. Corren J. The impact of allergic rhinitis on bronchial asthma.
J. Allergy Clin. Immunol 1998;101:S352-S356.
5. Townley RG, Kiboneka A. Allergic rhinitis: relationship to
asthma. Similarities, differences, and interactions [editorial].
Ann Allergy Asthma Immunol 1998; 80:137-9.
6. Kapsali T, Horowitz E, Diemer F, Togias A. Rhinitis is
ubiquitous in allergic asthmatics [abstract]. J. Allergy Clin.
Immunol 1997;99:S138.
7. Evans R III, Mullally DI, Wilson RW, et al. National
trends in the morbidity and mortality of asthma in the US:
prevalence, hospitalization and death from asthma over
two decades: 1965-1984. Chest 1987;91: S65-S74.
186
CPM 9TH EDITION
8. Leynaert B, Nuekirch F, Pascal D, Bousquet J. Epidemiologic evidence for asthma and rhinitis co-morbidity.
J. Allergy Clin. Immunol 2000;106:S201-S205.
9. Sibbald B, Rink E. Epidemiology of seasonal and perennial
rhinitis: clinical presentation and medical history. Thorax
1991;46:895-901.
10. Leynaert B, Bousquet J, Neukirch C et al. Perennial rhinitis: an independent risk factor for asthma in nonatopic subjects. Results from the European Community Respiratory
Health Survey. J. Allergy Clin. Immunol 1999;104:3014.
11. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology
of physician-diagnosed allergic rhinitis in childhood.
Pediatrics, 1994.
12. Settipane RJ, et al. Long-term risk factors for developing
asthma and allergic rhinitis: a 23-year follow-up study of
college students. Allergy Proc 1994:21-5.
13. Greisner WA, Settpane, et al. Co-existence of asthma and
allergic rhinitis: a 23-year follow-up of college students.
Allergy Asthma Proc 1998;19:185-8.
14. Huse DM, Harte SC, Russel MW, et al. Allergic rhinitis
may worsen asthma symptoms in children. The inter
national asthma outcomes registry. [abstract]. Am J. Respir.
Crit Care Med 1996;153:A860.
15. Halpern M, Richner R, Togias A, et al. Allergic rhinitis
may increase asthma costs [abstract] Am J. Respir. Crit
Care Med 1996;153:A860.
16. Welsh PW, Stricker EW, Chu-Pin C, et al. Efficacy of
beclomethasone nasal solution, flunisolide, and cromolyn
in relieving symptoms of ragweed allergy. Mayo Clin Proc
1987;62:125-34.
17. Corren J, Adinoff AD, Buchneier AD, Irvin CG. Nasal
beclomethasone prevents the seasonal increase in bronchial
hyperresponsiveness in patients with allergic rhinitis and
asthma. J Allergy Clin Immunol 1992; 90:250-6.
Question No. 2:
Is there a relationship between asthma and sinus
itis?
Answer:
Yes, it appears that asthma and sinusitis frequently
co-exist, and sinusitis can trigger asthma. However, as
shown in some studies, their causal relationship remains
controversial. [grade b]
Whether the relation between asthma and sinusitis is
causal or merely an epiphenomenon of an infectious or
immune-mediated disease affecting the entire respiratory tract is still a matter of debate. However, there
are certain characteristics that identify those patients
in whom sinusitis may play an important role in the
pathogenesis of asthma.1 These are as follows:
• Sinusitis preceding the development of asthma
symptoms
• Sinusitis in non-atopic patients (which implies that a
fundamental change has occurred in the sinus tissues
and airway)
• Aspirin sensitivity
• Corticosteroid dependency (suggests that an underlying sinus disease may be a trigger for asthma)
• Patients with asthma who are refractory to appropriate treatment
• When a child with asthma becomes symptomatic while
taking medications that were formerly effective
• When a patient receives a short-term course of
CPM 9TH EDITION
steroid therapy for an acute episode of asthma and is
still symptomatic after several days of treatment
Approximately 40-60% of asthmatic patients will show
radiographic evidence of sinusitis. Some patients with
recurrent sinusitis will develop chronic tissue inflammation
with mucosal thickening and formation of nasal polyps,
also called chronic hyperplastic sinusitis and nasal polyp
formation (CHS/NP). Pathologic examination of this tissue typically shows a striking inflammatory infiltrate of
eosinophils, somewhat similar to the inflammatory infiltrate
seen in asthma.2,3,4 In patients with coexisting asthma, the
development of CHS/NP often heralds a worsening in
asthma symptoms.
It was also postulated that a sino-nasal bronchial reflex exists
which could be mediated by the autonomic nervous system
or inflammatory mediators such as leukotrienes, prostaglandin
D2 and histamine.5 Other possible explanations include
micro- or macro-aspiration of sinus drainage, or a systemic
effect of cytokines. These hypotheses have all raised the issue
of whether sinusitis can contribute to the development of
asthma and whether sinusitis and asthma share a common
pathogenetic mechanism.
Although etiology may be murky, there are several empirical studies, which suggest that treatment of sinusitis or
rhinitis may improve asthma symptoms. For example, in a
study of 48 children with sinusitis and asthma, a reported
improvement in asthma symptoms was generally noted
after medical treatment for sinusitis.3 [level 4] In another
series of studies, Slavin and colleagues reported on the effect
of sphenoethmoidectomy in a series of adult patients with
difficult to control asthma and medically resistant sinusitis.1
A total of 65% of patients reported significant improvement
in their asthma symptoms after the procedure.
References:
1.
2.
3.
4.
5.
Slavin RG. Asthma and sinusitis. J Allergy Clin Immunol 1992;90:5347.
Harlin SL, Ansel DG, Lane SR, Myers J, Kephart GM, Gleich GJ. A
clinical and pathologic study of chronic sinusitis: the role of eosinophil.
J Allergy Clin Immunol 1988;81:867-75.
Demoly P, Crampette L, Mondain M, et al. Assessment of inflammation
in noninfectious chronic maxillary sinusitis. J. Allergy Clin Immunol
1994;94:95-108.
Guidelines for the Diagnosis and Management of Asthma. National
Asthma Education and Prevention Program. Expert Panel Report 2:
Bethesda, MD: National Institutes of Health; National Heart, Lung,
and Blood Institute 1997, NIH Publication 97 4051A.
Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus diseasee with
associated reactive airway disease with associated reactive airway
disease in children. Pediatrics. 1984;73:526-9.
Vaccines and Asthma
Question No. 1:
Does influenza vaccination have a role in asthma man
agement?
Answer:
Yes. Influenza vaccination has been found to decrease the
incidence of asthma exacerbations.1-3 [grade A]
Immunization with influenza vaccine is safe and not associated with any significant side effects in adult patients with
persistent asthma. Although pulmonary function abnormalities may occur as a complication of vaccination, the risk of
pulmonary complications is very small and outweighed by
the benefits of vaccination.1 [level 1] There are no data
from the published literature on whether pneumococcal
vaccines lead to asthma exacerbation.
International guidelines recommend the immunization
of patients with chronic pulmonary disease, including
ASthma
asthma, against influenza and pneumococcus. Despite these
recommendations, many asthmatic patients do not receive
vaccination because of some reports that vaccination,
particularly influenza, may lead to asthma exacerbation.
A double-blind placebo-controlled multicentre crossover
study was undertaken to assess the safety of influenza
vaccine in patients with asthma.2 Among 225 participants
with paired data, PEF fell to greater than 20% of baseline
in 11 patients given the vaccine compared to three patients
on placebo, and PEF fell more than 30% in eight patients
given the vaccine compared with none after placebo. However, when participants with colds were excluded from the
analysis, no significant difference was noted in the number
of patients whose PEF fell more than 20% between vaccine
and placebo. It was also noted that there was a significant
difference in patients whose PEF decreased more than
30% from baseline between the vaccine and the placebo
group. These findings indicate that pulmonary function
abnormalities may occur as a complication of influenza
vaccination, however, the risk of pulmonary complications
is very small. [level 2]
In a double-blind study by Steinus-Aarniala et al in 1988,
318 adult patients with chronic asthma were randomly
allocated to receive either active vaccine or placebo.3 Follow-up for eight months after the vaccination revealed no
difference in asthmatic symptoms between the patients
treated with active vaccine and those receiving placebo.
[level 2]
References:
1. Centers for Disease Control and Prevention. Prevention and control of
influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Mortal Morb Wkly Rep 1993; 42
(No. RR-6):1-14.
2. Nicholson KG, et al. Randomized placebo-controlled crossover trial
on effect of inactivated influenza vaccine on pulmonary function in
asthma. Lancet 1998; 351:326-31.
3. Steinus-Aarniala, et al. Lack of clinical exacerbation in adults with
chronic asthma after immunization with killed influenza virus. Chest
1986;89:786-9.
Appendix A
Abbreviations
AHR/BHR
Airway/Bronchial Hyperresponsiveness
Anti-LTs
Anti-leukotrienes
AOGAge of Gestation
BAL
Bronchoalveolar Lavage
BDP
Beclomethasone Dipropionate
BMD
Bone Mineral Density
BUD
Budesonide
CS
Corticosteroid
CHS/NP
Chronic Hyperplastic Sinusitis and Nasal Polyp
DPI
Dry Powder Inhaler
EBV
Epstein-Barr Virus
ECHRS
European Community Health Survey
ED
Emergency Department
EIA
Exercise Induced Asthma
EIB
Exercise Induced Bronchoconstriction
ETS
Environmental Tobacco Smoke
FACET
Formoterol and Corticosteroids Establishing Therapy
FEV1
Forced Expiratory Volume in 1second
FP
Fluticasone Propionate
FVC
Forced Vital Capacity
GERD
Gastro Esophageal Reflux Disease
GINA
Global Initiative for Asthma
GRASSIC
Grampian Asthma Study of Integrated Care Trial
HEPA
High Efficiency Particulate Air Cleaner
HFA
Hydrofluoralkane
HPA
Hypothalamus-Pituitary-Adrenal
ISAAC
International Study of Asthma and Allergy in Childhood
187
ASthma
ICS
IgE
IL-4
IL-5
IL-8
IL-12
IL-13
IFN-γ
LABA
LT
LTRA
MDI
MSG
NO2
NEB
O3
PCRADM
PC20
CPM 9TH EDITION
Methacholine resulting in a 20% in FEV1 from the baseline
PEF
Peak Expiratory Flow
PFT
Pulmonary Function Test
PM
Particulate Matter
PMA
Pre-Menstrual Asthma
PPD
Purified Protein Derivative
RCT
Randomized Control Trial
RSV
Respiratory Syncitial Virus
SABA
Short Acting β2-Agonist
SO2
Sulfur Dioxide
SR
Slow-release
TB
Tuberculosis
TH1
T-helper subtype 1 lymphocyte
TH2
T-helper subtype 2 lymphocyte
WHO
World Health Organization
Inhaled Corticosteroid
Immunoglobulin-E
Interleukin 4
Interleukin 5
Interleukin 8
Interleukin 12
Interleukin 13
Interferon gamma
Long Acting β2-Antagonist
Leukotriene
Leukotriene Receptor Antagonist
Metered-dose Inhaler
Monosodium Glutamate
Nitrogen Dioxide
Nebulization
Ozone
Philippine Consensus on Asthma
Diagnosis and Management
Provocative Concentration of
fall
Appendix B
Summary of Criteria for Rating Evidence
Table I. Levels of Evidence for Rating Studies on the Accuracy of Diagnostic Tests
Level 1
All 5 of the following criteria are satisfied:
a.
b.
c.
d.
e.
There was an independent interpretation of the results of the diagnostic test (without knowledge
of the results of the gold standard).
There was an independent interpretation of the results of the gold standard (without knowledge
of the results of the diagnostic test).
The study of patients consisted patients (but not known) to have the disorder of interest.
The diagnostic test and gold standard are both described in sufficient detail to allow reproducibility.
The study population consists of at least 50 patients with and 50 patients without the disorder
of interest.
Level 2
4 of the 5 criteria are met.
Level 5
Level 3
Level 6
None of the 5 criteria are met.
Level 4
Table II. Levels of Evidence for Rating Studies on the Effectiveness of Treatment
Level 1
A randomized controlled trial (RCT) that demonstrates a statistically significant difference in at least one major outcome - e.g., survival or major illness OR if the difference is not statistically significant, a RCT of adequate size to exclude 25% difference in relative risk with 80% power given the observed results.
Level 2
A RCT that does not meet the level 1 criteria.
Level 3
A non-randomized trial with concurrent controls selected by some systematic method (i.e., not selected on the basis of perceived suitability for one of the treatment options).
Level 4
Before-after study or case series (at least 10 patients) with historical controls or controls drawn from other studies.
Level 5
Case series (at least 10 patients) without controls
Level 6
Case series (fewer than 10 patients) or case reports
Table III. Levels of Evidence for Rating Review Articles
Level 1
All of the following criteria are met:
a. Comprehensive search for evidence
b. Avoidance of bias in the selection of articles
c. Assessment of the validity of each cited article; Conclusion supported by the data and analysis presented
Level 2
Level 4
Level 3
Level 5
None of the 4 criteria are met.
Table IV. Grading System for Recommendation
Grade A
The recommendation is based on one or more studies at Level 1.
Grade B
The best evidence available is at Level 2.
Grade C
The best evidence is at Level 3
Grade D
The best evidence available is lower than 3, and include experts' opinions, clinical experience, and common sense. These recommendations address practical issues of implementation and other factors existing in the local setting.
188
CPM 9TH EDITION
ASthma
Recommended Therapeutics
(Drugs Mentioned in the Treatment Guideline)
The following index lists therapeutic classifications as recommended by the treatment guideline. For the prescriber's
reference, available drugs are listed under each therapeutic class.
Anticholinergics
Fenoterol Br
Berotec
Ipratropium Br
Atrovent
Ipratropium Br/Fenoterol
Berodual
Ipratropium Br/Salbutamol
Combivent
Duavent
Tiotropium
Spiriva
Inhaled Steroids
Beclomethasone Dipropionate
Qvar
Budesonide
Asmavent
Budecort
Pharmachemie Budesonide
Cyclocaps
Budesonide/Formoterol
Symbicort Turbuhaler
Fluticasone
Flixotide
Flixotide Nebule
Ketotifens
Quomyl
Zadec/Zadec SRO
Zaditen
Leukotriene Antagonists
Montelukast
Singulair
Zafirlukast
Accolate
Sympathomimetics
Bambuterol
Bambec
Clenbuterol
Spiropent
Formoterol
Atock
Foradil
Oxis Turbuhaler
Orciprenaline/Bromhexine
Bisolpent
Procaterol
Meptin
Salbutamol
Activent
Airhexal
Airomir
Am-Europharma Salbutamol
Asbunyl
Asfrenon
Asmacaire CFC-Free
Asmalin Syrup
Asmalin Metered Dose Inhaler
Asmalin Pulmoneb
Asvent
Cletal
Drugmaker’s Biotech Salbutamol
Emplusal
Hivent
Librentin/Librentin Bronchoneb/Librentin inhaler (CFC free)
Pharmachemie Salbutamol Cyclocaps
Provexel NS
Prox-S
Resdil
Respolin
RiteMED Salbutamol
Salbumed
Ventar
Ventolin
Ventolin Volmax
Salbutamol/Guaifenesin
Asbunyl Plus
Asfrenon GF Expectorant
Broncaire Expectorant Syrup
Drugmaker's Biotech Guaifenesin/Salbutamol Expectorant
Venzadril
Salmeterol xinafoate
Serevent
Salmeterol xinafoate/
Fluticasone
Seretide
Terbutaline
Alloxygen
Bricanyl
Bronchodam
Myrex Terbutaline Sulfate Syrup
Pulmonyl
Pulmoxcel
RiteMED Terbutaline
Terbulin
Terbusol
Terbutaline/Guaifenesin
Bricanyl Expectorant
Drugmaker's Biotech Guaifenesin/Terbutaline
Xanthines
Doxofylline
Ansimar
Theophylline
Asmasolon
Brondil (Reformulated)
Nuelin
Phenedrine
Uni-Dur
Theophylline/Guaifenesin
Hallex
Betneton
Betamethasone/
Dexchlorphenamine maleate
Celestamine
Prednisolone/
Chlorphenamine maleate
Histacort Tablet
Adrenocorticosteroid hormones
Betamethasone
Betnelan
Celestone
Diprospan
Drugmaker's Biotech Betamethasone
Dexamethasone
Cordex 5
Decilone
Drenex
Oradexon
Dexamethasone Na Phosphate
Scancortin 5
Hydrocortisone Na Succinate
Pharmacort
Phoenix Hydrocortisone sodium succinate
Solu-Cortef
Methylprednisolone
Medrol
Methylprednisolone acetate
Depo-Medrol
Methylprednisolone sodium
succinate
Adrena
Solu-Medrol
Prednisolone
Drugmaker's Biotech Prednisolone
Liquipred
Optipred
Ritemed Prednisolone
Prednisone
Drugmaker's Biotech Prednisone
GXI Prednisone
Orasone5/Orasone 20
Pred 1/Pred 5/Pred 10/Pred 20/
Pred30/Pred 50
Prednisone Organon
Prolix
Triamcinolone
Kenacort
Triamcinolone acetonide
Kenacort-A intra-articular/ intradermal
Other Drugs for Asthma/
COPD
Lagundi
Ascof
Corticosteroids
Betamethasone/
Chlorphenamine maleate
189

Philippine College of Chest Physicians

Transcription

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