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AIR Research
Respir Med 2003 Mar;97 Suppl C:S23-31
The burden of COPD in Canada: results from the Confronting COPD survey.
Chapman KR, Bourbeau J, Rance L.
University of Toronto, Ontario, Canada. kchapman@ca.inter.net
Chronic obstructive pulmonary disease
(COPD) is a condition characterized by
progressive airflow limitation, with symptoms of dyspnoea, cough, and sputum
production. Aside from information on prevalence, mortality and hospital
resource utilization arising from COPD in Canada, there is a lack of data
on the
impact of the disease on primary care healthcare resource utilization and
the
economic burden of the disease (i.e. direct and indirect costs). Canada is
not
unusual in this respect, as surprisingly few studies have attempted to quantify
the impact of COPD on the healthcare system and society in other countries.
In
an attempt to address the need for information on the burden of COPD, an
economic analysis of data from a large-scale international survey, Confronting
COPD in North America and Europe, was conducted in Canada and six other
countries. The results of the Canadian survey estimated the direct cost of
the
disease at CA dollar 1997.81 per patient, with over half of this due to
inpatient hospitalizations. COPD also had an impact on the economy, with
indirect costs amounting to CA dollar 1198.18, a third of the total per patient
cost of COPD to society (CA dollar 3195.97). Reducing the impact of this disease
will necessitate improvements to the way the disease is managed in primary
care,
as poor symptom control and frequent exacerbations are key drivers of hospital
and other unscheduled care costs. Early diagnosis and the application of
available but underused interventions (e.g. smoking cessation, inhaled drug
therapies and pulmonary rehabilitation) could reduce the morbidity and costs
of
COPD in this country.
J Allergy Clin Immunol 2003 Feb;111(2):313-20
Effect of nasal triamcinolone acetonide
on lower airway inflammatory markers in
patients with allergic rhinitis.
Sandrini A, Ferreira IM, Jardim JR, Zamel N, Chapman KR.
Asthma and Airway Centre of the
Toronto Western Hospital, University Health
Network, Division of Respiratory Medicine, University of Toronto, 399 Bathurst
Street, Toronto, Ontario M5T 2S8, Canada.
BACKGROUND: Allergic rhinitis (AR)
and asthma are commonly associated, and
similar underlying inflammatory processes link both diseases. AR, even in
the
absence of asthma, is associated with increased levels of exhaled nitric oxide
(ENO) and hydrogen peroxide (H(2)O(2)) in exhaled breath condensate, 2
noninvasive markers of lower airway inflammation. OBJECTIVE: We sought to
evaluate the effect of treatment with the nasal steroid triamcinolone acetonide
on ENO and exhaled H(2)O(2) in subjects with AR. METHODS: We allocated 23
subjects in a randomized, double-blind, parallel-controlled fashion to 4-week
treatment with triamcinolone acetonide (220 microg/d) or matching placebo.
RESULTS: ENO levels were greater in the subgroup with concomitant asthma (16/23
subjects) and decreased significantly with triamcinolone acetonide treatment
in
this subgroup of patients in comparison with patients receiving placebo. Breath
condensate levels of H(2)O(2) were higher in patients with AR without asthma
than in those with asthma but decreased significantly with triamcinolone
acetonide treatment in both subgroups. No changes were observed in bronchial
hyperresponsiveness, nasal and asthma symptoms, or peak expiratory flow with
active treatment or placebo. CONCLUSION: We conclude that treatment of AR
with
triamcinolone acetonide results in decrease of 2 noninvasive markers of lower
airway inflammation, ENO and H(2)O(2), supporting that upper and lower airway
inflammation should be seen as a continuum in subjects with AR with and without
asthma. ENO might be a more specific marker of the lower airway inflammation
present in asthma.
Arch Intern Med 2002 Dec 9-23;162(22):2527-36
Corticosteroid therapy for patients
with acute exacerbations of chronic
obstructive pulmonary disease: a systematic review.
Singh JM, Palda VA, Stanbrook MB, Chapman KR.
Division of Internal Medicine,
Room 4-154, St Michael's Hospital, 30 Bond St,
Toronto, Ontario, Canada M5B 1W8.
OBJECTIVE: To determine whether
systemic corticosteroids are of benefit to
patients with acute exacerbations of chronic obstructive pulmonary disease
(COPD). METHODS: An English-language search of MEDLINE (1966 to February 2002)
and the Cochrane Library and a bibliographic review was performed to identify
published clinical trials of systemic corticosteroid administration in acute
exacerbations of COPD. All relevant English-language, randomized,
placebo-controlled clinical trials were considered. Trials investigating the
adverse effects of systemic steroids were also retrieved. Studies were assigned
a quality rating according to explicit criteria. Clinically relevant end points,
such as treatment failure and duration of hospital stay, were considered
preferentially. To compare outcomes across all qualifying studies, we considered
the difference in spirometric measures between treatment and placebo groups.
Potential confounding factors and bias relating to patient selection, treatment
protocols, and outcome measurement were considered independently for each
study.
RESULTS: Among the 8 studies that met all criteria, 5 found that significant
improvement in forced expiratory volume in 1 second (>20%) was associated
with
steroid administration. Two studies found improvement in clinically relevant
outcomes. One published study and 2 study abstracts did not find significant
improvement in spirometric measures with corticosteroid administration.
CONCLUSION: Short courses of systemic corticosteroids in acute exacerbations
of
COPD have been shown to improve spirometric outcomes (good-quality evidence)
and
clinical outcomes (good-quality evidence).
Can Respir J 2002 May-Jun;9(3):178-85
The addition of salmeterol 50 microg
bid to anticholinergic treatment in
patients with COPD: a randomized, placebo controlled trial. Chronic obstructive
pulmonary disease.
Chapman KR, Arvidsson P, Chuchalin
AG, Dhillon DP, Faurschou P, Goldstein RS,
Kuipers AF; International study group.
Toronto Western Hospital, Ontario. kchapman@ca.inter.net
BACKGROUND: In the past, the role
of long-acting beta(2-) agonists in chronic
obstructive pulmonary disease (COPD) relative to other agents has been unclear.
OBJECTIVES: To compare the effect of adding salmeterol (50 microg bid) or
placebo to concurrent anticholinergic therapy on symptom scores, quality of
life, prebronchodilator lung function and exacerbations in patients with
moderately severe COPD. METHODS: This was a double-blind, randomized,
parallel-group study in patients aged 40 years or older receiving
anticholinergic medication. Patients were randomly assigned to treatment with
placebo (n=207) or salmeterol (n=201) via a Diskus/Accuhaler inhaler for 24
weeks. RESULTS: The morning trough (prestudy drug) forced expiratory volume
in 1
s (FEV(1)) increased significantly above baseline levels among the
salmeterol-treated patients. Improvement in FEV(1) was greater in the salmeterol
group than in the placebo group at four weeks (difference 0.06 L, P<0.005),
eight weeks (0.06 L, P<0.005) and 16 weeks (0.05 L, P<0.05) after the
start of
treatment. There was a nonsignificant trend in favour of salmeterol after
24
weeks of treatment (P=0.198). Improvements in morning peak flow were
significantly greater in the salmeterol group over 24 weeks (P<0.01). Although
symptom scores were numerically higher in the salmeterol group than in the
placebo group and there was less requirement for rescue bronchodilator use,
these differences were not statistically significant. In the salmeterol group,
fewer patients had exacerbations of COPD, and there was a trend toward an
improved quality of life. The safety profile of the two groups was similar.
CONCLUSIONS: Salmeterol has a beneficial effect when added to existing
anticholinergic therapy in patients with COPD. The regular use of salmeterol
for
six months was not associated with worsening of the underlying airflow
obstruction; rather, there was a tendency for the trough FEV1 to improve above
the baseline levels over the treatment period.
Expert Opin Pharmacother 2002 Mar;3(3):341-50
Seretide for obstructive lung disease.
Chapman KR.
Asthma Centre and Pulmonary Rehabilitation
Program, Toronto Western Hospital,
University Health Network, Suite 4-011 ECW, 399 Bathurst Street, Toronto,
Ontario, M5T 2S8, Canada. kchapman@ca.inter.netSeretide (Advair [North America],
GlaxoSmithKline) is an inhaler combination formulation intended for the maintenance
therapy of obstructive airways disease.
Seretide was developed and made available initially as three multi-dose, dry
powder inhaler formulations delivering 50 microg/puff of the long acting beta(2)
agonist salmeterol and either 100, 250 or 500 microg/puff of the inhaled
corticosteroid fluticasone propionate. In addition to the initial multi-dose
dry
powder inhaler system (Diskus or Accuhaler), a chlorofluorocarbon (CFC)-free
pressurised aerosol formulation has become available. Studied mostly extensively
as a maintenance therapy for patients with persistent asthma, the combination
inhaler is at least equivalent to its components administered separately and
is
superior to monotherapy with salmeterol or inhaled corticosteroid in both
paediatric and adult populations. The combination has a logical role in the
treatment of moderate-to-severe asthma, offering the advantage of increased
convenience and possibly improved compliance. In addition to improvements
in
lung function, symptom scores and quality of life, the combination therapy
reduces exacerbation rates, an outcome that contributes to favourable
cost-effectiveness. A role as initial maintenance therapy in all forms of
persistent asthma is also plausible but there are fewer data concerning the
impact of Seretide in milder forms of persistent asthma. Clinical trials are
underway to examine the potential role of Seretide in patients with chronic
obstructive pulmonary disease (COPD). Salmeterol has been shown to be an
effective first-line bronchodilator in COPD and fluticasone has been shown
to
reduce the frequency and or severity of exacerbations in COPD patients in
two
key trials. At a time when the prevalence of both asthma and COPD is increasing,
Seretide is a valuable step in the management of these common obstructive
lung
diseases.
Am J Respir Crit Care Med 2002 Jan 15;165(2):190-4
Assessment of a medication-based asthma index for population research.
Ungar WJ, Chapman KR, Santos MT.Division
of Population Health Sciences, Hospital for Sick Children Research
Institute, University of Toronto, Ontario, Canada. wendy.ungar@sickkids.ca
Asthma management guidelines recommend
the use of preventive medications in
sufficient amounts to control asthma symptoms. The validity of a medication
use
index as a proxy for asthma severity has not been established. We recruited
1,279 Ontario adults with asthma or parents of children with asthma from a
community-based surveillance program in 1995-96. Participants completed a
telephone questionnaire at baseline, 3 and 6 mo. The questionnaire gathered
information about asthma medication use, health care utilization, and symptoms.
Asthma was classified as mild in 28%, moderate in 49%, or severe in 23% of
patients based on the amount and types of medication used. There were
significant differences among groups in health resource use such that adults
with higher medication use visited primary care physicians and specialists
more
frequently, had pulmonary functions tests more frequently, and were admitted
to
hospital more frequently. The findings among children were similar. There
were
weak positive correlations between medication use and symptom frequency in
adults and children. We conclude that a medication use index may be useful
in
population-based research where clinical asthma severity data are lacking.
Such
an index is distinct from but is related to disease control.
Chest 2001 Dec;120(6):1829-34
Inhaled beclomethasone dipropionate
improves acoustic measures of voice in
patients with asthma.
Balter MS, Adams SG, Chapman KR.
Asthma Education Clinic, Mt. Sinai
Hospital, University of Toronto, Toronto,
Canada. mbalter@mtsinai.on.ca
BACKGROUND: Inhaled corticosteroids
have the potential to produce upper-airway
side effects such as hoarseness. As new compounds and delivery devices are
developed and compared, it is difficult to quantify their adverse upper-airway
effects. OBJECTIVE: We undertook the following study to test the ability of
an
acoustic analysis technique to quantify changes in vocal function in
steroid-naive patients with asthma who receive inhaled beclomethasone
dipropionate (BDP), 1,000 microg/d for 4 months. METHODS: Patients
self-administered one of four regimens of inhaled BDP. Group 1 patients received
one 250-microg puff qid via metered-dose inhaler (MDI); group 2 patients
received one 250-microg puff qid via MDI with a holding chamber; group 3
patients received two 250-microg puffs bid via MDI; and group 4 patients
received two 250-microg puffs bid via MDI with a holding chamber. A smaller
cohort of nonsmoking asthmatic patients was managed without steroid intervention
for 4 months. At baseline and again at 8 weeks and 16 weeks after the initiation
of BDP treatment, patients underwent spirometry and methacholine challenge.
At
baseline and again at 2, 4, 8, 12, and 16 weeks, patients underwent voice
recording for analysis of voice parameters. The recorded vowels were low-pass
filtered (10 KHz), digitized (22 KHz), and analyzed by software to obtain
two
acoustic measures: (1) jitter, the cycle-to-cycle variation in the time period
of the voice signal; and (2) shimmer, the cycle-to-cycle variation in voice
signal amplitude. RESULTS: We recruited 77 patients for randomization to inhaled
steroid therapy and 10 patients who continued to receive only occasional inhaled
bronchodilator therapy. In all active treatment groups, FEV(1), FVC, and
provocative concentration of methacholine causing a 20% fall in FEV(1) improved
significantly after BDP treatment. Mean jitter scores, a measurement of
variation in voice pitch, were not significantly influenced by BDP treatment.
However, mean shimmer scores, a reflection of perturbation in vocal amplitude,
fell significantly (p < 0.05) in the active treatment groups. These reductions
in shimmer scores were not significantly different in the active treatment
groups. Shimmer scores in the bronchodilator-treated group were unchanged
during
the 16 weeks of follow-up. CONCLUSIONS: Our data show that a simple and
noninvasive acoustic analysis of voice is sensitive to subclinical changes
associated with inhaled corticosteroid therapy. We have shown that 1,000
microg/d of inhaled BDP actually improves specific acoustic measures of voice
in
patients with inadequately controlled asthma. These improvements were
uninfluenced by dosing schedule and whether a spacing chamber was used.
Patient handling of a dry-powder inhaler in clinical practice.
Epstein S, Maidenberg A, Hallett D, Khan K, Chapman KR.
Asthma Centre, Toronto Western
Hospital, University Health Network, Toronto,
Ontario, Canada.
BACKGROUND: Multi-dose dry-powder
inhalers are perceived as being easier for
patients to use than conventional pressurized aerosol inhalers; however, no
study has determined whether patients handle such devices adequately and whether
there is a need for patient education in this area. METHOD: We used trained
observers to assess the handling of a specific multi-dose dry powder inhaler
(Turbuhaler; AstraZeneca Canada; Mississauga, ON) by patients currently using
the device for the management of their asthma. Fourteen discrete steps were
scored independently by two observers simultaneously. Patients were divided
into
two groups for analysis: those who had received formal instruction in the
use of
the inhaler at The Asthma Centre and those who had received no formal
instruction in the community. RESULTS: There was no significant difference
between the formally trained groups and control groups in the percentage of
handling steps performed correctly (79% vs 78%, respectively; p > 0.05).
Fewer
than 50% of patients in both groups demonstrated optimal breath-holding when
using the device. CONCLUSION: Patient handling of Turbuhaler was generally
good,
with no evidence that a structured education intervention offered an advantage
over the usual education incidental to the prescribing or dispensing process.
The most common handling flaw, suboptimal breath-holding, is not specific
to
this device and is of uncertain clinical significance.
Am J Respir Crit Care Med 2001 Sep 15;164(6):1012-5
Exhaled nitric oxide and hydrogen
peroxide in patients with chronic obstructive
pulmonary disease: effects of inhaled beclomethasone.
Ferreira IM, Hazari MS, Gutierrez C, Zamel N, Chapman KR.
Asthma Centre, University of Toronto,
Toronto Western Hospital, University
Health Network, Toronto, Ontario, Canada.
There is controversy about the
role of inhaled corticosteroids in chronic
obstructive pulmonary disease (COPD). Although they appear to have little
impact
on airways obstruction or its progression, their use may reduce the frequency
and/or severity of exacerbations in a subset of patients. We undertook the
following study to determine the impact of inhaled corticosteroid on two
noninvasive markers of airways inflammation. We assigned 20 stable nonsmoking
patients with COPD in random, double-blind crossover fashion to two 2-wk
treatment periods with inhaled beclomethasone 500 microg twice daily or matching
placebo, followed by a 2-wk washout period. We measured exhaled nitric oxide
(ENO), breath condensate H(2)O(2), and flow volume spirometry at weekly
intervals. Median baseline ENO was 26.2 (19.3 to 54.8) ppb and fell
significantly following 1 and 2 wk of beclomethasone (-10.6 ppb, p = 0.002,
and
-6.3 ppb, p = 0.013, respectively) but was unchanged by placebo inhalation.
Breath condensate H(2)O(2) levels did not change significantly with inhaled
beclomethasone or placebo. Although there were no significant changes in FEV(1)
with BDP therapy, there was a moderate inverse correlation between changes
in
ENO and changes in FEV(1) (r -0.50). We conclude that inhaled beclomethasone
reduces ENO levels in stable nonsmoking patients with COPD, a finding compatible
with an antiinflammatory mechanism of action.
Can Respir J 2001 Jul-Aug;8(4):261-5
The impact of a nationally coordinated
pharmacy-based asthma education
intervention.
Diamond SA, Chapman KR.
Pedipharm Consultants, Toronto, Ontario. shedia@istar.ca
OBJECTIVE: To assess the impact
of a nationally coordinated pharmacy-based
educational intervention on self-management behaviour and markers of asthma
control in self-referred patients with asthma. DESIGN: An asthma clinic day
was
set up by a national chain of community pharmacies whereby pharmacists used
a
structured questionnaire to assess asthma control and self-care among
self-referred patients with doctor-diagnosed asthma. In a one-on-one counselling
session, each patient's educational needs were identified and the appropriate
education offered. A telephone follow-up 30 days later assessed the impact
of
teaching. SETTING: Community pharmacies across Canada. OUTCOME MEASURES: The
follow-up questionnaire quantified the number of wheezing episodes or other
symptoms per week, the number of night-time awakenings per week, and the
frequency of use of reliever and preventive medications. RESULTS: Of 4080
patients assessed, 22.2% used an inadequate inhaler technique, 16.4% used
a
short acting beta2-agonist excessively and 21.0% were not using an inhaled
corticosteroid daily despite a frequency of symptoms that would suggest that
it
was needed. Common educational interventions included a review of inhaler
technique (41.9%), a recommendation for regular inhaled corticosteroids (31.5%)
and a referral to the primary care physician (21.0%). Thirty days after the
educational intervention, patients reported significant decreases in the
frequency of daytime asthma symptoms, the frequency of nocturnal symptoms
and
the frequency with which short acting beta2-agonists were used, while reporting
significant increases in their use of preventive medication. CONCLUSIONS:
A
brief assessment and an educational intervention in the community pharmacy
can
produce significant short term improvements in patient-reported symptom control
and appropriate self-management behaviour.
Eur Respir J 2001 May;17(5):934-8
Exhaled nitric oxide in chronic
obstructive pulmonary disease: relationship to
pulmonary function.
Ansarin K, Chatkin JM, Ferreira IM, Gutierrez CA, Zamel N, Chapman KR.
Asthma Centre of the University Health Network, Toronto, Ontario, Canada.
The following study was undertaken
in order to determine how exhaled nitric
oxide (eNO) levels in former smokers with chronic obstructive pulmonary disease
(COPD) compared to eNO levels in patients with asthma and in healthy nonsmoking
volunteers. The study also aimed to determine any relationship between eNO
levels in COPD and: 1) conventional measures of lung function; and 2) inhaled
corticosteroid (ICS) use. In former smokers with COPD, nonsmokers with asthma
and volunteers, eNO levels, spirometry, lung volumes, carbon monoxide diffusion
capacity of the lung (DL,CO) and resting oxygen saturation (Sa,O2) were
measured. Median eNO was significantly higher among patients with COPD than
among healthy volunteers (p = 0.003) but lower than among patients with asthma
(p < 0.01). There was no significant difference in eNO levels between COPD
patients using ICS and those not using ICS. By contrast, eNO was lower among
asthma patients who used ICS (median 32 parts per billion (ppb); 25-75% range
16-54) than among asthma patients who did not (51 ppb; 32-87) (p = 0.034).
Among
patients with COPD, eNO was inversely correlated with forced expiratory volume
in one second, DL,CO and Sa,O2, and was positively correlated with the residual
lung volume/total lung capacity ratio. Among patients with asthma, no
significant correlations were found. Exhaled nitric oxide is increased in
patients with chronic obstructive pulmonary disease, an increase that is
influenced by structural abnormalities of tobacco-induced lung damage.
Chest 2001 Jun;119(6):1691-5
Gender bias in the diagnosis of COPD.
Chapman KR, Tashkin DP, Pye DJ.
Division of Respiratory Medicine,
Department of Medicine, University of Toronto,
Toronto, Ontario, Canada. kchapman@inforamp.net
BACKGROUND: COPD is thought to
be more prevalent among men than women, a finding
usually attributed to higher smoking rates and more frequent occupational
exposures of significance for men. However, smoking prevalence has increased
among women and there is evidence that women may be more susceptible to the
adverse pulmonary function effects of smoking than men. There may also be
underdiagnosis and misdiagnosis of COPD in both sexes because objective measures
of lung function are underused. OBJECTIVES: We undertook the present study
to
determine if there is gender bias in the diagnosis of COPD, such that women
are
less likely than men to receive a diagnosis of COPD. We also attempted to
determine if underuse of lung function measurements was a factor in any bias
detected. METHODS: We surveyed a random sample of 192 primary-care physicians
(96 American and 96 Canadian; 154 men and 38 women) using a hypothetical case
presentation and a structured interview. The case of cough and dyspnea in
a
smoker was presented in six versions differing only in the age and sex of
the
patient. After presentation of the history and physical findings, physicians
were asked to state the most probable diagnosis and to choose the diagnostic
studies needed. Physicians were then presented with spirometric findings of
moderate or severe obstruction without significant bronchodilator response,
and
the questions repeated. Finally, the negative outcome of an oral steroid trial
was described. RESULTS: Initially, COPD was given as the most probable diagnosis
significantly more often for men than women (58% vs 42%; p < 0.05). The
likelihood of a COPD diagnosis increased significantly and initial differences
between sexes decreased as objective information was provided. After spirometry,
COPD diagnosis rates for men and women were 74% vs 66% (p = not significant);
after the steroid trial 85% vs 79% (p = not significant). Only 22% of physicians
would have requested spirometry after the initial presentation. CONCLUSIONS:
In
North America, primary-care physicians underdiagnosed COPD, particularly in
women. Spirometry reduces the risk of underdiagnosis and gender bias but is
underused.
Can Respir J 2001 Mar-Apr;8 Suppl A:35A-40A
Comment in:
Can Respir J. 2001 Mar-Apr;8(2):65-8.
Control of asthma in Canada: failure to achieve guideline targets.
Chapman KR, Ernst P, Grenville A, Dewland P, Zimmerman S.
University of Toronto, Toronto, Canada. kchapman@inforamp.net
OBJECTIVE: To assess the degree
of asthma control achieved by patients with
asthma in Canada and to describe the impact of poor asthma control. DESIGN:
Population-based, cross-sectional telephone interview survey of Canadians
with
doctor-diagnosed asthma. SUBJECTS AND METHODS: Random digit dialing was used
to
identify a representative sample of Canadians with asthma. A total of 801
adults
and 200 parents of children aged four to 15 years were interviewed over the
telephone. Telephone interviews were also conducted with 266 physicians.
RESULTS: Only 24% of patients achieved disease control by meeting the six
symptom-based criteria listed by the 1996 Canadian Asthma Consensus Guidelines
as appropriate treatment targets. Fifty-seven per cent of patients failed
to
meet two or more of the six control criteria and were considered poorly
controlled. Fifty-one per cent had required urgent care for out of control
asthma at least once in the year before the survey. Nonetheless, 91% of patients
thought that their asthma was adequately controlled. Physicians shared this
optimism: 77% of family physicians and 90% of respirologists believed that
they
were usually able to achieve optimal asthma control in their patients. Few
physicians gauged asthma control by tracking more than one or two symptoms,
and
just over one-half (54%) of patients surveyed recalled ever having had a lung
function test. One-half (48%) of patients with poorly controlled asthma who
used
inhaled steroids did not understand the role of inhaled steroids; one-third
(32%) of patients with poorly controlled asthma who used short acting
bronchodilators misunderstood the action of quick relief bronchodilators.
CONCLUSIONS: The majority of Canadians with asthma suffer from inadequate
control of their disease. Suboptimal control of asthma is associated with
excess
health care use. Inadequate monitoring by physicians and poor patient education
may be factors contributing to this problem.
Can Respir J 2001 Mar-Apr;8 Suppl A:5A-27A
What is new since the last (1999) Canadian Asthma Consensus Guidelines?
Boulet LP, Bai TR, Becker A, Berube
D, Beveridge R, Bowie DM, Chapman KR, Cote
J, Cockcroft D, Ducharme FM, Ernst P, FitzGerald JM, Kovesi T, Hodder RV,
O'Byrne P, Rowe B, Sears MR, Simons FE, Spier S.
Hopital Laval, Sainte-Foy, Canada. lpboulet@med.ulaval.ca
The objective of the present document
is to review the impact of new information
on the recommendations made in the last (1999) Canadian Asthma Consensus
Guidelines. It includes relevant published studies and observations or comments
regarding what are considered to be the main issues in asthma management in
children and adults in office, emergency department, hospital and clinical
settings. Asthma is still insufficiently controlled in a large number of
patients, and practice guidelines need to be integrated better with current
care. This report re-emphasises the need for the following: objective measures
of airflow obstruction to confirm the diagnosis of asthma suggested by the
clinical evaluation; identification of contributing factors; and the
establishment of a treatment plan to rapidly obtain and maintain optimal asthma
control according to specific criteria. Recent publications support the
essential role of asthma education and environmental control in asthma
management. They further support the role of inhaled corticosteroids as the
mainstay of anti-inflammatory therapy of asthma, and of both long acting
beta2-agonists and leukotriene antagonists as effective means to improve asthma
control when inhaled corticosteroids are insufficient. New developments, such
as
combination therapy, and recent major trials, such as the Children's Asthma
Management Project (CAMP) study, are discussed.
Can Respir J 2001 Mar-Apr;8(2):81-8
Alpha1-antitrypsin deficiency:
a position statement of the Canadian Thoracic
Society.
Abboud RT, Ford GT, Chapman KR;
Stnadards Committee of the Canadian Thoracic
Society.
University of British Columbia, Vancouver, Canada. rtabboud@interchange.ubc.ca
OBJECTIVE: To prepare new guidelines
for the Canadian Thoracic Society (CTS)
regarding severe alpha1-antitrypsin (AAT) deficiency and AAT replacement
therapy. MATERIALS AND METHODS: Previously published guidelines and the medical
literature about AAT deficiency and AAT replacement were reviewed. The prepared
statement was reviewed and approved by the CTS Standards and Executive
Committees. RESULTS: Three studies evaluated AAT replacement. The National
Heart, Lung and Blood Institute's AAT Registry was a nonrandomized comparison
of
patients receiving and not receiving AAT replacement, and evaluated the decline
in forced expiratory volume in 1 s (FEV1) in 927 subjects. The rate of FEV1
decline was significantly less in those receiving AAT treatment (66 +/- SE
5
mL/year versus 93 +/- SE 11 mL/year; P=0.03) only in the subgroup with FEV1
35%
to 49% predicted. In another study comparing 198 German patients receiving
weekly AAT infusions and 97 untreated Danish patients, the mean annual decline
in FEV1 was significantly less in treated patients only in the subgroup with
FEV1 31% to 65% predicted (62 mL versus 83 mL, P=0.04). Neither of these studies
was a randomized, controlled study and, thus, cannot be taken as proof of
efficacy. A randomized, double-blind, placebo controlled trial of monthly
replacement therapy over three years in 56 exsmokers with severe AAT deficiency
and moderate emphysema showed a trend (P=0.07) favouring slower progression
of
emphysema by computed tomography scan in the group receiving AAT replacement.
CONCLUSIONS: AAT replacement therapy has not been proven definitively to be
clinically effective in reducing the progression of disease in AAT-deficient
patients, but there is a possible benefit to selected patients. A placebo
controlled, randomized clinical trial of AAT replacement therapy is required.
The authors recommend reserving AAT replacement therapy for AAT-deficient
patients with impaired FEV1 of 35% to 50% predicted who have quit smoking
and
are on optimal medical therapy but continue to show a rapid decline in FEV1,
and
participation of all AAT-deficient subjects in the Canadian AAT Registry.
Chest 2001 Mar;119(3):714-9
Effectiveness and safety of salmeterol in nonspecialist practice settings.
D'Urzo AD, Chapman KR, Cartier A, Hargreave FE, Fitzgerald M, Tesarowski D.
University of Toronto, Toronto, Ontario, Canada.
STUDY OBJECTIVES: To evaluate the
effectiveness and safety of inhaled salmeterol
in patients managed in nonspecialist practice settings. DESIGN: A randomized,
double-blind, 6-month, parallel-group study involving 253 centers. SETTING:
Primarily nonspecialist practices (n = 232). PATIENTS: A total of 911 subjects
(417 men; 494 women) who met American Thoracic Society asthma criteria were
enrolled and randomized to treatment with either twice-daily salmeterol aerosol
(50 microg; n = 455) or matching placebo twice daily (n = 456). Both groups
were
allowed to take salbutamol as needed. All subjects were previously treated
with
anti-inflammatory maintenance therapy that was continued throughout the study.
MEASUREMENTS AND RESULTS: The primary outcome variable was the proportion
of
subjects with serious asthma exacerbations defined as an exacerbation requiring
hospitalization, emergency department visit, or use of prednisone during the
treatment period. A total of 712 subjects competed the study. There was no
significant difference in the proportion of subjects experiencing serious
exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%,
respectively; p = 0.935; power > 88%). Peak expiratory flow was significantly
higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p <
0.01).
Median daily use of salbutamol was two inhalations for the salmeterol group
and
three inhalations for placebo (p < 0.001). The proportion of subjects sleeping
through the night was significantly higher in the salmeterol group (74%) as
compared to placebo (68%; p = 0.028). CONCLUSIONS: Salmeterol treatment is
effective in subjects typically cared for in the primary-care setting and
does
not increase the frequency of severe exacerbations.
Postgrad Med 2000 Dec;108(7):103-4, 107-10, 113-6
Chronic obstructive pulmonary disease.
Prevention, early detection, and
aggressive treatment can make a difference.
Fraser KL, Chapman KR.
University of Calgary, Faculty of Medicine, Alberta, Canada.
COPD is common, and certainly its
impact on healthcare systems is significant.
It is imperative to diagnose COPD early in patients with or without respiratory
symptoms. This requires office spirometry performed periodically in persons
at
risk, such as long-time cigarette smokers over 40 years of age. Once airflow
obstruction has been identified, smoking cessation is the priority to prevent
further deterioration. Our increased understanding of the underlying physiology
of COPD and recent developments in medical and surgical treatments have resulted
in many new therapeutic options. Many of these treatments have the potential
to
alleviate symptoms, reduce healthcare utilization, improve quality of life,
and
extend survival.
Can Respir J 2000 Sep-Oct;7(5):415-8
Difficult asthma: consider all of the possibilities.
Cicutto LC, Chapman KR, Chamberlain D, Downey GP.
Toronto Western Hospital, Toronto, Canada. lisa.cicutto@utoronto.ca
Asthma is a common respiratory
disease that can often be managed successfully.
However, there are patients that do not respond to the maximum doses of standard
therapy and subsequently have a reduced quality of life. Many factors can
contribute to a failure to respond to treatment, and a comprehensive approach
is
important when assessing and evaluating these patients. This report describes
a
patient referred for 'difficult to control asthma' who had multiple emergency
department visits and hospitalizations. In addition to a history of wheezing,
spirometry showed impaired flow and vital capacity was reduced. Further
investigation showed a normal total lung capacity, and a computed tomography
scan revealed main bronchus blockage by a tumour, which was confirmed by
bronchoscopy. This led to a surgical resection of a mucoepidermoid carcinoma.
This case highlights the need to consider all possibilities during the
evaluation of patients with difficult asthma.
J Asthma 2000 Jun;37(4):303-18
The placebo effect in asthma drug therapy trials: a meta-analysis.
Joyce DP, Jackevicius C, Chapman KR, McIvor RA, Kesten S.
Family Practice Unit, St. Michael's Hospital, Toronto, Canada.
A meta-analysis of randomized controlled
asthma drug therapy trials published in
the English literature from January 1991 to June 1995 was performed to estimate
the magnitude and direction of the placebo effect in stable ambulatory asthmatic
patients. Among placebo groups, the mean absolute increase in forced expiratory
volume in 1 sec (FEV1), weighted for sample size and variance, was 0.11 L/min,
and the mean percent increase in FEV1 was 4.81%. The corresponding placebo
group
changes in peak expiratory flow (PEF) were in an opposite direction to those
of
FEV1; there was a mean absolute decrease of 2.24 L/min, and a mean percent
decrease of 4.21%. Changes for active treatment groups were greater in
magnitude. However, there were no statistically significant differences in
mean
changes comparing the placebo groups to the treatment groups, for any of the
outcome measures. Mean increases in PEF and FEV1 exceeded 10% in 5 of 33 placebo
groups, as compared to 13 of 33 active treatment groups. In conclusion, in
well-designed long-term drug therapy studies in stable asthmatics the pooled
placebo effect is small but measurable, with FEV1 and PEF showing different
directions of response. Moreover, a modest number of patients receiving placebo
have changes in pulmonary function that might be interpreted as clinically
significant.
Can Fam Physician 2000 Apr;46(4):872-9
Leukotriene-receptor antagonists. Role in asthma management.
D'Urzo AD, Chapman KR.
Department of Family and Community Medicine University of Toronto.
OBJECTIVE: To examine the role
of leukotriene-receptor antagonists (LTRAs) in
management of asthma. QUALITY OF EVIDENCE: Most data were derived from
randomized, double-blind, controlled trials. MAIN MESSAGE: Leukotrienes appear
to have an important role in the pathophysiology of asthma, including airway
inflammation. Leukotriene-receptor antagonists are effective in improving
asthma
control end points, such as allergen, ASA, and exercise challenge, in clinical
models of asthma. In chronic asthma, LTRA administration reduces asthma symptoms
and rescue beta 2-agonist use, changes that are paralleled by improvements
in
lung function. Both zafirlukast and montelukast decrease circulating levels
of
eosinophils and could have other useful anti-inflammatory properties.
Administration of LTRAs allows doses of inhaled corticosteroids to be reduced.
Currently available LTRAs are free of serious side effects and are available
as
oral formulations. CONCLUSIONS: Leukotriene-receptor antagonists belong to
a new
class of asthma medication. While inhaled corticosteroids remain first-line
therapy for managing chronic asthma, LTRAs should be considered for patients
with ASA-sensitive asthma; as adjunct therapy when low to moderate doses of
inhaled steroid alone provide incomplete control; or as adjunct therapy to
allow
reduction in doses of inhaled corticosteroids.
J Allergy Clin Immunol 2000 Mar;105(3):495-9
Induced sputum: comparison of postinfectious
cough with allergic asthma in
children.
Zimmerman B, Silverman FS, Tarlo SM, Chapman KR, Kubay JM, Urch B.
Gage Occupational & Environmental
Health Unit, St Michael's Hospital, and the
Asthma Centre, Toronto Western Hospital, University of Toronto, Toronto,
Ontario, Canada.
BACKGROUND: Cough persisting after
a respiratory infection is common in children
and is often managed as asthma. However, little is known about the
pathophysiologic mechanisms of such cough and how it compares with asthma.
OBJECTIVE: We used the technique of induced sputum to examine the inflammatory
index values associated with persistent cough or allergic asthma in children.
We
hypothesized that the sputum from children with persistent postinfectious
cough
would differ from that of children with allergic asthma in that the former
would
lack eosinophils compared with the latter.Study design: Sputum production
was
induced with hypertonic saline solution in 34 children: 12 with cough persisting
for 1 month or more after an apparent respiratory tract infection, not treated
with corticosteroid; 11 with untreated atopic asthma, not using inhaled
corticosteroid; and 11 with treated atopic asthma using inhaled corticosteroid.
RESULTS: The percentage of eosinophils in the sputum of children with cough
was
significantly lower than in the sputum of children with untreated allergic
asthma (median 0.5% vs 14.5%, P <.0001). Similarly, the percentage of
eosinophils in the sputum of children with asthma treated with inhaled steroids
was significantly lower compared with untreated asthmatic children (1.5% vs
14.5%, P <.0001). The peripheral blood eosinophils, serum eosinophil cationic
protein, and nasal percent eosinophils of the patients with cough were also
significantly lower than those from patients with untreated asthma. Methacholine
challenge in 6 of the 11 cough patients tested showed mild-to-moderate
hyperresponsiveness, whereas the other 5 had a negative methacholine challenge.
CONCLUSIONS: Children with persistent postinfectious cough do not have airway
eosinophilia typical of untreated asthma. Despite the absence of eosinophilic
inflammation, some of the patients with chronic cough had reactive airways.
These results suggest that postinfectious cough in children has different
pathophysiologic features than allergic asthma and probably represents a
different disease.
Respir Med 2000 Jan;94(1):2-9
Improving patient compliance with asthma therapy.
Chapman KR, Walker L, Cluley S, Fabbri L.
Asthma Centre of the Toronto Hospital, Toronto, Canada.
Patients fail to comply with asthma
medication for a variety of reasons. These
range from physical inability to use an inhaler, through simple forgetfulness,
to a conscious decision not to use medication as prescribed due to internal
or
cultural health beliefs or socioeconomic factors. In some patients, poor
self-care because of deep-rooted psychological factors (i.e. factors of which
patients have only limited awareness) can affect compliance. Poor doctor-patient
communication can be the cause in many other individuals. Thus, there is no
single solution that will improve compliance in all patients. Simplifying
the
regimen or providing memory aids will be sufficient for some patients, while
education or psychological counselling will be more appropriate for others.
Doctors can also use a range of communication skills to improve the way in
which
they present information, motivate patients and reinforce progress. These
approaches, plus respect for patients' health beliefs and involving them in
treatment decisions, can help foster an atmosphere of mutual responsibility
and
concordance over medicine taking.
Can Respir J 1999 May-Jun;6(3):237-44
Inhaler education for hospital-based pharmacists: how much is required?
Jackevicius CA, Chapman KR.
The Toronto Hospital and Faculty
of Pharmacy, University of Toronto, Toronto,
Canada. t19nspm@torhosp.toronto.on.ca
OBJECTIVE: To compare the effectiveness
of a more intensive educational
intervention with a less intensive intervention on the ability of hospital
pharmacists to be prepared to educate patients regarding inhaled device
technique. DESIGN: Randomized controlled trial. Inhaler technique and knowledge
were assessed pre-education, immediately after and three months after education
by a research assistant blinded to the educational allocation. SETTING: Tertiary
hospital pharmacy department. POPULATION STUDIED: Hospital-based pharmacists.
INTERVENTION: A 1 h 'hands-on' session with feedback (more intense education,
MIE) or written materials describing inhaler use (less intense education,
LIE).
MAIN RESULTS: The change in overall score from pre-education to early
posteducation for MIE was greater than for LIE (mean [95% CI]) (2.64 [1.27
to
4.01] versus 1.26 [0.05 to 2.47], P<0.001). Assessment scores improved
for all
device demonstrations and general knowledge. The change in score from the
pre-education to the late posteducation period was only slightly higher in
the
MIE group than the LIE group, a difference that was not statistically
significant (1.78 [0.82 to 2.74] versus 1. 22 [0.06 to 2.39], P=0.09). Scores
in
both groups were lower in the late posteducation period compared with the
early
posteducation period. Greater increases in total score in the immediate
posteducation period were associated with a low baseline score and the MIE
intervention. CONCLUSION: Individual coaching in inhaler technique produces
greater improvement in inhaler knowledge among hospital pharmacists than
provision of written materials. However, the advantage of the more intensive
intervention was short-lived, with little advantage evident in three months.
Can Fam Physician 1999 Jun;45:1524-5
Erratum in:
Can Fam Physician 1999 Jul;45:1655
Case report: pneumothorax and asthma.
D'Urzo AD, D'Urzo DK, Chapman KR.
Department of Medicine, University of Toronto, Ontario.
Am J Respir Crit Care Med 1999 Jun;159(6):1810-3
Exhaled nitric oxide as a noninvasive assessment of chronic cough.
Chatkin JM, Ansarin K, Silkoff PE, McClean P, Gutierrez C, Zamel N, Chapman KR.
Divisions of Respiratory Medicine, University of Toronto, Toronto, Canada.
Exhaled nitric oxide (ENO) has
been suggested as a marker of airway
inflammation. This study aimed to evaluate the role of ENO in the investigation
of chronic cough. We measured ENO in 38 adult patients reporting chronic cough,
in 23 healthy control subjects, and in 44 asthmatics. In addition to the regular
investigation, ENO was measured by a chemiluminescent analyzer using the
restricted breath technique. In the chronic cough group, 30 were considered
as
nonasthmatic, whereas asthma was diagnosed in eight by a positive methacholine
challenge. ENO values were significantly higher in patients with chronic cough
attributable to asthma as compared with those with chronic cough not
attributable to asthma and to healthy volunteers (75.0 ppb; 16.7 ppb; and
28.3
ppb, respectively). The sensitivity and specificity of ENO for detecting asthma,
using 30 ppb as the ENO cutoff point, were 75 and 87%, respectively. The
positive and negative predictive values were 60 and 93%, and the positive
and
negative likelihood ratios were 5.8 and 0.3, respectively. We conclude that
ENO
may have a role in the evaluation of chronic cough. In this group of patients,
low ENO suggested little likelihood of asthma. The patients with chronic cough
not attributable to asthma showed a low ENO value as compared with healthy
volunteers and asthmatics.
Can Respir J 1999 Jan-Feb;6(1):45-51
Salmeterol and fluticasone propionate
(50/250 microg) administered via
combination Diskus inhaler: as effective as when given via separate Diskus
inhalers.
Chapman KR, Ringdal N, Backer V, Palmqvist M, Saarelainen S, Briggs M.
Toronto Hospital, Western Division, Toronto, Canada. kchapman@inforamp.net
OBJECTIVE: To compare the efficacy
and safety of a new combination Diskus
inhaler containing both salmeterol 50 mg and fluticasone propionate 250 mg
(Seretide) with the two drugs delivered via separate Diskus inhalers. DESIGN:
A
multicentre, double-blind, double-dummy study. Three hundred and seventy-one
symptomatic asthma patients (age range 13 to 75 years, mean 42 years) receiving
inhaled corticosteroids were randomly assigned to two treatment groups: 28
weeks' treatment with either salmeterol/fluticasone propionate (50/250 microg
bid) via a single Diskus inhaler (combination) and placebo bid via another
Diskus inhaler, or salmeterol 50 microg bid via one Diskus inhaler and
fluticasone propionate 250 microg bid via another (concurrent). Morning peak
expiratory flow rate (PEFR) and symptoms were measured for the first 12 weeks
and safety data were collected throughout the study. RESULTS: Over weeks 1
to
12, adjusted mean improvements in morning PEFR were 43 and 36 L/min for
combination and concurrent therapies, respectively. The difference between
the
two treatment arms was 6 L/min (90% CI -13 to 0 L/min; P=0.114), which was
within the predefined criteria for clinical equivalence. Adjusted mean
improvements in forced expiratory volume in 1 s from baseline for week 28
were
also similar between the two therapies. Thirty-five per cent of patients
receiving combination inhaler and 31% of those receiving concurrent therapy
had
a mean daytime symptom score of zero over weeks 1 to 12 compared with 1% and
2%,
respectively, at baseline. There was no difference in the incidence of adverse
events between the two treatment arms. Mean serum cortisol levels were similar,
and no differences in frequency of abnormal results were noted between the
two
groups. CONCLUSIONS: This study shows that the combination of salmeterol and
fluticasone propionate in a single inhaler is as efficacious in achieving
asthma
control and as well tolerated over a 28-week period as the two drugs
administered individually.
Can Respir J 1998 Nov-Dec;5(6):463-71
The patient level cost of asthma
in adults in south central Ontario. Pharmacy
Medication Monitoring Program Advisory Board.
Ungar WJ, Coyte PC, Chapman KR, MacKeigan L.
Department of Health Administration
and Division of Respirology, University of
Toronto, Toronto, Canada. wungar@utoronto.ca
OBJECTIVE: To assess the annual
cost of asthma per adult patient from the
perspectives of society, the Ontario Ministry of Health and the patient. DESIGN:
Prospective cost of illness evaluation. SETTING: Ambulatory out-patients
residing in southern central Ontario. POPULATION STUDIED: Nine hundred and
forty
patients with asthma over 15 years of age studied between May 1995 and April
1996. OUTCOME MEASURES: Direct costs, such as respiratory-related visits to
general/family practitioners, respiratory specialists, emergency rooms, hospital
admissions, laboratory tests, prescription medications, dispensing fees, devices
and out-of-pocket expenses, were calculated. Indirect costs, such as absences
from work or usual activities, and travel and waiting time, were studied.
MAIN
RESULTS: Unadjusted annual costs were $2,550 per patient. Hospitalizations
and
medications each accounted for 22% of the total cost and indirect costs 50%
of
the total costs. More severe disease, older age, smoking, drug plan availability
and retirement were significant predictors of costs. Annual costs per patient
varied from $1,255 (95% CI $1,061 to $1,485) in young nonsmokers with no drug
plan and mild disease to $5,032 (95% CI $4,347 to $5,825) in older smokers
with
drug plans and severe disease. Clinically important reductions in the quality
of
life occurred with increasing severity. CONCLUSIONS: Interventions aimed at
reducing productivity losses, admissions to hospital and medication costs
may
result in savings to society, the provincial government and the patient. The
quality of policy and allocation decisions may be enhanced by cost of illness
estimates that are comprehensive, precise and incorporate multiple perspectives.
J Allergy Clin Immunol 1999 Mar;103(3 Pt 1):427-35
Sustained bronchoprotection, bronchodilatation,
and symptom control during
regular formoterol use in asthma of moderate or greater severity. The Canadian
FO/OD1 Study Group.
FitzGerald JM, Chapman KR, Della
Cioppa G, Stubbing D, Fairbarn MS, Till MD,
Brambilla R.
Department of Medicine, Respiratory
Division, Vancouver Hospital and Health
Sciences Centre, Vancouver, British Columbia.
BACKGROUND: Recent studies have
raised concern that regular inhalation of beta2
-agonists may cause a worsening of asthma control compared with on-demand
dosing
regimens. OBJECTIVE: The objective of this study was to compare the effect
of
twice daily formoterol (Foradil), 4 times daily albuterol, and on-demand
albuterol on bronchial hyperresponsiveness (BHR), lung function measurements,
symptoms, and other indicators of disease control over 6 months inpatients
with
asthma of moderate or greater severity receiving concomitant inhaled
corticosteroids. We also looked for occurrence of rebound BHR on discontinuation
of treatment. METHODS: This was a multicenter, parallel-group, double-blind,
clinical trial. Methacholine PC20 was the primary outcome variable. Other
outcome variables included symptom scores, use of rescue medication, morning
peak expiratory flow (PEF), serial FEV1 measurements, and asthma exacerbations.
RESULTS: Of the 271 randomized patients, 217 completed the study. Formoterol
was
significantly superior to on-demand albuterol with regard to methacholine
PC20,
FEV1, PEF, symptom scores, and use of rescue medication at each measured time
point/interval. Regular albuterol was superior to on-demand albuterol with
regard to PC20 and FEV1, but not PEF or various clinical scores. After a small
drop in the magnitude of bronchoprotection and bronchodilatation occurring
shortly after randomization, there was no evidence of progressive tolerance
to
either regular treatment for any of the measured variables or of rebound
increase in BHR 2 days after the end of treatment. The formoterol group had
the
lowest number of exacerbation days, as defined by high intake of rescue
bronchodilator and/or symptom scores, whereas the number of exacerbations
requiring increased corticosteroid coverage was similar in the 3 groups.
CONCLUSION: In patients with asthma of moderate or greater severity receiving
inhaled corticosteroids, formoterol taken twice daily resulted in superior
bronchoprotection, bronchodilatation, and clinical control compared with
on-demand albuterol over 6 months. Four times daily albuterol was superior
to
on-demand albuterol for only some of the end points. Progressive tolerance
and a
rebound increase in BHR on discontinuation of beta-agonists were not found
Exhaled nitric oxide after beta2-agonist inhalation and spirometry in asthma.
Silkoff PE, Wakita S, Chatkin J,
Ansarin K, Gutierrez C, Caramori M, McClean P,
Slutsky AS, Zamel N, Chapman KR.
Division of Respiratory Medicine,
Faculty of Medicine, University of Toronto,
Canada.
Exhaled nitric oxide (ENO) is used
increasingly as a surrogate marker of airway
inflammation in research protocols that may incorporate standard efficacy
measures, such as spirometry before and after bronchodilator, which could
affect
ENO measurements. In seven healthy volunteers and 11 mild asthmatic subjects,
we
measured ENO before and serially for 1 h after spirometry. On two additional
days in the subjects with asthma, we reexamined the effect of spirometry as
before, followed by the serial measurement of ENO for 1 h after two puffs
of
salbutamol (100 microgram/puff) by metered-dose inhaler or matching placebo.
As
early as 1 min after spirometry, ENO fell by 13% and 10% in the normal and
asthmatic subjects, respectively. In both groups, ENO returned to baseline
over
1 h. In the asthmatic subjects, salbutamol caused a significant mean increase
of
the order of 10 parts per billion in ENO (p < 0.001) for 1 h as compared
with
placebo inhaler. We conclude that spirometry and beta2-agonist may perturb
ENO
values and recommend that studies control for these factors.
Can Respir J 1998 Sep-Oct;5(5):349-54
Effect of high dose inhaled acetic
acid on airway responsiveness in Fischer
rats.
Ariel AP, Furlott HG, Chapman KR, Slutsky AS, Webster P, Zamel N, Tarlo SM.
Department of Medicine, University of Toronto, Toronto, Canada.
BACKGROUND: Sudden, severe airway
injury has been associated with an acute, and
at times persisting, airway hyper-responsiveness with clinical features of
asthma, termed reactive airways dysfunction syndrome (RADS). An attempt was
made
to develop a rat model of RADS by exposing inbred Fischer rats to inhaled
8 N
acetic acid for 2 mins (13 N inhalation was lethal). METHODS: Lung resistance
(RL) and lung elastance (EL) were measured in 14 eight- to 10-week old male
rats. Baseline responsiveness to methacholine was quantified by calculating
the
dose required for doubling of RL. The next day, the study group (n=11) was
exposed to aerosolized acetic acid. Control animals (n=3) were similarly exposed
to buffered saline solution. RESULTS: Acetic acid exposure resulted in a
significant (P<0.02) increase in RL (by 80%) and EL (by 67%), lasting less
than
10 mins postexposure, but no significant change in methacholine responsiveness
at one day and seven days postexposure. CONCLUSIONS: Failure to induce
persistent airway hyper-responsiveness may relate to the choice of animal,
choice of irritant, or insufficient level or duration of exposure, or may
reflect a lack of individual predisposing cofactors such as smoking or
underlying asthmatic predisposition.
J Allergy Clin Immunol 1998 Sep;102(3):409-13
Validation of the Doser, a new device for monitoring metered-dose inhaler use.
Simmons MS, Nides MA, Kleerup EC,
Chapman KR, Milgrom H, Rand CS, Spector SL,
Tashkin DP.
UCLA School of Medicine, Los Angeles, Calif 90095-1690, USA.
BACKGROUND: Electronic monitoring
of medication use has proved valuable in both
clinical and research settings. The Doser, a new and inexpensive commercially
available device for monitoring metered-dose inhaler (MDI) use, displays 3
measures of daily use of an attached MDI: (1) the daily total of actuations,
(2)
the number of doses remaining in the MDI, and (3) the number of actuations
on
each of the preceding 30 days for later recall. OBJECTIVE: We sought to validate
the accuracy of the Doser with several commonly prescribed MDIs. METHODS:
In the
laboratory, clinic personnel actuated an MDI with an attached Doser several
times in succession on 3 consecutive days and recorded each of the 3 measures
of
MDI use (study 1). In study 2 clinic personnel carried an MDI and attached
Doser
with them for 4 weeks, actuating the MDI according to a prescribed protocol
each
morning and evening and again recording each of the 3 measures of daily use.
In
addition, during 2 weeks of study 2, a thermistor-based Nebulizer Chronolog
was
attached to the MDI to electronically record the date and time of each
actuation. In study 3 clinic patients had both a Doser and Nebulizer Chronolog
attached to their routinely used inhalers for 2 weeks and a Doser alone during
a
separate 2-week period. RESULTS: In study 1 agreement was 99% to 100% among
the
3 Doser measures, and each measure agreed with actual use by self-report 97%
of
the time. In study 2 agreement among the 3 Doser measures of use ranged from
98%
to 99%. Agreement between each of the 3 Doser measures and the Nebulizer
Chronolog ranged from 90% to 93%. Agreement between each of the 3 Doser measures
and actual use ranged from 96% to 97%, and the Nebulizer Chronolog agreed
with
actual use 93% of the time. In study 3 Doser and Nebulizer Chronolog agreement
with patient self-report were 85% and 80%, respectively. Agreement between
the
Doser and Nebulizer Chronolog was 76%. Several failures of the thermistor-based
Nebulizer Chronolog occurred, and occasional mechanical problems occurred
with
the Doser, primarily on particular types of MDI canisters. CONCLUSION: The
Doser
provides an accurate measure of MDI use with most commonly prescribed
medications and may be useful for monitoring MDI use by investigators,
clinicians, and patients.
J Asthma 1998;35(6):473-9
Exhaled nitric oxide and bronchial
reactivity during and after inhaled
beclomethasone in mild asthma.
Silkoff PE, McClean PA, Slutsky
AS, Caramori M, Chapman KR, Gutierrez C, Zamel
N.
Division of Respiratory Medicine,
Faculty of Medicine, The University of
Toronto, Canada. silkoffp@njc.org
The measurement of exhaled nitric
oxide (ENO) is recognized as a marker of
airway inflammation. ENO was measured in 10 nonsteroid-treated asthmatics
at
recruitment, during 3 weeks of inhaled beclomethasone (1000 microg/day) and
for
3 weeks after withdrawal. Baseline ENO was increased in asthma compared with
nonasthmatics (85.0+/-54.5 vs. 24.5+/-14.8 ppb, p < 0.0001). After inhaled
steroid, there was no significant change in forced expiratory volume in 1
sec
(FEV1) and forced vital capacity (FVC), but methacholine PC20 rose significantly
(p = 0.0345). ENO (mean+/-SD; % baseline) fell after 1 week on steroid to
60.6+/-31.1 and rose to 95.3+/-46.1 at 1 week after withdrawal. ENO did not
correlate with PC20 or FEV1. The changes in ENO and PC20 were inversely
correlated (r2 = 0.325). ENO may be an index of airway inflammation and
therapeutic response in bronchial asthma.
Effect of inhaled furosemide in acute asthma.
Pendino JC, Nannini LJ, Chapman KR, Slutsky A, Molfino NA.
Hospital Centenario, Universidad de Rosario, Argentina.
We assessed the acute bronchodilator
effect of nebulized furosemide when added
to conventional therapy of acute emergency department (ED) asthma. Using a
double-blind design, 42 patients with acute asthma were randomized to receive
2.5 mg nebulized salbutamol and either 40 mg of nebulized furosemide or saline
solution. We recorded clinical variables (respiratory rate, heart rate, and
pulsus paradoxus) and peak expiratory flow rates (PEFR) before and 15 and
30 min
after therapy. We found no significant difference in PEFR between
salbutamol/furosemide and salbutamol/saline-treated patients 15 and 30 min
following inhalation. Other endpoints were equally unaffected. However, when
we
examined separately those patients whose exacerbations were of relative short
duration (< 8 hr), PEFR improved significantly more in the furosemide-treated
group. At 15 min, PEFR increased by 82 +/- 48% in the furosemide group compared
to 35 +/- 40% in the control group (p = 0.03), an effect that was also evident
at 30 min when PEFR had increased by 113 +/- 49% in the furosemide group versus
61 +/- 35% in the control group (p = 0.014). Respiratory rate, heart rate,
and
pulsus paradoxus improved with no differences between the groups. The beneficial
effect of furosemide was not evident in patients who reported more prolonged
duration (> 8 hr) of asthmatic symptoms. The response to furosemide appeared
to
be unrelated to concomitant ED therapy with corticosteroids, to baseline
pulmonary function, or to patient demographic variables. We conclude that
furosemide may offer additive bronchodilator benefits in acute naturally
occurring asthma of relative short duration.
J Asthma 1997;34(6):483-91
Defining the asthma phenotype for the purpose of genetic analysis.
Kesten S, Dzyngel B, Chapman KR, Zamel N, Tarlo S, Malo JL, Slutsky AS.
University of Toronto, Canada. skesten@rush.edu
In 1991, we began a project to
search for the genetic basis of asthma using
linkage analysis. We encountered discord between a history of asthma and
physiological measures of variable airflow obstruction and sought to examine
the
frequency of such occurrences and the issues surrounding phenotyping of patients
with asthma. We reviewed our experience in ascertaining the asthma phenotype
in
50 nuclear families comprised of 219 subjects (110 male, 109 female). Three
respiratory physicians reviewed data including a questionnaire, skin testing,
objective measures of variable airflow obstruction [increase in FEV1 >
or = 15%
following salbutamol 400 micrograms of PC20 (methacholine) < or = 4 mg/ml],
and
serum for IgE. Thirty-eight percent of subjects had both objective and
questionnaire data consistent with asthma (++) whereas 39% had negative
objective and negative questionnaire findings (--) (i.e., no asthma). A positive
history but negative objective findings occurred in 7% of subjects, 2% had
a
negative history and positive objective findings. Retesting was requested
in 13%
of subjects; review of historical data was requested in 1% (i.e., childhood
asthma but no present asthma). Retesting was requested for either (a) positive
history, negative objective if symptoms were seasonal or the subject was using
medications known to affect the challenge study, (b) viral infection within
6
weeks of a positive methacholine study, or (c) technically inadequate study.
Overall, after the initial assessment, all members of only 22 families could
be
catagorized as either ++ or --. The diagnostic group requested at least 1
retest
in 19 families and a review of historical records in 2 families. We conclude
that discordance between self-reported questionnaire data and laboratory
measures of variable airflow limitation is common and will increase the numbers
of asthmatic subjects in studies that seek to determine the genetic basis
of
asthma.
Curr Opin Pulm Med 1996 Mar;2(2):148-54
Diagnosis of chronic obstructive
pulmonary disease and differentiation from
asthma.
McIvor A, Chapman KR.
Asthma Centre, Toronto Hospital, Ontario, Canada.
In the primary care setting, asthma
and chronic obstructive pulmonary disease
are common clinical challenges, which together affect approximately 25,000,000
Americans. As our therapeutic strategies for these two diseases diverge, it
becomes important to distinguish between them. Although this may be relatively
easy at the extremes of age using a combination of history and physical
examination, this review focuses on additional information that may allow
diagnostic distinctions to be made in the troublesome middle ground.
Ann Allergy Asthma Immunol 1997 Jul;79(1):35-42
Asthma and allergy avoidance knowledge and behavior in postpartum women.
Joyce DP, Chapman KR, Balter M, Kesten S.
Asthma Centre of The Toronto Hospital, University of Toronto, Canada.
OBJECTIVE: Based on family history,
infants may be classified as "high risk" or
"low risk" for the development of allergy or asthma. Failure to
breast-feed and
early exposure to cigarette smoke or aeroallergens increase the risk of
developing asthma or allergy. Since we suspect that physicians seldom educate
mothers on reducing environmental exposures in the postnatal period, we sought
to determine the level of maternal knowledge as well as actual avoidance
behaviors with respect to these risk factors in high risk and low risk families.
DESIGN: Questionnaire administered by a research assistant. SETTING: Obstetrics
unit of two tertiary care general hospitals. PATIENTS: A sample of 194
postpartum women with uncomplicated pregnancies, interviewed after 24-hours
postpartum. MAIN OUTCOME MEASURES: (1) Parental history of asthma, allergy
or
eczema; (2) potential for infant exposure to environmental risk factors for
asthma and allergy, as indicated by history of avoidance practices in the
home;
(3) parental knowledge of risk factors for asthma or allergy; and (4) physician
advise on avoidance. RESULTS: Of 194 women interviewed, a history of
doctor-diagnosed asthma, allergy/allergic rhinitis or eczema in either parent
was reported by 122 (high risk group). The remaining 72 patients had no history
of atopy (low risk group). Of those in the high risk group, 10% of mothers
smoked during pregnancy, and about 25% were exposed to second hand smoke on
a
daily basis. Most of the mothers in the high risk group planned to breast
feed
(89%). A large number of patients in the high risk group reported potential
risk
factors for allergy/asthma in their home environments. These included animals
in
the household (36%), dusty environments (10%) carpeting (47%), cigarette smoke
(18%), and others. Despite these risks, only 13% of patients reported being
educated by their physicians on improving their home environment. Exposures
to
environmental risk factors were not different between low and high risk groups.
Similarly, knowledge of environmental risk factors and avoidance behaviors
were
not significantly different between low and high risk groups. CONCLUSIONS:
Many
mothers whose infants are at high risk of developing asthma or allergies are
not
aware of and do not practice avoidance of risk factors. Physicians involved
in
prenatal care of women with a family history of atopy and asthma should offer
advice on reducing exposure to potential risk factors and how to modify their
environment in ways that can potentially decrease the risk of asthma or allergy
prevalence and severity.
Thorax 1997 Jun;52(6):535-9
Effects of the long acting beta
agonist formoterol on asthma control in
asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian
Formoterol Study Investigators.
van der Molen T, Postma DS, Turner
MO, Jong BM, Malo JL, Chapman K, Grossman R,
de Graaff CS, Riemersma RA, Sears MR.
Department of Pulmonology, University Hospital, Groningen, The Netherlands.
BACKGROUND: The long acting beta
2 agonist formoterol has proved to be an
effective bronchodilator with a prolonged action of 12-14 hours. However,
the
precise role of formoterol in the maintenance treatment of asthma is still
under
debate. A study was performed to investigate the efficacy and safety of
treatment with formoterol for six months in subjects with asthma. METHODS:
In a
multicentre double blind, placebo controlled, parallel group study 239 subjects
with mild to moderate asthma were randomly assigned to treatment with either
inhaled formoterol 24 micrograms twice daily (n = 125) or placebo (n = 114)
during eight months. The study consisted of a four week run in period, a 24
week
treatment period, and a four week washout period. All subjects were using
regular inhaled corticosteroids (100-3200 micrograms daily) but were still
needing at least five inhalations of short acting beta 2 agonist per week
for
symptom relief. The study was performed in 10 outpatient clinics in Canada,
and
five outpatient clinics and one coordinating centre for 44 Dutch general
practitioners in The Netherlands. Twice daily self-reported peak expiratory
flow
(PEF) measurements, symptom scores, and rescue beta 2 agonist use during the
last 28 treatment days compared with baseline values were used as main outcome
measures. Spirometric values were measured at entry, at the start of treatment,
after four, 12 and 24 weeks of treatment, and after four weeks washout. RESULTS:
One hundred and twenty five subjects received formoterol 24 micrograms twice
daily via Turbohaler and 114 received placebo. Baseline FEV1 was 67.1% predicted
and mean bronchodilator reversibility was 26%. The mean total asthma symptom
score was 3.6 (maximum possible 21). A significant decrease in symptoms in
favour of formoterol (difference from placebo -0.64, 95% CI -0.04 to -1.23,
p =
0.04) was observed. Compared with placebo, morning PEF increased (difference
from placebo 28 l/min, 95% CI 18.3 to 37.7, p = 0.0001) and the use of short
acting beta 1 agonists decreased (daytime difference from placebo -1.1
inhalation, 95% CI -1.4 to -0.7, p = 0.0001) in the formoterol group. PEF
returned to baseline following discontinuation of formoterol, as did asthma
symptom scores. Thirty three patients treated with formoterol and 32 treated
with placebo required treatment with prednisolone during the study (58 and
55
courses, respectively). CONCLUSIONS: Adding formoterol 24 micrograms twice
daily
by Turbohaler to inhaled corticosteroids was effective in improving symptom
scores and morning PEF, and decreasing the use of rescue beta 2 agonists.
There
was no apparent loss of asthma control during 24 weeks of treatment with
formoterol.
Am J Respir Crit Care Med 1997 Jun;155(6):1835-40
Comment in:
Am J Respir Crit Care Med. 1997 Jun;155(6):1825-7.
Inhibitory effects of an anti-IgE
antibody E25 on allergen-induced early
asthmatic response.
Boulet LP, Chapman KR, Cote J,
Kalra S, Bhagat R, Swystun VA, Laviolette M,
Cleland LD, Deschesnes F, Su JQ, DeVault A, Fick RB Jr, Cockcroft DW.
Centre de Pneumologie, Hopital Laval, Sainte-Foy, Quebec, Canada.
Inhaled allergens, acting through
IgE-dependent mechanisms, are important
triggers of asthma symptoms and inducers of airway hyperresponsiveness and
airway inflammation. The effect of anti-IgE recombinant humanized monoclonal
antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing
a
15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic
response (EAR) was assessed in a multicenter, randomized, double-blind, parallel
group study. Ten of 11 allergic asthmatic subjects randomized to receive
intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14,
28,
42, 56, and 70 completed the study; nine received intravenous placebo. The
allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20
on
Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active
group) was withdrawn because of a generalized urticarial rash after the first
dose. Compared with baseline values (Day -1), the median allergen PC15 on
Days
27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log
PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses
with placebo (p < or = 0.002). Methacholine PC20 improved slightly after
rhuMAb-E25, this change becoming statistically significant on Day 76 (p <
0.05);
no change was observed in the placebo group. Mean serum-free IgE fell by 89%
after rhuMAb-E25 while there was no significant change after placebo. The
inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may
be
an effective, novel antiallergic treatment for asthma.
Chest 1997 Feb;111(2):311-5
The clinical efficacy of combination
nebulized anticholinergic and adrenergic
bronchodilators vs nebulized adrenergic bronchodilator alone in acute asthma.
Canadian Combivent Study Group.
FitzGerald JM, Grunfeld A, Pare PD, Levy RD, Newhouse MT, Hodder R, Chapman KR.
Respiratory Clinic, Vancouver Hospital, BC. Canada.
The role of ipratropium bromide
as adjunct therapy to beta-agonists in acute
asthma is uncertain. We therefore decided to compare the use of 3 mg of
salbutamol sulfate alone vs 3 mg salbutamol sulfate with 0.5 mg ipratropium
bromide in patients with acute asthma. Patients presenting with acute asthma
and
an FEV1 less than 70% predicted were randomized to a single combination
treatment vs salbutamol alone. All patients received supplemental oxygen and
methylpred-nisolone, 125 mg, IV. Baseline measurements were repeated at 45
and
90 min and these included spirometry, oximetry, and vital signs. A total of
952
patients were screened of whom 342 patients were deemed eligible and were
randomized in two groups of 171 patients. The mean (SE) age was 30 years (0.9)
vs 29 years (0.7), women, 103 (60.2%) vs 110 (64%), 81 (47.4%) never-smoked
vs
83 (48.5%), and duration of asthma in years 16.0 (0.8) vs 16.6 (0.8) were
no
different in the combination vs salbutamol alone group, respectively. Likewise,
there was no significant difference in asthma therapy received in the 24 h
prior
to presentation; most notably, 151 (88.3%) vs 153 (89.5%) received inhaled
beta-agonists in that period. Baseline FEV1 was 1.62 L (0.05 L) vs 1.53 L
(0.03
L), and median time to treatment being received was no different between both
groups. Both treatment arms improved significantly. The increase in FEV1 in
the
combination group was 0.6I L (0.04 L) and in the salbutamol alone group was
0.52
L (0.04 L) at 90 min. There was a trend toward greater bronchodilation in
the
combination group, but this did not reach statistical significance. Fewer
hospitalizations, 5.9% vs 11.2%, occurred in the combination group, but this
did
not reach statistical significance. In conclusion, this large multicenter
study
failed to show a significantly better response to a combination of salbutamol
and ipratropium bromide vs salbutamol alone.
Chest 1997 Feb;111(2):296-302
Prehospitalization inhaled corticosteroid use in patients with COPD or asthma.
Jackevicius C, Joyce DP, Kesten S, Chapman KR.
Asthma Centre of The Toronto Hospital, Ontario.
BACKGROUND: Guidelines for the
treatment of obstructive lung diseases suggest a
primary role of inhaled corticosteroids (ICs) in asthma, but only a minor
role
in COPD. However, surveys of physicians' prescribing habits have suggested
that
there is little difference in the use of ICs between these two conditions.
OBJECTIVES: To determine the prevalence of IC use before and during
hospitalization among patients with COPD or asthma. DESIGN: Retrospective
chart
review. SETTING: Tertiary care university teaching hospital. PATIENTS: Adult
inpatients, aged 18 or older, with physician-diagnosed COPD or asthma.
MEASUREMENTS: Patient-reported prescription drug use at hospital admission,
and
medical chart record of in-hospital and discharge prescriptions. RESULTS:
Of 350
charts reviewed, 102 patients were admitted to the hospital for unstable COPD,
133 patients had stable COPD, 36 patients were admitted with unstable asthma,
and 79 patients had stable asthma. At hospital admission, 48% of unstable
COPD
patients, 26% of stable COPD patients, 56% of unstable asthma patients, and
44%
of stable asthma patients reported having a current prescription for ICs.
The
proportion of all asthmatic patients reporting a current prescription for
ICs at
admission (48%) was significantly higher than the proportion of all COPD
patients receiving an IC at admission (35%). However, there was no significant
difference in the proportion of COPD and asthma patients with a current
prescription of any form of corticosteroid (oral or inhaled). The proportion
of
COPD patients likely to respond to IC therapy is significantly different from
the observed use at hospital admission. CONCLUSIONS: The proportion of patients
found to be using ICs is much higher than the proportion expected to respond.
There was little difference in the use of ICs for asthma and COPD patients
at
hospital admission. Most COPD patients using an IC were receiving the regimen
on
admission to hospital, indicating that there is need for education in the
community and in the hospital regarding use of ICs in COPD patients.
Chest 1997 Feb;111(2):290-5
Factors associated with emergency department dependence of patients with asthma.
Hanania NA, David-Wang A, Kesten S, Chapman KR.
Asthma Centre, Toronto Hospital, University of Toronto, Ontario, Canada.
BACKGROUND: Dependence on crisis-oriented
care rather than continuous ambulatory
care for asthma is thought to contribute to asthma morbidity and mortality.
We
contrasted the characteristics of patients who depend on emergency department
(ED) care for the management of their asthma exacerbations to the
characteristics of patients employing self-management plans in an ambulatory
setting. METHODS: In prospective fashion, we used a structured interview and
charted information to survey two cohorts of patients suffering from an acute
exacerbation of asthma; those seen in a hospital ED (n = 80) and those seen
in
an ambulatory asthma care facility (Asthma Center [AC]) (n = 40) at the same
hospital. We looked for differences in socioeconomic characteristics, asthma
severity, asthma knowledge, and asthma self-management skills between groups.
RESULTS: There were no significant differences in mean age (SD) (ED vs AC:
36.65
[13.8] vs 40 [13.8] years) or female to male ratio (ED vs AC: 2/1 vs 2.5/1)
between the two groups. There were no major differences in ethnic origin,
educational status, marital status, smoking history, employment status, number
of children in the household, possession of an extended health insurance plan,
sick leave benefits, and child care availability between the two groups.
Patients seeking ED care were more likely to have resided in the city for
< 5
years (34% vs 8%; p < 0.05), and more likely to be living alone (35% vs
15%; p <
0.05). Significantly more patients from the ED group had a below average gross
annual income (55% vs 3%; p < 0.05). There were several significant differences
between groups in their knowledge of asthma and its therapy. Most striking,
79%
of AC patients reported having a predetermined crisis plan vs just 23% of
ED
patients (p < 0.001). Although measurements of airflow (percent predicted
FEV1)
were significantly lower in the ED group than the AC group (mean, 50% vs 78.4%;
p < 0.001), other indexes reflecting the degree of asthma severity over
the long
term such as past use of oral steroids, history of hospitalization, or ICU
admission for asthma and the mean total days of disability within the preceding
year were not significantly different between the two groups. Most of the
ED
patients had more than one previous visit to the ED for asthma exacerbation
within the preceding year while most exacerbations of AC patients had been
treated in the ambulatory care setting. Only 17% of ED patients initiated
or
increased inhaled or oral steroids before seeking medical care vs 89% of AC
patients (p < 0.001). CONCLUSION: We conclude that a subgroup of asthmatics
depends primarily on crisis-oriented care for the management of asthma. These
patients are more likely to have lower income, to live alone, and to have
resided at their current address for less time than patients seeking less
urgent
ambulatory care. Moreover, such patients are less knowledgeable about asthma
and
its management and are less likely to have a predetermined crisis plan.
Ann Pharmacother 1997 Feb;31(2):160-4
Prevalence of inhaled corticosteroid
use among patients with chronic obstructive
pulmonary disease: a survey.
Jackevicius CA, Chapman KR.
Toronto Hospital, Ontario, Canada.
OBJECTIVE: To determine the extent
of inhaled corticosteroid use among patients
with chronic obstructive pulmonary disease (COPD). DESIGN: Review of medical
records. SETTING: Tertiary-care university teaching hospital. PATIENTS:
Seventy-two consecutive patients prescribed an inhaled corticosteroid during
hospitalization. INTERVENTION: None. MEASUREMENTS: Patient demographics, inhaled
corticosteroid regimen, respiratory diagnosis, and inhaled corticosteroid
use
before and during hospitalization. RESULTS: The majority of patients (85%)
were
receiving their prescribed corticosteroid inhaler prior to admission.
Beclomethasone dipropionate 250 micrograms/puff was the most commonly prescribed
inhaled corticosteroid formulation accounting for 43% of the total
corticosteroid inhaler orders. COPD was the most common respiratory diagnosis
(43%) associated with inhaled corticosteroid use, followed by asthma (37%),
COPD/asthma (13%), and no diagnosis (7%). During the study period, the
proportion of all hospitalized patients with COPD who also received inhaled
corticosteroid prescriptions (35%) was not significantly different from all
hospitalized patients with asthma who received inhaled corticosteroid
prescriptions (33%). CONCLUSIONS: The rate of inhaled corticosteroid use far
exceeds the rate expected among the general population of patients with COPD.
Educational intervention is needed to encourage compliance with published
guidelines for the management of COPD.
Ann Allergy Asthma Immunol 1997 Jan;78(1):59-63
Albuterol via Turbuhaler versus
albuterol via pressurized metered-dose inhaler
in asthma.
Chapman KR, Friberg K, Balter MS,
Hyland RH, Alexander M, Abboud RT, Peters S,
Jennings BH.
University of Toronto, Canada.
BACKGROUND: Inhaled albuterol is
most commonly self-administered by patients
using a pressurized metered-dose inhaler (pMDI) but patients often have
difficulty using the device. Dry powder devices such as the multi-dose,
inspiratory flow driven inhaler (Turbuhaler) are often better handled by
patients. OBJECTIVE: We sought to compare the efficacy and tolerability of
100
micrograms of albuterol delivered by a multi-dose, inspiratory flow driven
inhaler (Turbuhaler) to a standard dose (200 micrograms) delivered by a pMDI
(Ventolin) in chronic reversible obstructive airways disease. METHOD: In 6
centers, we studied 37 adults [19 men and 18 women, mean age 39 +/- 12 years;
mean baseline forced expiratory volume in one second (FEV1) 72 +/- 13% (%
predicted)] with stable but symptomatic reversible obstructive airways disease
as demonstrated by 15% or greater increase in FEV1 following two puffs (200
micrograms) albuterol by pMDI. The crossover design comprised a 1-week run-in
and two 2-week treatment periods separated by a 1-week washout. At the start
and
end of each treatment period, FEV1 was measured at the clinic. Patients
self-administered albuterol 100 micrograms (2 x 50 micrograms) via Turbuhaler
or
200 micrograms (2 x 100 micrograms) via pMDI in a double-blind fashion four
times daily. Morning and evening peak expiratory flow (PEF) was noted daily.
All
non-study bronchodilators were withheld while open-label albuterol pMDI was
offered for rescue. RESULTS: Of the 37 patients, 30 used inhaled steroids
in
constant doses throughout the study, one used inhaled cromoglycate and six
used
no anti-inflammatory therapy. There was no difference between treatment periods
in morning PEF, diurnal fluctuation in PEF, increase in PEF following study
drug, baseline FEV1 and FEV1 increase following study drug. Although there
was
no difference in symptom scores between treatments, the use of rescue beta
2-agonist was slightly but significantly higher during the Turbuhaler treatment
period (1.34 versus 1.08 inhalations/ day, P = .04). Compliance with study
drug
was slightly but significantly lower during the Turbuhaler treatment period
(87
versus 95%) such that the total number of beta 2-agonist puffs inhaled
(scheduled plus rescue) was similar between treatments. With regard to adverse
events, both treatments were well tolerated. CONCLUSIONS: These results suggest
that the efficacy and tolerability of albuterol 100 micrograms qid inhaled
via
Turbuhaler is similar to albuterol 200 micrograms qid, inhaled via pMDI in
stable reversible obstructive airways disease.
J Allergy Clin Immunol 1997 Jan;99(1 Pt 1):13-21
A twelve-week comparison of salmeterol
and salbutamol in the treatment of
mild-to-moderate asthma: a Canadian multicenter study.
Boulet LP, Laviolette M, Boucher S, Knight A, Hebert J, Chapman KR.
Centre de Pneumologie, Hopital Laval, Sainte-Foy, Quebec, Canada.
BACKGROUND: A long-acting inhaled
bronchodilator that is both well tolerated and
effective could allow for improved control of both daytime and nighttime
symptoms in patients with asthma who use frequent as-needed short-acting
bronchodilators despite antiinflammatory treatment. OBJECTIVE AND METHODS:
We
compared the efficacy and safety of inhaled salmeterol, 50 micrograms twice
daily, with inhaled salbutamol, 200 micrograms four times daily, delivered
through a metered-dose inhaler for 3 months in a multicenter, randomized,
double-blind, parallel-group study of 228 patients (aged 12 to 76 years) with
mild-to-moderate asthma. RESULTS: A single morning dose of salmeterol produced
improvement in FEV1 that was significantly greater (p < or = 0.012) than
that
produced by two doses of salbutamol (taken 6 hours apart) when patients were
assessed 3 to 6 hours and 10 to 12 hours after the dose. This greater
bronchodilation was present on day 1 of the study and after 4, 8, and 12 weeks
of regular treatment. Over the 12 weeks, compared with salbutamol, salmeterol
treatment was associated with a greater mean improvement in morning peak
expiratory flow (35 L/min vs -3 L/min, p < 0.001), a higher percentage
of days
with no symptoms (29% vs 15%; p = 0.012), and a higher percentage of nights
with
no awakenings (14% vs -1%; p < 0.001). Adverse events were similar for
both
treatments. CONCLUSIONS: In this study salmeterol, 50 micrograms twice daily,
was well tolerated and more effective than salbutamol, 200 micrograms four
times
daily, in improving symptoms and lung function in patients with mild-to-moderate
asthma.
Marked flow-dependence of exhaled
nitric oxide using a new technique to exclude
nasal nitric oxide.
Silkoff PE, McClean PA, Slutsky
AS, Furlott HG, Hoffstein E, Wakita S, Chapman
KR, Szalai JP, Zamel N.
Department of Medicine, the University of Toronto, Ontario, Canada.
Exhaled nitric oxide (NO) may aid
in monitoring pulmonary disease. The
single-breath NO profile (subjects with nose clip) was described as a NO peak
followed by a plateau (NO(PLAT)). Published exhaled NO values vary greatly,
possibly due to contamination with nasal NO and differing respiratory maneuvers.
We developed a technique to measure pulmonary NO, without nasal NO, by having
the subject maintain a positive expiratory pressure (ensuring vellum closure),
and we examined the variation in NO(PLAT) over a range of expiratory flows
(4.2
to 1,550 ml/s). NO(PLAT) values rose almost 35-fold (3.2 +/- 1.4 ppb to 110.5
+/- 54.8 ppb) with decreasing flow, described by NO(PLAT) = 208.6795 x (flow
rate)(-0.5995). However, NO excretion showed an almost 11-fold rise as flow
increased. In summary, we present a simple technique for measuring exhaled
NO
without contamination by nasal NO. There is a marked flow dependence of exhaled
NO concentration and excretion. Exhaled pulmonary NO is best measured at very
low flow rates to amplify the signal and must be related to the expiratory
flow
employed.
Chest 1996 Sep;110(3):595-603
Cardiovascular safety of high doses
of inhaled fenoterol and albuterol in acute
severe asthma.
Newhouse MT, Chapman KR, McCallum
AL, Abboud RT, Bowie DM, Hodder RV, Pare PD,
Mesic-Fuchs H, Molfino NA.
McMaster University, Hamilton, Ontario, Canada.
BACKGROUND: It has been suggested
that overuse of fenoterol metered-dose
inhalers (MDIs) may increase the risk of death from asthma due to cardiac
arrhythmias. Our primary objective was to compare the cardiovascular safety
of
fenoterol and albuterol MDIs when administered in maximal bronchodilating
or
maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency
department (ED) treatment of acute severe asthma. METHODS: Asthmatic patients
presenting to the ED with acute severe asthma (FEV1 less than 50% of predicted)
were enrolled in a multicenter, randomized, double-blind, parallel-group study.
Following baseline measurements, (medical history, physical examination,
determination of serum potassium and serum theophylline levels, oximetry,
12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol,
200 micrograms per puff, or albuterol, 100 micrograms per puff, 1 puff every
30
s via an MDI attached to a holding chamber. Additional doses of inhaled beta
2-agonist were administered by dose titration, 2 puffs every 10 min to a maximal
cumulative dose of 16 puffs of albuterol or fenoterol, side effects were
intolerable to the patient, or an FEV1 plateau (i.e., < 10% improvement
for 2
consecutive doses) occurred. ECG was recorded continuously via Holter monitor,
and respiratory rate, BP, dyspnea (Borg scale), and FEV1 were assessed after
each dose. RESULTS: 128 patients were randomized to receive fenoterol and
129 to
receive albuterol. Overall, fenoterol increased FEV1 160 mL more than albuterol.
The mean (SEM) FEV1 increase from baseline was 0.75 +/- 0.06 L in the fenoterol
group and 0.59 +/- 0.06 L in the albuterol group (p < 0.03). Both beta
2-agonists caused a decrease in serum potassium level that was significantly
greater in the fenoterol (0.23 +/- 0.04 mmol/L) than in the salbutamol (0.06
+/-
0.03 mmol/L) group (p = 0.0002). There was also a greater increase in the
Q-Tc
interval in the fenoterol group, 0.011 +/- 0.003 s compared with 0.003 +/-
0.003
s in the albuterol group (p < 0.05). Differences in hypokalemia and Q-Tc
prolongation associated with fenoterol and albuterol were significantly
different only after 8 puffs of fenoterol had been given. 32 patients exhibited
ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol
group. There were 34 patients with episodes of supraventricular premature
beats,
17 in each group. No episodes of sustained ventricular tachycardia were detected
in either group. CONCLUSIONS: In adequately oxygenated patients, using dose
titration of fenoterol, in a formulation of 200 micrograms per puff by MDI
valved holding chamber and mask, to a total dose of 3,200 micrograms and
salbutamol (100 micrograms per puff) to a total dose of 1,600 micrograms over
90
min, showed cardiovascular safety in acute severe asthma. This was evidenced
by
absence of cardiovascular mortality or clinically significant arrhythmias
in
either group. The 100% greater dose of fenoterol improved FEV1 significantly
more than salbutamol and was associated with a relatively small but
significantly greater prolongation of the Q-Tc interval and decrease in serum
potassium level. This study does not exclude the possibility that adverse
cardiac events could occur with severe hypoxemia.
Clin Exp Immunol 1996 Apr;104(1):144-53
Analysis of the T cell receptor
Vgamma region gene repertoire in bronchoalveolar
lavage (BAL) and peripheral blood of atopic asthmatics and healthy subjects.
Molfino NA, Doherty PJ, Suurmann IL, Yang SX, Kesten S, Chapman KR, Slutsky AS.
Respiratory Division, Department
of Medicine, University of Toronto, Ontario,
Canada.
We analyzed the T cell receptor
(TCR) Vgamma repertoire in BAL and peripheral
blood (PBL) of three mild stable atopic asthmatics and two non-asthmatic
controls. We used the polymerase chain reaction (PCR) to establish the
expression of the four Vgamma families, and to detect oligo or monoclonal
expansion of gammadelta+ T cells, we resolved the PCR projects on denaturing
and
non-denaturing gels to find the extent of junctional diversity arising from
differences in the lengths of the V(D)J junctions. We also subcloned and
sequenced the PCR products to characterize fully the sequence diversity. BAL
T
lymphocytes from two asthmatic patients (treated with inhaled steroids)
expressed only VgammaII and, in one of them, VgammaIIJgamma usage was restricted
to JgammaP and JgammaP1 gene segments, contrasting with the VgammaJgamma
repertoire found in his respective PBL. Analyses in denaturing and
non-denaturing gels showed that the BAL VgammaIIJgammaP and VgammaIIJgammaP1
PCR
products resolved into few bands, suggesting deletions at the juctions due
to
oligoclonal expansion. BAL T lymphocytes from the third asthmatic (not receiving
inhaled steroids) expressed VgammaI, II and III, and the sequences of the
in-frame TCR transcripts from this asthmatic and one healthy volunteer who
expressed a similar BAL VgammaTCR repertoire showed clonal expansion of T
cells
expressing all three Vgamma families. Our analyses showed that much of the
GammaDeltaT cell population found in BAL fluid of humans derives from clonally
expanded T cells.
Chest 1996 Mar;109(3):697-701
Prior diagnosis and treatment of
patients with normal results of methacholine
challenge and unexplained respiratory symptoms.
Joyce DP, Chapman KR, Kesten S.
Asthma Centre of The Toronto Hospital, University of Ontario, Canada.
OBJECTIVE: Previous research indicates
that asthma has been underdiagnosed.
However, we suspect that recent widespread attention to the underdiagnosis
of
asthma has led to an overdiagnosis of asthma in some settings. We therefore
sought to examine prior diagnosis and treatment of patients referred to our
facility and subsequently found to have no objective evidence of variable
airflow limitation. DESIGN: Retrospective chart review. SETTING: Hospital-based
asthma center. PATIENTS: A referred sample of 263 patients in whom a
methacholine challenge (MCC) was conducted after evaluation by our
pulmonologists; complete medical histories were available. MAIN OUTCOME
MEASURES: Prior respiratory diagnoses, duration of treatment with asthma
medications, and diagnosis following assessment by our pulmonologists in 175
patients with a provocative concentration of the substance causing a 20% fall
in
FEV1 (PC20) greater than 8.0 mg/mL and 88 with a PC20 of 8.0 mg/mL or less.
RESULTS: Of those with a PC20 greater than 8 mg/mL, a diagnosis of asthma
or
possible asthma prior to the challenge study was recorded by their primary
care
physician in 129 patients (74%). One hundred sixty of 172 patients (88%) with
a
PC20 greater than 8 mg/mL were diagnosed as not having asthma by our
pulmonologists; 109 of 172 patients (62%) had been previously treated with
asthma medication(s). The mean duration of asthma treatment was 25.9+/- 56.3
months, a
