ASTHMA
(Diagnosis, Diagnostics, Immunodiagnosis,
Immunodiagnostics, Pathogenesis,
Vaccines & Drugs)
ABSTRACTS
1149.
Anonymous. The use of inhaled corticosteroids in adults with asthma. [Review]
[31 refs] Drug & Therapeutics Bulletin. 38(1):5-8, 2000 Jan.
Abstract
Inhaled corticosteroids have now been used for the treatment of
asthma for over 25 years. They have largely replaced oral corticosteroids for
the prevention of asthma symptoms and asthma attacks, and for most patients
they have become the first line of preventive drug therapy. We recently
discussed the role of inhaled corticosteroids in the management of childhood
asthma. Here, we review their place in the management of adults with asthma. A
forthcoming article will review the various types of inhaler now available for
delivering drugs for asthma. [References: 31]
1150.Appleton
S. Smith B. Veale A. Bara A.
Long-acting beta2-agonists for chronic obstructive pulmonary disease. [Review]
[4 refs] Cochrane Database of Systematic Reviews [computer file]. (2):CD001104, 2000.
Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is
characterised by airflow limitation which is only partially reversible. Long
acting beta2-agonists, effective in the management of asthma,are also
recommended for COPD management so it is important to establish whether these
drugs are effective in reducing COPD symptoms in view of the potential side
effect and cost burden. OBJECTIVES: To determine the effectiveness of long
acting beta2-adrenoceptor agonists in improving lung function and quality of
life and reducing dyspnoea in patients with COPD. SEARCH STRATEGY: A search was
carried out using the Cochrane Airways Group register. Bibliographies of
identified RCTs were searched for additional relevant RCTs. Abstract of
identified RCTs were contacted for other published and unpublished studies. In
addition, unpublished studies were also obtained from the pharmaceutical
companies that manufacture long acting beta2-
adrenoceptor agonists. SELECTION CRITERIA: All randomised controlled
trials over four weeks in duration comparing treatment with long-acting
beta2-adrenoceptor agonists (salmeterol and formoterol) with placebo in
patients with stable non-reversible COPD. Outcome measures included forced
expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR),
symptom scores, six minute walk distance, quality of life scores, Borg scores
for dyspnoea and rescue bronchodilator use. DATA COLLECTION AND ANALYSIS: Data
extraction and study quality assessment was performed independently by two
reviewers. Where further or missing data were required, Abstract of
studies were contacted. MAIN RESULTS: Thirty three Abstracts were
identified as potentially relevant. Of these, four randomised controlled trials (RCTs) were included in this review.
Two were parallel group studies of 16
week duration and two were cross-over studies
with four week treatment arms. All four RCTs assessed the efficacy
of salmeterol in COPD. In a 16 week
study of salmeterol 50 mcg and 100 mcg twice daily treatment, a significant
increase in FEV1 was seen in both
treatment groups. The weighted mean difference (WMD) for the increase
in FEV1 for the 50 mcg group was 0.10
litre (95% CI: 0.05;0. 15) and in the
100 mcg group the WMD was 0.12 litre (95% CI: 0.06; 0. 17 ). In the two cross-over studies of four weeks treatment,
salmeterol 50 mcg twice daily treatment
did not show significant increases in FEV1 (WMD = 0.04 litre, 95% CI: -0.06; 0.15). Similarly, morning and
night time PEFR was not significantly
improved with salmeterol treatment. In a 16 week study, disease-specific quality of life, measured
using the St. George's Respiratory
Questionnaire (SGRQ), showed a significant improvement after 50 mcg twice daily, but not after 100 mcg
twice daily. This improvement exceeded
the threshold for a clinically significant change with this questionnaire. General health status, as
measured by the Medical Outcomes Short
Form 36, did not improve in any of the eight components with either salmeterol
dose. No significant difference was demonstrated in the mean change from
baseline in the six minute walk distance (WMD = 1.9 metres, 95% CI:
-15.4;19.3). Breathlessness was reduced in one study in patients receiving
salmeterol 50 mcg twice daily group. Significantly more patients in this group
had Borg scores for breathlessness less than three (a score of three indicating
moderate dyspnoea) compared to the placebo treated group (Peto Odds Ratio =
0.60, 95% CI: 0.40; 0.88). Neither dose of salmeterol influenced the incidence
of COPD exacerbations, (50 mcg: Peto Odds Ratio = 0.74, 95% CI: 0.47, 1.15) and
(100 mcg: Peto Odds Ratio =0.98, 95% CI: 0.64, 1.52). REVIEWER'S CONCLUSIONS:
Treatment of patients with COPD with long acting beta2-agonists produces only
small increases in FEV1. In one study, a dose of salmeterol 50 mcg twice daily
produced a reduction in breathlessness and a clinically significant improvement
in quality of life. (ABSTRACT
TRUNCATED) [References: 4]
1151.
Bingham CO
3rd. Austen KF. Mast-cell responses in
the development of asthma. [Review] [106 refs] Journal of Allergy &
Clinical Immunology. 105(2 Pt
2):S527-34, 2000 Feb.
Abstract
Many cells participate in the pathogenesis of asthmatic
inflammation. The mast cell is localized at the interface of the internal and
external environment within the lung where it may respond to allergens and
other exogenous stimuli. The activation of mast cells leads to the release of
mediators that contribute to the early phase of asthmatic inflammation.
Mast-cell-derived products may also contribute to the late-phase asthmatic response. This review summarizes the
developmental biologic features of the mast cell, its receptor-mediated
activation, and its range of preformed, newly synthesized, and induced
mediators that contribute to asthmatic inflammation. [References: 106]
1152. Bjorksten
B. Unmet needs in the treatment of asthmatic children and adolescents:
2.[Review] [9 refs] Clinical & Experimental Allergy. 30 Suppl 1:73-6, 2000 Jun.
Abstract
The five main unmet needs in the treatment of asthma in children
and adolescents are the treatment of
infants, the treatment of adolescents, the efficacy of medication, the lack of
clinical trials in children and the need for prevention. Asthma is a dynamic
disease that changes over time and there are several patterns of asthma in
children. One of the greatest needs is to identify those children with chronic
asthma where undertreatment is more of a problem than overtreatment. Although
the treatment of asthma in children is the same in principle as adults, there
are several practical difficulties with infants, such as accurately assessing
lung function and administering drugs. Teenage asthma creates a distinct
management problem. Not only is asthma underdiagnosed but acceptance of diagnosis and compliance is
often poor. Existing therapies need to
be used more effectively in adolescents. It is particularly important to
establish a partnership with teenage asthmatics and motivate them to create
their own treatment goals. This requires passing on knowledge. The efficacy of
asthma medication may be different in children than in adults and clinical studies
should be performed to optimize therapy with existing drugs. The only proven
primary preventive measure to prevent wheezing and asthma is to avoid passive
tobacco smoke exposure. Possible intervention strategies include early
intervention with anti-inflammatory therapy, allergen avoidance and vaccine
approaches but more of them have proven efficacious. Although modern asthma
treatment has improved patient quality of life and long-term prognosis, there
is still a need for further improvement. [References: 9]
1153. Blumenthal
MN. Genetics of asthma and allergy. [Review] [23 refs] Allergy & Asthma
Proceedings. 21(1):55-9, 2000 Jan-Feb.
Abstract
Asthma and allergies are complex conditions involving multiple
steps and pathways, which are
influenced by both genetic and environmental factors. The genes involved in
these processes are just being identified. Most likely asthma is a result of
several genes and their interaction with other genes as well as the
environment. Management involves the proper diagnosis, modulating the genetic
and environmental factors involved as well as interfering with the activated
pathways. Using this approach will lead to a more rational method of managing
individuals with allergies and asthma. [References: 23]
1154. Boguniewicz
M. Schneider LC. Milgrom H.
Newell D. Kelly N. Tam P. Izu AE. Jaffe HS. Bucalo LR. Leung DY. Treatment of steroid-dependent
asthma with recombinant interferon-gamma. Clinical & Experimental
Allergy. 23(9):785-90, 1993 Sep.
Abstract
We have recently reported that treatment of patients with severe
atopic dermatitis with recombinant
interferon-gamma (rIFN-gamma) resulted in clinical improvement as well as a
reduction of circulating eosinophils. Since IgE-dependent late phase allergic
reactions and eosinophilic infiltration are thought to play an important role
in the pathogenesis of asthma, we conducted a two centre randomized
double-blind placebo-controlled trial of rIFN-gamma in the treatment of
steroid-dependent asthma. Patients were treated with daily subcutaneous
injections of either 0.05 mg/m2 rIFN-gamma (n = 9) or placebo (n = 11) for 90
days. All patients completed the study without significant drug toxicity noted. Oral prednisone dose, forced
expiratory volume in 1 second (FEV1),
peak expiratory flow rates (PEFR) and circulating eosinophil counts were
monitored throughout the trial. There was no significant difference between the
two treatment groups in per cent reduction from baseline of daily prednisone (P
= 0.51). There was also no significant difference between the two treatment
groups in per cent change from baseline in FEV1 (P = 0.54) or in PEFR (P =
0.75). Total circulating eosinophil counts decreased by 31% in the rIFN-gamma
group and increased by 8.5% in the placebo group (P = 0.09). We conclude that
this treatment regimen was not effective in patients with steroid-dependent
asthma.
1155. Brown
MA. Halonen M. Perinatal events in the
development of asthma. [Review] [74 refs] Current Opinion in Pulmonary
Medicine. 5(1):4-9, 1999 Jan.
Abstract
Many potential factors are likely involved in the pathogenesis of
asthma. These include prenatal, peripartum, and postnatal influences.
Prenatally, genetic endowment, maternal smoking, in utero allergen
sensitization, and alterations in maternal immune function, especially at the
placental level, may increase the risk for asthma and atopy. In the peripartum
period, suspected factors include obstetric practices (eg, the use of
prostaglandins, hormones, and other agents) and prematurity. Postnatally
passive smoke exposure, neonatal or early childhood infections and
breast-feeding are under increasing scrutiny as to their possible role in the
development of asthma. Despite the volumes of work already reported, much more is left to be done to sort out the
complex interrelationships of these and
other as yet unsuspected influences on the development of asthma. [References: 74]
1156. Cantani
A. Specific immunotherapy in children: past and present. [Review] [20 refs]
European Review for Medical & Pharmacological Sciences. 3(2):93-5, 1999 Mar-Apr.
Abstract
Specific immunotherapy (SIT) in children is usually completely
neglected. Pediatric SIT being not an
optional treatment should be administered as soon as possible, also in children
aged 2-3 years, due to the very early asthma and rhinitis onset, contrarily to
a recent publication that continues to stress the danger of anaphylactic
reactions without displaying reliable data. On the other hand drugs represent
only a symptomatic treatment, therefore SIT is the only treatment which can
alter the natural course of respiratory diseases. [References: 20]
1157. Cates
CJ. Jefferson TO. Bara AI.
Rowe BH. Vaccines for preventing influenza in people with asthma.
[Review] [11 refs] Cochrane Database of Systematic Reviews [computer
file]. (2):CD000364, 2000.
Abstract
BACKGROUND: Influenza vaccination is recommended for asthmatic
patients in many countries as observational studies have shown that influenza
infection can be associated with asthma exacerbations, but influenza
vaccination itself has the potential to adversely affect pulmonary function. A
recent overview concluded that there was no clear benefit of influenza
vaccination in patients with asthma but this conclusions was not based on a
systematic search of the literature. OBJECTIVES: Whilst influenza may cause
asthma exacerbations, there is controversy about the use of influenza
vaccinations, since they may precipitate an asthma attack in some people. The
objective of this review was to assess the effects of influenza vaccination in
children and adults with asthma. SEARCH STRATEGY: We searched the Cochrane
Airways Group trials register and checked
reference lists of articles. SELECTION CRITERIA: Randomised trials of
influenza vaccination in children (over two years of age) and adults with
asthma. Studies involving people with chronic obstructive pulmonary disease
were excluded. DATA COLLECTION AND ANALYSIS: Inclusion criteria and assessment
of trial quality were applied by two reviewers independently. Data extraction
was done by two reviewers independently. Study Abstract were contacted
for missing information. MAIN RESULTS: Nine trials were included. Four of these
trials were of high quality. One further article has been included since the
previous version of this review. Inclusion of the new trial has not altered the
conclusions of this review. The
included studies covered a wide diversity of people, settings and types of
influenza vaccination, so data from the different trials were not pooled. In
one trial, no protective effect of influenza vaccination against asthma
exacerbation was demonstrated, but the incidence of influenza was low during
the study period. A higher number of asthma exacerbations following killed
influenza vaccination was found in one trial (risk difference 3 1%, 95%
confidence interval 0.3% to 5.8%). When people with upper respiratory tract
infections were excluded, this difference was no longer significant. A small
trial using recombinant vaccine found no significant difference in asthma
exacerbations between the vaccinated and placebo groups. REVIEWER'S
CONCLUSIONS: There is not enough evidence to assess the benefits and risks of
influenza vaccination for people with asthma. [References: 11]
1158. Chipps
BE. Chipps DR. Approach to the
difficult pediatric asthmatic. [Review] [32 refs] Current Opinion in Pulmonary
Medicine. 5(1):52-7, 1999 Jan.
Abstract
Wheezing in infants and children presents a difficult differential
diagnosis contingent on the presenting symptoms and age of the child. A
determination of the anatomy of the lower airway, combined with allergic,
infectious, and noninfectious irritants, is requisite to a complete evaluation.
The intervention strategies to decrease wheezing and bronchial
hyperresponsiveness may include both nonpharmacologic and pharmacologic
management. The nonpharmacologic management of asthma in children is contingent
on aggressive treatment of dietary protein sensitivity and strict environmental
control. The treatment of bronchial hyperresponsiveness with pharmacologic
intervention in infants and children is
relegated to the optimal use of sodium cromoglycate and inhaled corticosteroid.
[References: 32]
1159. Christman
JW. Sadikot RT. Blackwell TS. The role of nuclear
factor-kappa B in pulmonary diseases. [Review] [45 refs] Chest. 117(5):1482-7, 2000 May.
Abstract
Nuclear factor-kappa B (NF-kappaB) is a family of DNA-binding
protein factors that are required for transcription of most proinflammatory
molecules, including adhesion molecules, enzymes, cytokines, and chemokines.
NF-kappaB activation seems to be a key early event in a variety of cell and
animal model systems developed to elucidate the pathobiology of lung diseases.
The purpose of this short review is to describe what is known about the
molecular biology of NF-kappaB and to review information that implicates
NF-kappaB in the pathogenesis of lung disease, including ARDS, systemic
inflammatory response syndrome, asthma, respiratory viral infections,
occupational and environmental lung disease, and cystic fibrosis. [References:
45]
1160. Clark
CE. Coote JM. Silver DA. Halpin DM.
Asthma after childhood pneumonia: six year follow up study. BMJ. 320(7248):1514-6, 2000 Jun 3.
Abstract
OBJECTIVE: To establish the long term cumulative prevalence of
asthma in children admitted to hospital
with pneumonia and to examine the hypothesis
that some children admitted to hospital with pneumonia may be presenting with undiagnosed asthma. DESIGN: Prospective
study of a cohort of children previously
admitted to hospital with pneumonia, followed up by postal questionnaires to their general
practitioners and the children or their
parents. SETTING: General practices in southwest England. PARTICIPANTS:
78 children admitted to the Royal Devon
and Exeter Hospital between 1989 and
1991 with a diagnosis of pneumonia confirmed on independent review of
x ray films. MAIN OUTCOME MEASURES: Any
diagnosis of asthma, use of any
treatment for asthma, and asthma symptom scores. RESULTS: On the basis
of a 100% response rate from general
practitioners and 86% from patients or
parents, the cumulative prevalence of asthma was 45%. A diagnosis
of asthma was associated with a family
history of asthma (odds ratio 11.23;
95% confidence interval 2.57 to 56.36; P=0.0002). Mean symptom scores
were higher for all children with
asthma (mean score 2.4; chi(2)=14.88; P=0.
0001) and for children with asthma not being treated (mean 1.4; chi(2)=6.2; P=0.01) than for those without
asthma (mean 0.2). CONCLUSIONS: A considerable
proportion of children presenting to a district general hospital with pneumonia
either already have unrecognised asthma or subsequently develop asthma. The
high cumulative prevalence of asthma
suggests that careful follow up of such children is worth while. Asthma
is undertreated in these children; a
structured symptom questionnaire may
help to identify and reduce morbidity due to undertreatment.
1161. Dellaripa
PF. Wechsler ME. Roth ME.
Drazen J. Recurrent panniculitis in a man with asthma receiving
treatment with leukotriene-modifying agents. Mayo Clinic Proceedings. 75(6):643-5, 2000 Jun.
Abstract
Leukotriene-modifying drugs are novel agents introduced recently
to treat asthma. Both 5-lipoxygenase
inhibitors, such as zileuton, and leukotriene
receptor antagonists, such as zafirlukast and montelukast, have
proved effective in the treatment of
asthma. To our knowledge, there have been no
detailed reports regarding dermatologic manifestations of this class
of drugs. This article describes an
unusual case of erythema nodosum in a
46-year-old asthmatic man who received 2 different leukotriene
modifiers.
1162. Dickinson
JA. Meaker M. Searle M. Ratcliffe G.
Screening older patients for obstructive airways disease in a semi-rural practice [see comments].Thorax. 54(6):501-5, 1999 Jun.
Abstract
BACKGROUND: Obstructive airways disease in older patients is
reported to be not only common, but frequently overlooked and untreated by
general practitioners. This study examines the value of screening elderly
patients in a large semi-rural general practice for potentially treatable
asthma and chronic obstructive pulmonary disease (COPD). METHODS: A random
sample of 353 patients aged 60-75 years attended a nurse run screening clinic
for pulmonary function testing, serial peak flow recording, and completion of a
symptom questionnaire. Patients with a low forced expiratory volume in one
second (below the fifth centile of their predicted value) or >15% mean
diurnal variation in peak flow were referred to a doctor's clinic for further
diagnostic assessment and/or to discuss possible treatment where appropriate.
RESULTS: Fifty eight patients (16.4%) had obstructive airways disease, the
prevalence of asthma being 6.5% and that of COPD 9.9%. Of these, 30 had no
previous diagnosis of airways disease and were not on treatment; eight of them
had significant airways reversibility and 10 were current smokers. No newly
diagnosed patients had severe disease as
measured by pulmonary function or quality of life assessment, and
six patients accepted treatment.
CONCLUSION: Few older patients benefited from
a screening programme for obstructive airways disease in a semi-rural general practice.
1163. Fick
RB Jr. Anti-IgE as novel therapy for the treatment of asthma. [Review] [30
refs] Current Opinion in Pulmonary Medicine.
5(1):76-80, 1999 Jan.
Abstract
Immunoglobulin-E (IgE) is believed to be the central effector
antibody reacting to allergen in patients with allergic asthma. Clinical
manifestations of allergic asthma result from the release of chemical mediators
from mast cells and basophils on exposure to allergen. A humanized murine
monoclonal antibody to IgE, rhuMAb-E25, recognizes the specific Fc epsilon3
portion of circulating IgE that binds to the high-affinity IgE receptor, Fc
epsilonRI. In clinical studies, ingle and multiple doses of subcutaneous and
intravenous rhuMAb-E25 have been shown to reproducibly reduce the serum free
IgE concentrations in a dose-dependent manner. Clinical trials conducted in aeroallergen
bronchoprovocation laboratories demonstrated that decreasing circulating IgE
resulted in significant attenuation of the early and late asthmatic responses.
Studies completed in moderate to severe allergic asthmatics have extended the
safety and efficacy of rhuMAb-E25. Significant improvements in asthma symptoms,
meaningful reductions in corticosteroid agents while decreasing reliance on
bronchodilator rescue drugs, decreased asthma exacerbations, and improved
quality of life have been documented. Because of the remarkable protein
engineering and the humanization technology now available, rhuMAb-E25 therapy
has elicited no antibody responses and has been safely administered to atopic
subjects. rhuMAb-E25 as a novel monoclonal antibody, the first to be applied to
lung diseases, holds promise for the
control of many IgE-mediated diseases. [References: 30]
1164. Finkelstein
JA. Barton MB. Donahue JG.
Algatt-Bergstrom P. Markson LE. Platt R.Comparing asthma care for Medicaid
and non-Medicaid children in a health
maintenance organization. Archives of Pediatrics & Adolescent
Medicine. 154(6):563-8, 2000 Jun.
Abstract
OBJECTIVE: To compare ambulatory visit patterns, rates of
medication use, and emergency department and hospital utilization for children
with asthma covered under Medicaid and commercial payers within the same health
maintenance organization (HMO). DESIGN: Retrospective cohort study. SETTING:
Eleven staff-model pediatric departments of an HMO. PATIENTS: A total of 1928
Medicaid and 11007 non-Medicaid children aged 2 to 18 years with at least 1
encounter with a diagnosis of asthma between October 1, 1991, and September 30,
1996. METHODS: We linked patient-level data from the HMO's automated medical
record system for ambulatory encounters, a claims system for emergency
department and hospital care, and an automated pharmacy dispensing database.
Medicaid and non-Medicaid patients were compared for all encounter types and
for prescribing and dispensing of beta-agonist and controller medications
(inhaled corticosteroids and cromolyn sodium). Incidence rate ratios were
calculated from Poisson regression
models to control for age, sex, and, when appropriate, beta-agonist dispensing rate. The number of
refills authorized on each prescription and the fraction of medications
dispensed as refills compared with new prescriptions were compared for Medicaid
and non-Medicaid patients. RESULTS: Medicaid-insured children in the HMO were
1.4 times (95% confidence interval, 1.2-1.5) more likely to receive care in
emergency departments and 1.3 times (95% confidence interval, 1.1-1.5) more
likely to be hospitalized for their asthma compared with non-Medicaid members.
Medicaid and non-Medicaid enrollees had similar yearly rates of nonurgent (1.32
vs 1.17) and urgent (0.38 vs 0.31) ambulatory visits. Beta-agonists were dispensed roughly equally to Medicaid and
non-Medicaid members. Although Medicaid
patients were less likely to have controller
medications dispensed (relative risk, 0.72; 95% confidence interval,
0.69-0.74), they were equally likely to have them prescribed. CONCLUSIONS: Differences in ambulatory contact for
Medicaid members do not explain the higher rates of emergency department visits
and hospitalization in this population. Reasons for lower rates of dispensing
of controller medications should continue to be investigated as one cause of
increased morbidity for low-income children with asthma.
1165. Flaherty
KR. Kazerooni EA. Martinez FJ. Differential diagnosis of
chronic airflow obstruction. [Review] [147 refs] Journal of Asthma. 37(3):201-23, 2000 May.
Abstract
Chronic obstructive pulmonary disease is a syndrome including
illnesses such as asthma, chronic
bronchitis, and emphysema. Although these diseases share a common obstructive
component, their optimal treatment and prognosis differ. This article examines
the salient features of the history, physical exam, pulmonary function tests,
and radiological evaluation which may allow the clinician to differentiate the
various diseases that make up COPD; thus allowing the clinician to better
target the multiple therapeutic modalities available. [References: 147]
1166. Floreani
AA. Rennard SI. The role of cigarette
smoke in the pathogenesis of asthma and as a trigger for acute symptoms.
[Review] [86 refs] Current Opinion in Pulmonary Medicine. 5(1):38-46, 1999 Jan.
Abstract
Although it has been long believed that cigarette smoke is
injurious to the lower respiratory tract, the exact early mechanisms and early
events responsible for this injury remain
unclear. Maternal smoking, particularly in utero, is clearly associated with an
increased risk for the later development of childhood atopy and asthma. Smoking
is known to increase the inflammatory burden of the lower respiratory tract
through a number of related but separate mechanisms. These include the
recruitment of increased numbers of inflammatory cells, alteration in cell
subtypes, enhancement of some cellular functions, and proinflammatory mediator
release. In addition, cigarette smoking in vitro and in animal models appears
to promote neurogenic inflammation, increase oxidative stress and lead to the
elevation of cysteinyl leukotrienes, all of which could potentially lead to an amplification of the
airway inflammation already present in asthmatics. Greater and more consistent
effort must be given to encourage the young asthmatic not to smoke. In
addition, greater effort must be spent on smoking cessation, especially in
pregnant women and young asthmatics. [References: 86]
1167. Foresi
A. Teodoro C. Leone C. Pelucchi A. D'Ippolito R. Chetta A. Olivieri D.
Eosinophil apoptosis in induced sputum from patients with seasonal allergic rhinitis and with asymptomatic and
symptomatic asthma. Annals of Allergy, Asthma, & Immunology. 84(4):411-6, 2000 Apr.
Abstract
BACKGROUND: Eosinophilic inflammation is known to play an
important role in the pathogenesis of allergic diseases. Apoptosis, a form of
programmed cell death, is characterized by morphologic cell changes and leads
to recognition and ingestion by macrophages. Apoptosis could be an important
mechanism controlling the resolution of tissue eosinophilia. OBJECTIVE: This
study was designed to investigate the presence of apoptotic eosinophils in
induced sputum of patients with seasonal allergic rhinitis (SAR), when examined
during natural pollen exposure and of patients with perennial asthma of
different degrees of severity. METHODS: We recruited 11 patients with SAR to
grass pollens, 26 patients with symptomatic asthma (AA), and 18 patients with
symptomatic asthma (SA). The severity of asthma was assessed by clinical
scoring. Sputum was induced following a standard method and differential cell
count was estimated. Eosinophils showing cell shrinkage and nuclear coalescence
were classified as apoptotic. The
number of apoptotic eosinophils was expressed as the percentage of total cells
in sputum and as the proportion of apoptotic eosinophils relative to normal
bilobed eosinophils ("apoptotic ratio"). RESULTS: We found the number
of eosinophils in the SA group was significantly greater than that in the SAR
and the AA groups (P < .001 and P < .0001 respectively). The number of
apoptotic eosinophils in the AA group was significantly lower than that in the
SAR group (P < .001) and in the SA group (P < .0001). The apoptotic ratio
for eosinophils in the SAR group was significantly greater than in the AA group
(P < .05) and in the SA group (P < .05). There was no difference in the
apoptotic ratio between the AA and SA
groups. CONCLUSIONS: This study confirms that apoptotic eosinophils are detectable in induced sputum
of allergic patients. Further, the results of our study suggest that apoptosis
could be an important mechanism in the control of acute eosinophilic inflammation
in patients with SAR exposed to the sensitizing antigens. It appears that the
apoptotic mechanism could be less effective in controlling tissue eosinophilia
in asthmatic patients with chronic eosinophilic inflammation.
1168. Frew
AJ. Chan H. Chan-Yeung M. Lack of role for mononuclear cell-derived histamine
releasing factors in occupational asthma due to western red cedar. Clinical
& Experimental Allergy.
23(10):861-7, 1993 Oct.
Abstract
Occupational asthma due to Western Red Cedar (WRCA) is attributed
to sensitization to plicatic acid (PA),
but does not appear to be dependent on PA-specific IgE antibodies. Exposure to
PA induces histamine release in vivo and in vitro, so if IgE is not important,
other mechanisms of histamine release must presumably operate in WRCA. To
explore the possible role of histamine-releasing factors in WRCA, peripheral
blood mononuclear cells were obtained and cultured with PA, PA-albumin
conjugate plicatic acid-human serum albumin (PA-HSA), grass pollen or
Concanavalin A using a standard histamine releasing factor (HRF) generation
protocol. Supernatants were dialysed to remove endogenous histamine and then
assayed for histamine releasing activity using human basophils as targets and a
Con A-induced bulk supernatant as an internal HRF standard. In contrast to some
previous reports, spontaneous HRF release from the peripheral blood mononuclear
cells (PBMC) of WRCA patients (n=9) and atopic asthmatic subjects (n=5) was not elevated compared
with the non-asthmatic controls (n=11; five atopic and six non-atopic). Both PA
and PA-HSA induced the production of small amounts of HRF by PBMC of WRCA
patients, but a similar degree of HRF generation was also observed in PBMC from
the atopic asthmatic, atopic nonasthmatic, and non-atopic subjects. In
contrast, grass pollen induced the production of HRF by PBMC from the subjects
with positive skin tests to grass pollen but not by PBMC of non-atopic
subjects, confirming that our methods and assay were capable of detecting
antigen-specific HRF production. Since neither PA nor PA-HSA induced
significantly elevated HRF production from PBMC of WRCA patients, it seems
unlikely that PA-induced HRFs play a substantial role in the pathogenesis of
WRCA.
1169. Garty
BZ. Monselise Y. Nitzan M.Soluble CD14 in children with
status asthmaticus. Israel Medical Association Journal: IMAJ. 2(2):104-7, 2000 Feb.
Abstract
BACKGROUND: Inflammation is a major component in the pathogenesis
of asthma. CD14 is an endotoxin (lipopolysaccharide) receptor, and is expressed
mainly on monocytes and macrophages. Binding of LPS to CD14 activates the
monocyte or macrophage and causes the release of different cytokines. The
soluble form of CD14 is present in serum, and its concentration increases in
several clinical conditions, including infections, autoimmune disorders,
allergic disorders, and lung diseases. The possible role of CD14/sCD14 in
asthma has been investigated in a few adult patients only. OBJECTIVES: To
measure serum concentrations of sCD14 in children with status asthmaticus.
METHODS: We compared serum
concentration of sCD14 in 10 children with status asthmaticus
measured within 24 hours of admission
and after recovery from the acute episode. RESULTS: Levels of sCD14 were
significantly higher during acute asthma attacks than at recovery. CONCLUSIONS:
The elevated serum levels of sCD14 during status asthmaticus may be the result
of the activation of monocytes, macrophages or other cells. The influence of
medications on serum sCD14 cannot be ruled out. The possible use of sCD14 as a
marker of lung inflammation in asthma warrants further investigation.
1170. Gibson
PG. Henry RL. Coughlan JL. Gastro-oesophageal reflux treatment for asthma in
adults and children. [Review] [10 refs] Cochrane Database of Systematic Reviews
[computer file]. (2):CD001496, 2000.
Abstract
BACKGROUND: Asthma and gastro-oesophageal reflux are both common
medical conditions and often co-exist.
Studies have shown conflicting results
concerning the effects of lower oesophageal acidification as a trigger
of asthma. Furthermore, asthma might
precipitate gastro-oesophageal reflux.
Thus a temporal association between the two does not establish that gastro-oesophageal reflux triggers asthma.
Randomised trials of a number of
treatments for gastro-oesophageal reflux in asthma have been conducted, with conflicting results. OBJECTIVES: The
objective of this review was to
evaluate the effectiveness of treatments for gastro-oesophageal reflux
in terms of their benefit on asthma.
SEARCH STRATEGY: The Cochrane Airways
Group trials register, review articles and reference lists of
articles were searched. SELECTION
CRITERIA: Randomised controlled trials of
treatment for oesophageal reflux in adults and children with a diagnosis
of both asthma and gastro-oesophageal reflux. DATA COLLECTION AND ANALYSIS:
Trial quality and data extraction were carried out by two independent reviewers. Abstract were
contacted for confirmation or more
data. MAIN RESULTS: Nine trials met the inclusion criteria.
Interventions included proton pump
inhibitors (n=3), histamine antagonists (n=5), surgery (n=1) and conservative
management (n=1). Treatment duration ranged from 1 week to 6 months. A temporal
association between asthma and gastro-oesophageal reflux was investigated in 4
trials and found to be present in a proportion of participants in these trials.
Anti-reflux treatment did not consistently improve lung function, asthma
symptoms, nocturnal asthma or the use of asthma medications. REVIEWER'S
CONCLUSIONS: In asthmatic subjects with
gastro-oesophageal reflux, (but who were not recruited specifically on the
basis of reflux-associated respiratory symptoms), there was no overall
improvement in asthma following treatment for gastro-oesophageal reflux.
Subgroups of patients may gain benefit, but it appears difficult to predict
responders. [References: 10]
1171. Grasemann
H. Yandava CN. Storm van's Gravesande K. Deykin A.
Pillari A. Ma J. Sonna LA.
Lilly C. Stampfer MJ. Israel E.
Silverman EK. Drazen JM. A
neuronal NO synthase (NOS1) gene polymorphism is associated with asthma. Biochemical & Biophysical Research
Communications. 272(2):391-4, 2000
Jun 7.
Abstract
Recent family-based studies have revealed evidence for linkage of
chromosomal region 12q to both asthma and high total serum immunoglobulin E
(IgE) levels. Among the candidate genes in this region for asthma is neuronal
nitric oxide synthase (NOS1). We sought a genetic association between a
polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control
design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1
gene were significantly different between 490 asthmatic and 350 control
subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49
[95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the
asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm
these results we genotyped an
additional 1131 control subjects and found the frequencies of alleles 17
and 18 to be virtually identical to those ascertained in our original control
subjects. Total serum IgE was not associated with any allele of the
polymorphism. These findings provide support, from case-control association
analysis, for NOS1 as a candidate gene for asthma. Copyright 2000 Academic Press.
1172.
Gupta G. Anti-leukotrienes in asthma: yet to arrive. [Review] [35 refs] Indian
Journal of Pediatrics. 67(2):113-7,
2000 Feb.
Abstract
Inflammation plays a predominant role in the pathogenesis of
asthma. The leukotrienes (LTs) exert
their actions by binding to and activating various receptors. Leukotrienes B4,
C4, D4, and E4 have been shown experimentally to play a role in inflammatory
mechanisms, producing the pathologic changes seen in asthma. Antileukotrienes
represent a new class of anti-asthma drugs with anti-inflammatory role. In
asthma management, LT modifiers from the groups of 5 lipoxygenase inhibitor and
Cys LT1 receptor antagonists are found useful. LAs are of main use in mild to
moderate chronic asthma. Their usefulness is also observed in allergic rhinitis
and even in severe chronic cases of asthma which are resistant to steroids. In
chronic asthma they are required to be used for prolonged periods with other
agents viz. inhaled steroids and beta 2 agonists. These agents are essentially
safe. Except for Montelukast, which can be used in children above six years of
age, the paediatric use of other agents is yet to be established. LAs are gradually becoming available in increasing
number of countries. In India, we have
to presumably wait for sometime before these
drugs reach the market. The cost of LAs is reasonably high. Thus,
India awaits arrival of LAs, may be for
good, as more concrete information from
various trials will permit us to practice more evidence based
medicine. [References: 35]
1173. Hancox
RJ. Cowan JO. Flannery EM. Herbison
GP. McLachlan CR. Wong CS.
Taylor DR. Randomised trial of an inhaled beta2 agonist, inhaled
corticosteroid and their combination in the treatment of asthma. Thorax. 54(6):482-7, 1999 Jun.
Abstract
BACKGROUND: Although many asthmatic patients are treated with a
combination of beta2 agonist and corticosteroid inhalers, the clinical effects
of combining the drugs are unknown. Studies on the early asthmatic response to
allergen suggest that beta2 agonists may reduce the benefit of inhaled
corticosteroids. A study of the effects of combining the drugs on asthma
control was undertaken. METHODS: Sixty one subjects with mild to moderate
asthma were randomised to a double blind crossover comparison of inhaled
budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four
times daily), combined treatment, and placebo. Each treatment was given for six
weeks following a four week washout period. Ipratropium was used for symptom
relief. Treatments were ranked from worst (1) to best (4) based on need for
oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function
and bronchial hyperresponsiveness were measured before and after each
treatment. RESULTS: Evaluable data for all four treatments were obtained from
47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline =
2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was
ranked significantly better than any other treatment (p<0.01). Mean (95% CI)
morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min
higher, respectively, during combined treatment than during budesonide, and 27
(17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma
symptoms tended to be least frequent during combined treatment but were not
significantly different from budesonide
alone. There was no significant difference between combined treatment and budesonide alone for lung
function and bronchial hyperresponsiveness.
CONCLUSIONS: In this group of mild to moderate
asthmatic subjects the combination of beta2 agonist and
corticosteroid gave better asthma
control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the
beneficial effect of inhaled
corticosteroid.
1174. Hancox
RJ. Stevens DA. Adcock IM.
Barnes PJ. Taylor DR. Effects of
inhaled beta agonist and corticosteroid treatment on nuclear transcription
factors in bronchial mucosa in asthma. Thorax.
54(6):488-92, 1999 Jun.
Abstract
BACKGROUND: Inhaled corticosteroids and beta agonists are the most
commonly used treatments in asthma and are often used together. Recent evidence suggests that many of the
anti-inflammatory actions of
corticosteroids are mediated by cross-talk between the activated glucocorticoid receptor (GR) and other
transcription factors such as the
pro-inflammatory nuclear factor kappa B (NFkappaB). Beta agonists
can activate the transcription factor
cAMP response element binding protein (CREB). A mutual inhibition between GR
and CREB occurs in vitro which raises
the possibility of a negative interaction between corticosteroid and beta agonist drugs. A study was
undertaken to determine whether these
interactions occur during treatment with beta2 agonists and
corticosteroids in asthma. METHODS: Seven subjects who were participating in a
randomised, placebo controlled, crossover study of six weeks treatment with
inhaled budesonide (400 microg twice daily), terbutaline (1 mg four times
daily), and combined treatment were recruited. Biopsy samples of the bronchial
mucosa were obtained after each treatment and analysed for the DNA binding
activity of GR, CREB, and NFkappaB. RESULTS: Budesonide increased GR activity
(p<0.05) and decreased NFkappaB activity(p<0.05). No treatment
combination altered CREB activity and terbutaline had no significant effects on any transcription factor.
CONCLUSIONS: Inhaled corticosteroids have significant effects on GR and
NFkappaB activity in bronchial mucosa. A negative interaction between inhaled
corticosteroids and beta agonists was not found.
1175. Hauk
PJ. Hamid QA. Chrousos GP. Leung DY.
Induction of corticosteroid insensitivity in human PBMCs by microbial
superantigens. Journal of Allergy & Clinical Immunology. 105(4):782-7, 2000 Apr.
Abstract
BACKGROUND: Microbial superantigens have been described to
contribute to the pathogenesis of chronic inflammatory diseases often
complicated by insensitivity to
glucocorticoid therapy. In bronchial asthma glucocorticoid insensitivity has
been associated with increased expression of glucocorticoid receptor beta, an
endogenous inhibitor of the classic glucocorticoid receptor alpha. OBJECTIVE:
To study a potential mechanism by which superantigens could contribute to poor
disease control, we examined their capacity to alter steroid sensitivity and
expression of glucocorticoid receptor beta. METHODS: The capacity of
dexamethasone to inhibit stimulation of PBMCs from 7 healthy subjects with the
prototypic superantigens, staphylococcal enterotoxin (SE) B, toxic shock
syndrome toxin (TSST)-1 and SEE, versus PHA, was tested. The expression of
glucocorticoid receptor beta in normal PBMCs after stimulation with SEB, versus
PHA, was assessed by immunocytochemistry. RESULTS: Dexamethasone 10(-6) mol/L
caused a 99% inhibition of PHA-induced PBMC proliferation but only a 19%
inhibition of the SEB-induced, 26% inhibition of the TSST-1, and 29% inhibition
of the SEE-induced PBMC proliferation (P <.01 for all superantigens versus
PHA) demonstrating that superantigens can induce steroid insensitivity. Stimulation of normal PBMCs with SEB
induced a significant increase of glucocorticoid receptor beta compared with
PHA and unstimulated cells (P <.01).
CONCLUSION: We have demonstrated the capacity
of microbial superantigens to induce glucocorticoid insensitivity,
which should be considered in the
diagnosis and treatment of patients with superantigen-triggered diseases. These
data suggest that superantigens may contribute to glucocorticoid insensitivity
through induction of glucocorticoid
receptor beta.
1176. Helms
PJ. Corticosteroid-sparing options in the treatment of childhood asthma.
[Review] [75 refs] Drugs. 59 Suppl
1:15-22; discussion 43-5, 2000.
Abstract
During the last 30 years, a significant rise in wheezing illness
has occurred in the child population. Despite its high prevalence there is no
clear definition of the disease, which includes a heterogeneous group of
syndromes ranging from transient wheezing in infancy to atopic asthma with
persistence into adult life. Molecular advances and further epidemiological
information from well characterised individuals and their families are likely
to clarify the different subtypes of wheezing illness and inform therapeutic options.
With the recognition that chronic airway inflammation is a feature of
persistent disease, at least in adults, there has been a trend towards the
early introduction of anti-inflammatory treatment and particularly inhaled
corticosteroids (ICS). However, the natural resolution of much wheezing
illness, particularly in young children
and in children with viral-induced episodes, suggests that newly presenting children should remain on
symptomatic therapy alone while the
severity of the disease is being assessed. Although ICS have become
a cornerstone of management of chronic
persistent disease, their ability to
protect against exacerbations in young and mildly affected children
is questionable. Alongside concerns
about long term use of ICS and possible
systemic adverse effects, there remains a need for alternative
approaches to the control of the disease in children. Extrapolation of the
findings of large multicentre adult studies into childhood, particularly for
doubling the doses of ICS and long-acting beta2-agonists, may be unsound. Other
approaches include the early introduction of inhaled cromones, use of second
generation antihistamines, low dose theophyllines and, more recently,
leukotriene modifiers. As the majority of preschool children will become
asymptomatic by mid-childhood, there is an urgent need to identify those in
whom chronic airway inflammation is developing, as it is in this group that
early introduction of ICS may be of maximum benefit. In the remainder, other
approaches, including use of corticosteroid-sparing longacting P2-agonists and
leukotriene modifying drugs, may be more appropriate. Safe and effective oral
preparations such as leukotriene modifying drugs are likely to establish a
significant role in the management of
symptoms in children of all ages and with all types of asthma and wheezing illness. [References:
75]
1177. Henderson
CE. Ownby DR. Trumble A. DerSimonian
R. Kellner LH. Predicting asthma
severity from allergic sensitivity to cockroaches in pregnant inner city women.
Journal of Reproductive Medicine.
45(4):341-4, 2000 Apr.
Abstract
OBJECTIVE: To measure and compare cockroach (CR)-specific
immunoglobin E (IgE) in sera from pregnant women with mild, moderate and severe
asthma. STUDY DESIGN: CR IgE levels were measured in stored sera collected
during the Collaborative Perinatal Project. Three matched groups of 93 women
were formed: group I (mild), history of asthma but no acute exacerbation; group
II (moderate), acute asthma exacerbation; group III (severe), required
hospitalization for a diagnosis of status asthmaticus. ANOVA was used to
compare the three means. RESULTS: Mean CR IgE paralleled prenatal asthma
severity. Mean values were 6.50, 13.12 and 28.99 kU/L for groups I, II and III,
respectively (P = .06). High allergen sensitivity, defined as CR IgE > 60
kU/L, was identified in 8 of the 93 study samples. The prevalence of high
allergen sensitivity increased as clinical asthma became more severe. Sixty-two
percent (5/8) of the high allergen sensitivity occurred in group III.
CONCLUSION: There appears to be a positive correlation between sensitivity to
CR allergens and asthma severity during pregnancy, and these findings support
further evaluation of CR allergen sensitivity as a predictor of asthma severity
in pregnancy.
1178.
Hirst SJ. Airway smooth muscle as a target in asthma. [Review] [15 refs] Clinical & Experimental Allergy. 30 Suppl 1:54-9, 2000 Jun.
Abstract
Traditionally, the contractile properties of airway smooth muscle
have been regarded as its sole contribution to the pathogenesis of asthma.
However, our understanding of the role that this structural cell plays in
asthma is changing. Airway smooth muscle can undergo hyperplasia and/or
hypertrophy leading to structural changes in the airway wall which contribute
to the development of persistent airway obstruction and increased non-specific
airway hyperresponsiveness in chronic severe asthma. Many studies in vitro have
characterized airway smooth muscle proliferation induced by various pro-inflammatory
mediators, growth factors and components of the extracellular matrix, but the
mediator(s) responsible for the observed increase in airway wall smooth muscle
content in vivo remain to be determined. In addition to geometric obstruction
by increased airway wall thickening, proliferating airway smooth muscle cells
undergo phenotypic modulation from a contractile to synthetic-proliferative
state where additional functions of airway smooth muscle such as
cytokine/chemokine and extracellular matrix secretion may become more apparent.
This may be especially relevant in the diseased airway where the content of
airway smooth muscle as a fraction of the total cells present in the airway
wall is already increased. Airway smooth muscle cells may also interact by
direct contact with immunocytes such as T lymphocytes through expression of
cell adhesion molecules with the result that myocyte DNA synthesis is induced.
As additional functions of airway smooth muscle are described, a more
contemporary view is emerging that airway smooth cells may adopt an
immuno-effector role in chronic asthma by proliferating, secreting cytokines,
expressing adhesion molecules and by
interacting with various inflammatory cells. This may involve changes in the
phenotypic status of airway smooth muscle, and as a result, these cells may
play an active role in perpetuating and
orchestrating airway inflammation in the remodelled airway. An important
phase for future airway smooth muscle research will be to determine the extent
that these putative mechanisms exist in vivo in the pathogenesis of chronic
severe asthma. [References: 15]
1179. Holgate
ST. The role of mast cells and basophils in inflammation. [Review] [27 refs]
Clinical & Experimental Allergy. 30
Suppl 1:28-32, 2000 Jun.
Abstract
Mast cells are positioned in the asthmatic airways so that they
are able to respond to the inhaled environment. During active disease, the
cells are primed to secrete an array of preformed and newly generated
inflammatory mediators including histamine, neutral proteases and heparin
sulphate, prostaglandins and cysteinyl leukotrienes as well as an array of
cytokines and chemokines that are involved in leucocyte recruitment and
activation. These cells are a potent source of mediators in both allergen- and
exercise-induced asthma and possibly in asthma provoked by other stimuli such
as adenosine and inhaled air pollutants. The important role played by mast
cells in maintaining airway dysfunction in asthma is underpinned by the
efficacy of mediator inhibitors, such as those interfering with the release or
action of the leukotrienes, agents that inhibit mast cell activation such as
sodium cromoglycate and the recently
studied E-20 humanized monoclonal antibody that binds to and removes
IgE. The recent discovery of novel inhibitory pathways involving inhibitory
motifs (ITIMS) on critical cell surface signalling molecules has opened up new
possibilities for preventing mast cell activation. Future research will focus
on more effective ways for inhibiting the mast cell's contribution to asthma
and understanding what role this unique cell has in the pathogenesis of airway
wall remodelling. [References: 27]
1180. Irvin
CG. Interaction between the growing lung and asthma: role of early intervention. [Review] [34 refs] Journal of
Allergy & Clinical Immunology.
105(2 Pt 2):S540-6, 2000 Feb.
Abstract
Asthma is a syndrome where an imbalance exists between the forces
that maintain airway patency and the forces that act to narrow, or close,
airways. The child with asthma is a particular problem because of the rapid
growth of the lung during growth that leaves it vulnerable. There is some
evidence that asthma leads to impaired lung function in children because those
children with untreated asthma show a loss of lung growth velocity. For unclear
reasons, asthma is more frequent in boys. What drugs to use to treat childhood
asthma is uncertain. Data show that glucocorticoids prevent the structure of
the lung from fully developing. In children, the rationale for early intervention
seems clear, but the exact means and criteria for initiation of the
intervention are uncertain. Finally, childhood asthma raises fundamental issues
and questions that are unique to the child with asthma and presents unique and
many unresolved treatment dilemmas. [References: 34]
1181. Jang
AS. Choi IS. Park CS. Immunohistochemically stained activated eosinophils in
sputum in patients with asthma. Respiration.
67(2):183-8, 2000.
Abstract
BACKGROUND: Eosinophils play an important role in asthmatic airway inflammation. Monoclonal antibody EG2 has
been considered to identify activated
eosinophils. OBJECTIVE: The present study was aimed to investigate whether
immunohistochemically stained EG2+ eosinophils in sputum reflect the severity
of asthma. METHODS: Sputum was obtained in 23 asthmatic patients, of whom 13
patients were examined before and after antiasthma treatment including steroid
preparations. We used immunohistochemical staining to detect EG2+ (activation
marker) eosinophils and fluoroimmunoassay to detect eosinophil cationic
protein (ECP). RESULTS: Moderate to
severe asthmatics had a significantly higher
proportion of eosinophils and EG2+ eosinophils and higher levels of
ECP compared to mild asthmatics (40.9
+/- 5.8 vs. 6.4 +/- 1.2%, 35.5 +/- 5.6
vs. 2.7 +/- 1.0%, 1.470.2 +/- 251.5 vs. 210.6 +/- 52.0 microgram/l, respectively; p < 0.01). Significant
increases in proportions of eosinophils, EG2+ eosinophils and ECP in the sputum
from patients with exacerbated asthma were evident. The proportions of
eosinophils, EG2+ eosinophils, and the levels of ECP were reduced following
treatment with antiasthmatic drugs. FEV(1) and FEV(1)/FVC were significantly
correlated with EG2+ eosinophils. CONCLUSION: These findings demonstrate that
EG2+ eosinophils in sputum are closely related to the clinical status in
patients with asthma. Copyright 2000 S. Karger AG, Basel.
1182.
No Abstract
1183. Koshino
T. Teshima S. Fukushima N. Takaishi
T. Hirai K. Miyamoto Y. Arai Y. Sano
Y. Ito K. Morita Y. Identification of basophils by immunohistochemistry in
the airways of post-mortem cases of fatal asthma. Clinical & Experimental
Allergy. 23(11):919-25, 1993 Nov.
Abstract
There is increasing evidence for the role of basophils in the
pathogenesis of bronchial asthma. To examine the presence of basophils in the
airways of patients with fatal asthma by immunohistochemistry, we stained lung
tissues from four post-mortem cases who had died from severe asthmatic attacks
and four controls with a monoclonal antibody raised against tryptase (AA-1) and
anti-IgE. Mast cells and basophils were identified in the bronchioles as AA-1-
and anti-IgE-positive cells, and anti-IgE-positive cells, respectively. Airway
mast cells were found beneath the basement membrane, near blood vessels in the
submucosa, and adjacent to the submucosal glands, and scattered throughout the
muscle bundles. There was a significant
increase of mast cells in the asthma group compared with the control group
(203.5+/-84.6/mm2, mean+/-s.d. vs 37.7+/-8.7/mm2, P<0.05, n=4). In contrast,
basophils were observed in the airway lumen, in the bronchial epithelium and in
the submucosa. The number of basophils in the bronchioles was 81.8+/-55.5/mm2
(n = 4); however, basophils were not found at all in the airways of the control
group. Although eosinophils, B lymphocytes and macrophages bear low affinity
IgE receptors and could react with anti-IgE, the location of these cells in the
close sections did not correspond closely with basophils. The presence of
basophils in lung tissues obtained from fatal asthma patients supports the view
that basophils play a role in the pathogenesis of bronchial asthma.
1184. Kumar
RK. Bronchial asthma: recent advances. [Review] [19 refs] Indian Journal of
Pediatrics. 67(4):293-8, 2000 Apr.
Abstract
Asthma is one of the oldest diseases about which there are lots of
myths in most parts of the world. The exact cause of this global disease still
eludes scientists. The recent knowledge about the pathogenesis of the disease,
led to rationalise the medications into different groups. Parallel to the
increasing incidence of this disease, is the knowledge about the trigger
factors and steps to reduce their exposure. Childhood asthma is a lot different
from asthma in adults, as many children won't be able to use the inhalers like
adults and most children will not be able to do lung function tests until they
are about 6 years of age. Unlike for any other diseases, research has helped
year after year in developing new strategies for management of asthma. Starting
from definition of the disease to inventing newer medications, management of
asthma has revolutionised in the last
few years and has also accounted for the decreasing mortality in many
countries. This article tries to give an overview of bronchial asthma in
children including recent advances and possible future developments.
[References: 19]
1185. Laitinen
LA. Altraja A. Karjalainen EM. Laitinen A. Early interventions in asthma with inhaled
corticosteroids. [Review] [15 refs] Journal of Allergy & Clinical
Immunology. 105(2 Pt 2):S582-5, 2000
Feb.
Abstract
We have earlier shown epithelial damage in the airway mucosa in
patients with asthma. Later other structural changes have been recognized in
asthma, such as deposition of collagen and tenascin in the subepithelial
basement membrane and changes in the laminin subchain composition. These
processes are modified by an inflammatory process in the airways. Both the
United States National Institutes of Health and the British Thoracic Society guidelines
on the management of asthma emphasize the need for early use of
anti-inflammatory drugs. Many clinical studies that used airway biopsy
specimens have shown a decrease in airway inflammatory cell numbers after
inhaled corticosteroid therapy. However, there is very little information on
the effects of asthma medication on the structural components of the airways.
Both the synthesis and degradation of many
extracellular matrix components may be affected by the disease process
and the drugs resulting in altered remodeling and gene expression in the
airways. Because there are only a few studies that try to identify early
changes in asthma, it is not known whether the anti-inflammatory treatment of
asthma proposed by the guidelines is started early enough. [References: 15]
1186. Leung
DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. [Review] [148 refs] Journal of
Allergy & Clinical Immunology.
105(5):860-76, 2000 May.
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that
frequently predates the development of allergic rhinitis or asthma. It is an
important skin condition with significant costs and morbidity to patients and
their families; the disease affects more than 10% of children. Recent studies
have demonstrated the complex interrelationship of genetic, environmental, skin
barrier, pharmacologic, psychologic, and immunologic factors that contribute to
the development and severity of AD. The current review will examine the
cellular and molecular mechanisms that contribute to AD as well as the
immunologic triggers involved in its pathogenesis. These insights provide new
opportunities for therapeutic intervention in this common skin condition.
[References: 148]
1187. Lodha
R. Bagga A. Traditional Indian systems
of medicine. [Review] [52 refs] Annals
of the Academy of Medicine, Singapore.
29(1):37-41, 2000 Jan.
Abstract
INTRODUCTION: A number of traditional systems of medicine exist in
India of which Ayurveda is the most popular. Despite being in use for more than
3000 years, few properly designed trials have scientifically examined the
clinical potential of Ayurvedic and other medications. METHODS: We reviewed the
MEDLINE database to identify clinical trials conducted using traditional Indian
medicines. Single case reports were excluded. RESULTS: Ayurvedic preparations
have been successfully used for the treatment of bronchial asthma, ischaemic
heart disease and hyperlipidaemia. Formulations containing curcumin were
reported to reduce inflammation and disability in double-blind clinical trials
on patients with rheumatoid arthritis. A number of products are reported to be
useful in patients with acute viral hepatitis. A multicentric study by the
Indian Council of Medical Research showed that a preparation from Pterocarpus
marsupium was effective in reducing levels of blood glucose and glycosylated
haemoglobin in patients with non-insulin-dependent diabetes mellitus. In
another multicentric trial, patients
with fistula-in-ano were randomised to surgery or application of medicated
seton (Ksharsootra). Surgical treatment led to a faster cure but recurrence
rates were lower with medicated seton. Administration of extract from Bacopa
monnieri, to children with mental retardation, was reported to significantly
improve short-term and long-term memory. CONCLUSIONS: Evidence-based studies on
the efficacy and safety of traditional Indian medicines are limited. The
essential ingredient in most formulations is not precisely defined. High
quality studies are necessary to evaluate and compare the value of traditional Indian drugs to modern medicine.
[References: 52]
1188. Louahed
J. Toda M. Jen J. Hamid Q. Renauld JC.
Levitt RC. Nicolaides NC.
Interleukin-9 upregulates mucus expression in the airways [see comments]. American Journal of Respiratory Cell &
Molecular Biology. 22(6):649-56, 2000
Jun.
Abstract
Interleukin (IL)-9 has recently been shown to play an important
role in allergic disease because its
expression is strongly associated with the
degree of airway responsiveness and the asthmatic-like phenotype. IL-9
is a pleiotropic cytokine that is active on many cell types involved in the
allergic immune response. Mucus hypersecretion is a clinical feature of chronic
airway diseases; however, the mechanisms underlying the induction of mucin are
poorly understood. In this report, we show that IL-9 regulates the expression
of a subset of mucin genes in lung cells both in vivo and in vitro. In vivo,
the constitutive expression of IL-9 in transgenic mice results in elevated MUC2
and MUC5AC gene expression in airway epithelial cells and periodic
acid-Schiff-positive staining
(reflecting mucous glycogenates). Similar results were observed in
C57BL/6J mice after IL-9 intratracheal instillation. In contrast, instillation
of the T helper 1-associated cytokine interferon gamma failed to induce mucin
production. In vitro, our studies showed that IL-9 also induces expression of
MUC2 and MUC5AC in human primary lung cultures and in the human muccoepidermoid
NCI-H292 cell line, indicating a direct effect of IL-9 on inducing mucin
expression in these cells. Altogether, these results suggest that upregulation
of mucin by IL-9 might contribute to the pathogenesis of human inflammatory
airway disorders, such as asthma. These data extend the role of the biologic
processes that IL-9 has on regulating the many clinical features of asthma and
further supports the IL-9 pathway as a key mediator of the asthmatic response.
1189. Matkar
NM. Rupwate RU. Desai NK.
Kamat SR. Comparative study of platelet histamine and serotonin with
their corresponding plasma oxidases in asthmatics with normals. Journal of the
Association of Physicians of India.
47(9):878-82, 1999 Sep.
Abstract
OBJECTIVE: Asthma is well controllable but non-curable disease.
Exact pathophysiology involved is
unresolved till today. Role of allergic
hypersensitivity reaction in asthmatic on-set is well established.
Present work is an effort to elucidate
some basic points of unresolved pathophysiology of asthma taking platelets as
marker. MATERIAL AND METHODS: A group of 52 normal human subjects in the age
group of 20-60 years were studied for platelet histamine and serotonin levels
and also for their plasma metabolising enzymes diamine oxidase (DAO) and monoamine
oxidase (MAO). The data was collected for 79 asthmatic patients at different
stages of asthma and accordingly were studied as four different groups of
seventy nine asthmatics those were on regular treatment and were comfortable
with drugs and were free from symptomatic attack formed gr. I; these (79)
patients were followed-up during their symptomatic phase (gr. II) and same (79)
patients immediately after their recovery from symptomatic stage studied as gr.
III members. All the 79 asthmatic patients fall in gr. I, II and III in a
serial manner i.e. all (n = 79) in each group. A separate group of thirty seven
patients with known history of asthma but were symptom free and also off drugs
for last 2-4 years formed gr. IV. RESULTS: Results showed mean platelet count
in asthmatics at all four stages were in the normal range but were slightly low
in comparison with normals. Both the enzymatic levels (DAO and MAO) in gr. I,
II and III were significantly higher than normals but were same in the case of
gr. IV patients. Low levels of platelet biogenic amines were observed in asthmatics (gr. I to gr. IV)
than normals. CONCLUSIONS: Thus, study parameters showed significant difference
in asthmatics and normals. Findings of the study have been utilized to
understand unanswered hypersensitivity shown by the asthmatics over normal
individuals (non-asthmatics).
1190. Mellins
RB. Evans D. Clark N. Zimmerman
B. Wiesemann S. Developing and
communicating a long-term treatment plan for asthma [see comments]. [Review]
[15 refs] American Family Physician.
61(8):2419-28, 2433-4, 2000 Apr 15.
Abstract
The treatment of asthma, according to current guidelines, requires
complex treatment regimens that change as clinical conditions improve or
deteriorate. We have developed a practical way to communicate long-term
treatment plans in chart form in the primary care setting that is easy for
patients to follow and use. The chart has been an important element in two
interventions that have resulted in positive changes in health behavior and
health outcomes in children with asthma. The plan provides recommendations for
patients and families to make adjustments in medication based on changes in
symptoms or peak expiratory air flow, or both, that are consistent with the
Asthma Guidelines Expert Panel Report 2, 1997. The plan also indicates when the
number and dosage of drugs should be
increased or decreased and when emergency care should be sought, consistent with the Asthma Guidelines. By
placing considerable control in the
family's hands and by clearly delineating the conditions under which medicines
can be reduced or discontinued, the physician provides incentives for families
to adhere to the long-term treatment plan for asthma. [References: 15]
1191.
Niimi A. Matsumoto H. Serum measurement
of eosinophil cationic protein in the management of asthma. [Review] [63 refs]
Current Opinion in Pulmonary Medicine.
5(2):111-7, 1999 Mar.
Abstract
Asthma is a disease characterized by chronic eosinophilic
inflammation of the airways. Serum eosinophil cationic protein (ECP) has been
increasingly used as a noninvasive inflammatory marker in asthma. The serum ECP
level seems to reflect, although indirectly, the intensity of ongoing
eosinophilic inflammation of the airways and respond sensitively to intervention,
whereas it is unlikely to be useful for establishing the diagnosis of asthma in
an individual patient. Monitoring of serum ECP could be of utility in the
long-term follow-up of asthmatic patients. However, further longitudinal
studies are required to establish the role of serum ECP measurement in the
treatment modulation in asthma. [References: 63]
1192. Nocker
RE. Out TA. Weller FR. de Riemer
MJ. Jansen HM. van der Zee
JS. Induced sputum and bronchoalveolar lavage as tools for evaluating
the effects of inhaled corticosteroids
in patients with asthma. Journal of Laboratory & Clinical Medicine. 136(1):39-49, 2000 Jul.
Abstract
Changes in airway inflammation can be studied with bronchoalveolar
lavage, but the widespread use of this procedure is limited by its
invasiveness. The aim of this study was to evaluate the usefulness of induced
sputum as a non-invasive alternative to bronchoalveolar lavage for studying
changes in airway inflammation in patients with asthma. Thirty patients were treated
for 12 weeks with an inhaled corticosteroid (fluticasone propionate (FP), 250
microg twice daily) or a short-acting beta-agonist (salbutamol (Sb), 400 microg
twice daily) in a double-blind, double-dummy, randomized parallel group study.
Sputum induction with hypertonic saline solution was performed twice before
treatment and after 4, 8, 10, and 11 weeks of treatment. Bronchoalveolar lavage
fluid divided into two pools (first 60 mL portion as bronchoalveolar
lavage/bronchial wash (BAL/BW) and subsequent 80 mL as bronchoalveoalar lavage
(BAL)) was obtained before and after 12 weeks of treatment. Changes in cell
differentials and plasma-protein leakage (alpha2-macroglobulin, albumin, and
their ratio (relative coefficient of
excretion, RCE)) were analyzed in induced sputum and were compared with changes
in BAL/BW and BAL. During treatment with FP, the PC20histamine (interpolated
concentration of histamine that caused a fall in FEV1 of 20% of the baseline
value) increased (P < .0001), and the percentage of eosinophils (P = .004),
levels of (alpha2-macroglobulin (P = .09) and RCE (P = .007) decreased in
sputum. These changes were different from those in the Sb group (PC20histamine
P< .0001, eosinophils P= .004, alpha2-macroglobulin P= .003, RCE P = .01),
in which alpha2-macroglobulin showed a significant increase (P = .015). Changes
in the percentage of eosinophils and in the levels of alpha2-macroglobulin in
sputum were associated with changes in the PC20histamine (Rs = -0.59, P = .007
and Rs = -0.47, P = .03, respectively). These correlations did not reach
significance in BAL/BW and BAL fluid. The statistical power to detect changes in induced sputum was higher
for the percentage of eosinophils and similar for plasma protein leakage as
compared with analysis of BAL/BW and BAL fluid. We conclude that the analysis
of induced sputum is a useful, non-invasive alternative to bronchoalveolar
lavage for assessing the effects of antiinflammatory drugs in asthma.
1193. O'Byrne
PM. Inman MD. New considerations about
measuring airway hyperresponsiveness. [Review] [71 refs] Journal of
Asthma. 37(4):293-302, 2000 Jun.
Abstract
Measuring airway responsiveness to inhaled bronchoconstrictor
stimuli, such as methacholine or histamine, has become an important tool in the
diagnosis of asthma. This is measured by patients inhaling increasing doses or
concentrations of the bronchoconstrictor stimulus until a given level of
bronchoconstriction is achieved. Inhaled allergens initiate processes that
increase airway inflammation and enhance airway hyperresponsiveness in
asthmatic subjects. Studies using inhaled allergen challenges have provided
insight into how changes in airway
hyperresponsiveness are regulated by induced inflammatory processes.
These changes in airway hyperresponsiveness
(1-2 doubling doses) have been shown to be of much smaller magnitude than those
demonstrated when asthmatics with stable airway hyperresponsiveness are
compared to normals (4-8 doubling doses). These allergen-induced changes would
be of little relevance in subjects with normal airway responsiveness, because
they would not increase the degree of airway responsiveness into the asthmatic
range. They are, however, important in asthmatics who already have airway
hyperresponsiveness because they are similar to changes associated with
worsening asthma control. It is likely that the mechanisms responsible for the
changes in airway hyperresponsiveness following experimental allergen exposure
are similar to those producing transient worsening of control in asthmatics.
Nevertheless, it is unlikely that the mechanisms of the transient
allergen-induced airway hyperresponsiveness will explain the underlying
mechanisms of the persistent airway hyperresponsiveness in asthmatic patients
when compared with normal individuals. [References: 71]
1194. Oddy
WH. Breastfeeding and asthma in children: findings from a West Australian study. Breastfeeding Review. 8(1):5-11, 2000 Mar.
Abstract
The primary aim was to determine whether there was an inverse
association between the duration of
exclusive breastfeeding and the development of
traits associated with asthma in children at age six years. A
prospective cohort study of children
from Western Australia was enrolled prior to birth and followed to age six. Two
thousand, nine hundred and seventy-nine children were recruited through
antenatal clinics at the major tertiary obstetric hospital in Perth.
Unconditional logistic regression was used to model the association between
duration of exclusive breastfeeding and outcomes related to asthma or atopy at
age six allowing for a number of important confounders. These included gender,
gestational age, smoking in pregnancy and early child care. After adjustment
for confounders, the introduction of milk other than breastmilk before four
months of age was a significant (p < 0.05) risk factor for all
asthma-related outcomes in six-year-old children: (i) doctor diagnosed asthma
odds ratio :OR: = 1.25 (95% CI
1.02-1.54); (ii) wheeze three or more times since the age of one year OR 1.42
(1.15-1.76); (iii) wheeze in the last twelve months OR 1.28 (1.02-1.76); (iv)
sleep disturbance due to wheeze within the last twelve months OR 1.41
(1.04-1.90); (v) age at doctor diagnosis (hazard ratio :HR: 1.22 :1.03-1.43:);
(vi) age at first wheeze (HR 1.36 :1.17-1.59:) and; (vii) positive reaction to
common aeroallergens OR 1.27 (1.01-1.59). There is a substantial reduction in
risk of childhood asthma as assessed at age six years, if exclusive
breastfeeding is continued for at least the first four months of life. These
findings are important for our understanding of the aetiology of and for the
potential prevention of asthma in children.
1195. Oh
JW. Lee HB. Yum MK. Kim CR. Kang JO.
Park IK. ECP level in asopharyngeal secretions and serum from children
with respiratory virus infections and asthmatic children. Allergy & Asthma
Proceedings. 21(2):97-100, 2000
Mar-Apr.
Abstract
Infection with respiratory virus has been shown to exacerbate
asthma in humans. However, the role of a respiratory virus in the pathogenesis
of chronic asthma and/or wheezing in young children has not been clearly
defined. It has also been debated whether virus-induced wheezing in young
children is one entity and allergic asthma another, or whether they are
different expressions of the same disease. The present study was done to
compare ECP concentrations in nasopharyngeal secretions and serum from 32
nonasthmatic wheezing children with viral infections (RSV in 15 children;
influenza B virus in 17 children detected by immunofluorescence antibody
technique), 8 asthmatic children without viral infections, and 13 normal
children as the controls to understand the role of eosinophil inflammation. The
geometric mean of ECP in nasopharyngeal secretions was significantly higher in
asthmatic children than in children with virus-induced wheezing (p < 0.05).
ECP levels of nasopharyngeal secretions from children with the virus-induced
wheezing were significantly greater than those of the controls. However, there
were no significant differences in ECP levels in serum among subjects.
1196. Orenstein
SR. Shalaby TM. Di Lorenzo C. Putnam PE. Sigurdsson L.
Kocoshis SA. The spectrum of pediatric eosinophilic esophagitis beyond infancy:
a clinical series of 30 children.
American Journal of Gastroenterology.
95(6):1422-30, 2000 Jun.
Abstract
OBJECTIVES: Eosinophilic esophagitis, previously confused with
esophageal inflammation due to
gastroesophageal reflux, has recently begun to be distinguished from it. We undertook this analysis of our large
series of children with the condition
to clarify its spectrum: its presenting symptoms; its relation to allergy,
respiratory disease, and reflux; its endoscopic and histological findings; and
its diagnosis and therapy. METHODS: We analyzed the details of our clinical
series of 30 children with eosinophilic esophagitis, defining it as > or =5
eosinophils per high power field in the distal esophageal epithelium.
Retrospective chart review was supplemented by prospective, blinded, duplicate
quantitative evaluation of histology specimens, and by telephone contact with
some families to clarify subsequent course. Presentation and analysis of the
series as a whole is preceded by a case illustrating a typical presentation with dysphagia and recurrent
esophageal food impactions. RESULTS: Presenting symptoms encompass vomiting,
pain, and dysphagia (some with impactions or strictures). Allergy, particularly
food allergy, is an associated finding in most patients, and many have
concomitant asthma or other chronic respiratory disease. A subtle granularity
with furrows or rings is newly identified as the endoscopic herald of
histological eosinophilic esophagitis. Histological characteristics include
peripapillary or juxtaluminal eosinophil clustering in certain cases.
Association with eosinophilic gastroenteritis occurs, but is not common.
Differentiation from gastroesophageal reflux disease is approached by analyzing
eosinophil density and response to therapeutic trials. Therapy encompasses
dietary elimination and anti-inflammatory pharmacotherapy. CONCLUSION:
Awareness of the spectrum of eosinophilic esophagitis should promote optimal
diagnosis and treatment of this elusive entity, both in children and in adults.
1197. Osann
KE. Lowery JT. Schell MJ. Small cell lung cancer in women:
risk associated with smoking, prior respiratory disease, and occupation. Lung
Cancer. 28(1):1-10, 2000 Apr.
Abstract
Small cell carcinoma of the lung (SCLC) occurs most frequently in
heavy smokers, yet exhibits a lesser
predominance among men than other smoking-associated lung cancers. Incidence
rates have increased more rapidly in women than men and at a faster rate among
women than other cell types. To investigate the importance of smoking and other
risk factors, a case-control study of SCLC in women was conducted. A total of
98 women with primary SCLC and 204 healthy controls, identified by random-digit
dialing and frequency matched for age, completed telephone interviews. Data
collected include demographics, medical history, family cancer history,
residence history, and lifetime smoking habits. Odds ratios (ORs) and 95%
confidence intervals (95% CI) were calculated using logistic regression
analysis. Risk for small cell carcinoma in women is strongly associated with current use of cigarettes.
Ninety-seven of 98 cases had smoked cigarettes; 79% of cases were current
smokers and 20% were former smokers at the time of diagnosis compared to 13%
current and 34% former smokers among controls. The ORs associated with smoking
are 108.7 (95% CI 14.8-801) for ever-use of cigarettes, 278.9 (95% CI
37.0-2102) for current smoking, and 31.5 (95% CI 4. 1-241) for former smoking.
Risk increases steeply with pack-years of smoking and decreases with duration
of smoking cessation. After adjusting for age, education, and lifetime smoking
history, medical history of physician-diagnosed respiratory disease including
chronic bronchitis, emphysema, pneumonia, tuberculosis, asthma, and hay fever
is not associated with a significant increase in lung cancer risk. Employment
in blue collar, service, or other high risk occupations is associated with a
two to three-fold non-significant increase in risk for small cell carcinoma
after adjusting for smoking.
1198.
Plotnick LH. Ducharme FM. Combined inhaled anticholinergic
agents and beta-2-agonists for initial treatment of acute asthma in children.
[Review] [11 refs] Cochrane Database of
Systematic Reviews [computer file].
(2):CD000060, 2000.
Abstract
BACKGROUND: Anti-cholinergic agents and beta2-agonist drugs are both bronchodilators used to reverse acute
bronchospasm in children with asthma.
These drugs have different modes of action, so may have complementary or
additive effects. OBJECTIVES: The objective of this review was to assess the
effects of adding inhaled anti-cholinergics to beta2-agonists in acute
paediatric asthma. SEARCH STRATEGY: We searched Medline (1966 to 1996), Embase
(1980 to 1995), Cinahl (1982 to 1995) and reference lists of studies. We also
contacted drug manufacturers and researchers. SELECTION CRITERIA: Randomised
trials comparing the combination of inhaled anti-cholinergics and
beta2-agonists with beta2-agonists alone in children aged 18 months to 17 years
with acute asthma. DATA COLLECTION AND
ANALYSIS: Assessments of trial quality and data extraction were done by two
reviewers independently. MAIN RESULTS: Ten trials involving a total of 836
children were included. Most trials were of high quality. When only one dose of
anti-cholinergic inhalation was added to beta2-agonist therapy, there was an
improvement in forced expiratory volume in one second after 60 minutes with
combination therapy (weighted mean difference 16.1%, 95% confidence interval
5.5 to 26. 7% reduction). There was no reduction in hospital admission (odds
ratio 0.80, 95% confidence interval 0.35 to 1.82, using a random effects
model). For multiple doses in children with severe asthma, there was a
reduction in forced expiratory volume in 1 second (weighted mean difference
9.8% predicted, 95% confidence interval 6. 5 to 13.1% predicted). There may
also be a reduction in hospital admission (odds ratio 0.62, 95% confidence
interval 0.38 to 0.99). Eleven children would need to be given multiple doses
of anti-cholinergics in combination with beta2-agonists to avoid one hospital
admission compared to children given beta2-agonists alone. REVIEWER'S CONCLUSIONS: In children with
acute asthma, the addition of multiple doses of anti-cholinergics to inhaled
beta2-agonists appears to improve lung function modestly and may decrease
hospital admission. There is no associated increase in adverse effects. Single
doses of anti-cholinergics may improve lung function in children with severe
asthma, but do not appear to reduce hospital admissions. [References: 11]
1199. Quaratino
D. Romano A. Di Fonso M. Papa G. Perrone MR.
D'Ambrosio FP. Venuti A.
Tolerability of meloxicam in patients with histories of adverse reactions to
nonsteroidal anti-inflammatory drugs. Annals of Allergy, Asthma, &
Immunology. 84(6):613-7, 2000 Jun.
Abstract
BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory
drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria
or asthma. The need to identify an alternative drug that is safe and reliable
is a common problem in clinical practice. OBJECTIVE: To assess the tolerability
of meloxicam, a new NSAID that selectively inhibits the inducible isoform of
cyclooxygenase, in a group of NSAID-sensitive patients. PATIENTS AND METHODS:
We studied 177 patients who had suffered adverse reactions to one or more
NSAIDs. Cutaneous reactions were reported by 83.1% of the subjects (urticaria
in 55, angioedema in 52, urticaria/angioedema in 39, and maculopapular rash in
1), respiratory symptoms by 3.9%, both cutaneous and respiratory symptoms by
9%, Stevens-Johnson's syndrome by 2.3%,
and anaphylactoid reactions by 1.7%. All subjects underwent a single-blind,
placebo-controlled oral challenge with divided therapeutic doses of meloxicam
(1.9 mg + 5.6 mg 1 hour later = cumulative dose 7.5 mg). RESULTS: Positive
reactions were observed in only two cases (1.1%), both manifested exclusively
by cutaneous symptoms
(urticaria/angioedema in one case and maculopapular rash/facial edema in
the second). CONCLUSION: Meloxicam seems to be well tolerated by NSAID-sensitive
subjects whose reactions are manifested by urticaria/angioedema. Additional
study is needed for a more complete assessment of its tolerability in patients
with aspirin-induced asthma and other severe manifestations of NSAID
sensitivity.
1200. Quirce
S. Gala G. Perez-Camo I.
Sanchez-Fernandez C. Pacheco
A. Losada E.
Irritant-induced asthma: clinical and functional aspects. Journal
of Asthma. 37(3):267-74, 2000 May.
Abstract
We report on three patients who experienced persistent asthma
symptoms after repetitive irritant exposure which took place over a period from
several days to months. Airway inflammation was assessed by induction of sputum
and functional follow-up information was obtained from serial lung function
tests. All patients had bronchial hyperresponsiveness to methacholine at the
time of diagnosis. However, induced sputum samples did not show increased
differential count of eosinophils. Treatment with inhaled corticosteroids was
started in all of the patients and two of them were removed from work. In the
two patients who left the workplace, methacholine inhalation test became
negative when symptoms disappeared, whereas the patient who continued working
had persistent asthma symptoms and a deterioration of bronchial
hyperresponsiveness.
1201. Rajajee
S. Geetha S. Janani S. Sino-bronchial syndrome in children with asthma. Indian
Journal of Pediatrics. 63(4):549-52,
1996 Jul-Aug.
Abstract
Thirty children in the age group of 2 to 12 years were brought
with a history of recurrent non-seasonal moderate to severe wheezy episodes
associated with symptoms of nasal congestion, sneezing and occasional headache.
All of them had maxillary or pan sinusitis with 26 having associated right,
left or bilateral lower lobe pneumonitis or bronchiectasis. Serum
immunoglobulins were normal in 22 and was not done in eight. There was positive
(2 to 4+ above negative control) skin test response to dust and dust mite in 15
of the 22 children tested. Throat swabs/sputum or nasal secretions grew
B-hemolytic streptococcus or streptococcus pneumoniae in twenty-seven. All the
children were put on bactericidal drugs
for 6 to 8 weeks and bronchodilators were used when needed. At the end of 6 to
8 weeks follow-up X-ray of sinuses and chest showed significant clearing of the
lesions which coincided with marked clinical improvement. Sinus X-ray should be
considered in bronchial asthma resistant to medical management since untreated
bacterial sinusitis can be an underlying cause of chronic poorly controlled
asthma.
1202. Rosi
E. Ronchi MC. Grazzini M. Duranti
R. Scano G. Diagnostic accuracy of
sputum outcomes in chronic stable asthma. Clinical & Experimental Allergy.
30(4):577-84, 2000 Apr.
Abstract
BACKGROUND: Asthma with non-remitting airflow obstruction may not
always be differentiated from COPD with airway hyperreactivity. Many attempts
have been made to find useful markers for the distinction between these two
disorders. OBJECTIVE AND METHODS: In order to help the finding of a useful
marker for the diagnosis of asthma in the population of patients with airway
obstruction we analysed the diagnostic accuracy of sputum eosinophils and
sputum ECP in 91 patients with asthma, 15 patients with chronic bronchitis, 32
patients with chronic obstructive pulmonary disease (COPD) and 20 controls
subjects, by performing ROC analysis. RESULTS: Sputum eosinophils were above
the normal range of our laboratory (0-3.7%) in 48 asthma patients and in six
COPD patients, while sputum ECP (normal range < 85 microg/L) was high in 65
asthma patients, in 24 COPD patients and in nine chronic bronchitis patients.
The ROC analysis revealed that sputum eosinophils count (AUC = 0.82) was more
accurate than both sputum ECP levels
(AUC = 0.56) (P < 0.0001) and beta2-reversibility (AUC = 0.53) (P = 0.0001)
in differentiating asthmatic from non-asthmatic subjects (COPD, chronic
bronchitis patients and normal subjects). The diagnostic accuracy of ECP was
similar to that of bronchial reversibility (P = 0.76). When ROC analysis was
performed by including only patients with airway obstruction (36 asthmatics
with airway obstruction and COPD patients), both eosinophil count (AUC = 0.77)
and beta2-reversibility (AUC = 0.66) were more accurate than ECP measurement
(AUC = 0.39) in discriminating asthmatics from COPD patients (P < 0.00001
and P = 0.04, respectively). CONCLUSION: Sputum eosinophils seem to be valid
markers for detecting asthma in a population of patients with airway
obstruction. Moreover, the higher diagnostic accuracy of eosinophils in the
sputum compared to sputum ECP and
bronchial reversibility reinforces the role of cytological analysis of sputum
in the diagnosis of chronic stable bronchial asthma.
1203. Shapiro
G. Lumry W. Wolfe J. Given J. White MV.
Woodring A. Baitinger L. House
K. Prillaman B. Shah T. Combined salmeterol 50 microg and
fluticasone propionate 250 microg in the diskus device for the treatment of
asthma. American Journal of Respiratory
& Critical Care Medicine. 161(2 Pt 1):527-34, 2000 Feb.
Abstract
Three hundred forty-nine patients with asthma previously treated
with medium doses of inhaled corticosteroids during a 2-wk, single-blind,
run-in period were randomized to treatment with salmeterol 50 microg combined
with fluticasone propionate (FP) 250 microg, salmeterol 50 microg, FP 250
microg, or placebo, each given twice daily through a Diskus device for 12 wk.
Mean change in FEV(1) at endpoint was significantly (p </= 0.001) greater
with the salmeterol/FP combination product (0.48 L) than with placebo (-0.11
L), salmeterol (0.05 L), or FP (0.25 L). The combination product significantly
increased the area under the 12-h serial FEV(1) curve relative to baseline over
that with placebo, salmeterol, or FP at Day 1, Week 1, and Week 12 (p </=
0.025). Patients in the combination-product
group had a significantly greater probability of remaining in the study without
being withdrawn because of worsening asthma than did patients in the placebo,
salmeterol, or FP groups (p </= 0.002). The combination product
significantly increased (p < 0. 001) morning PEF at endpoint (53.5 L/min) as
compared with placebo (-14 L/min), salmeterol (-11.6 L/min), or FP (15.2
L/min). The combination product significantly (p </= 0.011) reduced asthma
symptom scores and supplemental albuterol use, and significantly increased the
percentage of nights with no awakenings as compared with placebo, salmeterol,
and FP (p </= 0.016). Combination treatment with salmeterol 50 microg and FP
250 microg given twice daily from the Diskus device provided better asthma control
and greater improvement in pulmonary function than did the individual
agents, and may simplify the management
of asthma in patients who need both classes of drugs for optimal control of
their disease.
1204.
Sharek PJ. Bergman DA. The effect of inhaled steroids
on the linear growth of children with asthma: a meta-analysis. Pediatrics. 106(1):E8, 2000 Jul.
Abstract
OBJECTIVE: To determine whether inhaled steroid therapy causes
delayed linear growth in children with asthma. DATA SOURCES: Medline (1966-1998),
Embase (1980-1998), and Cinahl (1982-1998) databases and bibliographies of
included studies were searched for randomized, controlled trials of inhaled
steroid therapy in children with asthma that evaluated linear growth. STUDY
SELECTION: Studies were included if they met the following criteria: subjects 0
to 18 years of age with the clinical diagnosis of asthma; subjects randomized
to inhaled beclomethasone, budesonide, flunisolide, fluticasone, or
triamcinolone versus a nonsteroidal inhaled control for a minimum of 3 months;
single- or double-blind; and outcome
convertible to linear growth velocity. English- and
non-English-language trials were
included. DATA EXTRACTION: Data were extracted using a priori guidelines. Methodologic quality was assessed
independently by both Abstract. Outcome
was extracted as linear growth velocity. RESULTS: Included trials were
subgrouped by inhaled steroid. The beclomethasone subgroup, with 4 studies and
450 subjects, showed a decrease in linear growth velocity of 1.51 cm/year (95%
confidence interval: 1.15,1.87). The fluticasone subgroup, with 1 study and 183
subjects, showed a decrease in linear growth velocity of.43 cm/year (95%
confidence interval:.01,.85). Sensitivity analysis in the beclomethasone
subgroup, which evaluated study quality, mode of medication delivery, control
medication, and statistical model, showed similar results. CONCLUSIONS: This
meta-analysis suggests that moderate doses of beclomethasone and fluticasone in
children with mild to moderate asthma
cause a decrease in linear growth velocity of 1.51 cm/year and.43 cm/year, respectively. The effects of inhaled
steroids when given for >54 weeks,
or on final adult height, remain unknown.
1205. Short
JA. Barr CA. Palmer CD. Goddard
JM. Stack CG. Primhak RA. Use of diclofenac in children with asthma.
Anaesthesia. 55(4):334-7, 2000 Apr.
Abstract
This study investigated the effect of diclofenac on the lung
function of 70 children aged 6-15 years with a diagnosis of asthma, recruited
from a hospital respiratory clinic. Peak flow and a forced expiratory
flow-volume loop were measured and the patients were then given 1-1.5 mg.kg-1
effervescent diclofenac orally. Spirometry was repeated at 10, 20 and 30 min, a
15% decrease in results being considered a significant reduction in lung
function. No patient demonstrated a consistent reduction in lung function of
> 15% during the study and there were no reports of wheezing or increased
bronchodilator use after completion of the spirometry. In conclusion, we
studied a group of genuine asthmatics and found no clinically significant
incidence of bronchospasm with the use of a single therapeutic dose of
diclofenac.
1206. Somu
N. Gowrishankar NC. Subramaniam L. Vijayasekaran D. Muhajir
BM. Balachandran A. Childhood
asthma--advances in pathogenesis [see comments]. [Review] [34 refs] Indian Journal of Pediatrics. 63(1):25-36, 1996 Jan-Feb.
Abstract
Increase in morbidity and mortality of asthmatics in the world is
a cause of concern. Many researchers have described various aspects of
etiopathogenesis which has thrown light on the better understanding of asthma.
Our experience with nearly 3 lakhs of asthmatic children, over a period of
twenty-five years and our studies in Asthma clinic of ICH & HC, Madras generated
new ideas to propose a hypothesis on etiopathogenesis of asthma. "Asthma
is a disease caused by a specific infective agent in a genetically predisposed
individual resulting in altered cellular response initially leading to
hyperactive bronchial tree which on exposure to various aggravating factors
manifest clinically as recurrent cough, dyspnoea and wheeze". Category of
wheezers who manifest asthma is also discussed. [References: 34]
1207. Tanaka
H. Miyazaki N. Oashi K.
Tanaka S. Ohmichi M. Abe S. Sputum matrix metalloproteinase-9:
tissue inhibitor of metalloproteinase-1 ratio in acute asthma. Journal of
Allergy & Clinical Immunology.
105(5):900-5, 2000 May.
Abstract
BACKGROUND: The ratio of matrix metalloproteinase-9 (MMP-9) and
its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) may be a marker
of the balance between airway tissue destruction and repair. TIMP-1 may
potentially contribute to the pathogenesis of increased submucosal
extracellular matrix deposition in asthma. OBJECTIVE: Our purpose was to assess
the variation in sputum MMP-9 and TIMP-1 during acute asthma. METHODS: We
evaluated the MMP-9 and TIMP-1 balance in sputa of 16 asthmatic patients
admitted with spontaneous exacerbation, conducting measurement before (day 1)
and after methylprednisolone infusion therapy (days 2, 3, 5, and 7), and on
remission days. RESULTS: Peak expiratory
flow and eosinophilic cationic protein levels were significantly (P
<.05) improved within 7 days in all
patients. Sputum MMP-9 levels on day 2
tended to be lower than on day 1, but not significantly. Zymography
revealed that the main enzyme was identified immunologically as MMP-9, and
gelatinase activity on day 1 had a tendency to decrease for the following 7
days. The TIMP-1 levels gradually increased until day 5, were significantly (P
<.05) high on day 5, and decreased on day 7. The MMP-9/TIMP-1 molar ratios
were significantly (P <.05) decreased on days 2, 3, 5, and 7 compared with
day 1. Sputum levels of MMP-9 and TIMP-1 and the MMP-9/TIMP-1 molar ratios on
day 1 were significantly higher (P <.02) than those on remission days. CONCLUSIONS: An imbalance between MMP-9
and TIMP-1 was present in acute asthma, with an excess of MMP-9 resulting in a
high ratio of MMP-9/TIMP-1 before treatment, and over time with
glucocorticosteroid the TIMP-1 levels rose, dropping the ratio of MMP-9/TIMP-1.
It was suggested that overproduction of MMP-9 and TIMP-1 after asthma
exacerbation might contribute significantly to airway tissue remodeling and
that TIMP-1 production in acute asthma might not be suppressed by
glucocorticosteroid.
1208. Thien
F. Leukotriene antagonists. Do they offer new hope for asthmatics?. [Review]
[20 refs] Australian Family Physician.
29(6):547-51, 2000 Jun.
Abstract
BACKGROUND: Leukotrienes are potent chemical mediators important
in allergic inflammation. Leukotriene receptor antagonists are a new class of
oral asthma drugs which target and block the action of these mediators.
OBJECTIVE: To review the action of leukotrienes and the clinical effects of
leukotriene receptor antagonists in asthma. DISCUSSION: Leukotrienes mediate
bronchospasm, airway oedema, mucus hypersecretion and increased airway
reactivity. Leukotriene receptor antagonist drugs have a mild short and long
term bronchodilator effect, with evidence of an anti inflammatory effect. The
clinical benefits include improved symptoms, reduced rescue bronchodilator
requirements, and reduced inhaled steroid requirements. Their oral formulation
may provide improved adherence compared to inhaled medication. Clinical studies
suggest they may be less efficacious than inhaled steroids or long acting beta
2 agonists in improving lung function and symptom control, but there was a
heterogeneity in response to all classes of asthma drugs. Hence, currently, the
only way to judge effectiveness is a
therapeutic trial for 4-6 weeks. Although they are unlikely to replace
currently available asthma medication, they are likely to be useful adjuncts to
treatment. [References: 20]
1209. Tsai
JJ. Shen HD. Chua KY. Purification of group 2 Dermatophagoides pteronyssinus
allergen and prevalence of its specific IgE in asthmatics. International Archives of Allergy &
Immunology. 121(3):205-10, 2000 Mar.
Abstract
Group 2 allergens are a major cause of sensitization in patients
allergic to house dust mites. This study was performed to determine the
prevalence of hypersensitivity to group 2 allergens (Der p 2) of
Dermatophagoides pteronyssinus (Dp) in
asthmatic patients in Taiwan. To facilitate the analysis of Der p 2-specific
IgE, we raised a panel of monoclonal antibodies (MoAbs) to Der p 2 antigens.
Purified Der p 2 was obtained after MoAb affinity column purification. There
were 82 asthmatic patients (41 adults and 41 children) with hypersensitivity to
Dp who were analyzed for hypersensitivity to Der p 2. All of them were both
skin test- and serology test-reactive to Dp. Using purified Der p 2, 87.8%
(72/82) of patients had a skin-test-positive reaction. Six adults (6/41) and 4
children (4/41) had negative skin tests for Der p 2. Ten families (both parents
and children were asthmatics) of the 82 patients were selected for Der p 2 skin testing and Der p 2-specific
IgE determination using immunoblot analysis. Results showed that 90% (18/20) of
patients' skin reactions to Der p 2 and serum contained specific IgE to Der p
2. Because 87.8% (85.4% of adults and 90.2% of children) of the asthmatic
patients with Dp hypersensitivity were allergic to Der p 2, its role in the
pathogenesis of asthma in Taiwan appears to be important. Purified Der p 2
allergens can be further used for allergen skin testing and immunotherapy.
Copyright 2000 S. Karger AG, Basel
1210. van
Grunsven PM. van Schayck CP. van Deuveren M. van Herwaarden CL.
Akkermans RP. van Weel C.
Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or
chronic obstructive pulmonary disease (COPD): results of the Detection,
Intervention, and Monitoring Program of
COPD and Asthma (DIMCA) Study. Journal of Asthma. 37(3):225-34, 2000 May.
Abstract
In a prospective study, we investigated the long-term compliance
to fluticasone propionate (FP) by dry powder inhalation (Rotadisk) in subjects
with early signs of asthma and chronic obstructive pulmonary disease (COPD)
without an established diagnosis. Subjects were selected from a large screening
program on early stages of asthma and COPD (Detection, Intervention, and
Monitoring Program of COPD and Asthma [DIMCA] program) in the general practice.
Forty-eight adult subjects with "early signs of COPD" (slightly
increased forced expiratory volume in 1 sec [FEV1] decline of >0.04L/year)
and 29 adult subjects with "early signs
of asthma" (signs of bronchial hyperresponsiveness or
reversibility) participated in a
randomized placebo-controlled trial with FP (Flixotide 500 microg daily) versus placebo with a
duration of 2 years or 1 year,
respectively. Compliance was measured by counting Rotadisks returned.
By means of a questionnaire,
participants were asked about perceived effects and/or side effects of the trial drug. The mean overall
individual compliance rates of 72%
(range 7%-102%) in the early COPD trial and 71% (range 8%-99%) in the early
asthma trial were maintained throughout the study. Perceived effectiveness (12%
of the participants) or side effects (30% of the participants) of the trial
drug were not related to compliance. The willingness of patients to use the
trial drug in daily practice if efficacy would be proved was statistically
significantly related to compliance during the trial (p = 0.017). It was
concluded that the compliance rates found were relatively high in patients with
symptoms of mild asthma or COPD without
an established diagnosis. Conviction of the importance of treatment influenced
compliance more positively than
perceived (side) effects. These results again emphasize the importance
of patient education in establishing
early treatment with inhaled
corticosteroids.
1211. van
Schayck CP. van Der Heijden FM. van Den Boom G. Tirimanna PR. van
Herwaarden CL. Underdiagnosis of asthma: is the doctor or the patient to blame?
The DIMCA project. Thorax. 55(7):562-5, 2000 Jul.
Abstract
BACKGROUND: It is important to diagnose asthma at an early stage
as early treatment may improve the prognosis in the long term. However,
many patients do not present at an
early stage of the condition so the physician may have difficulty with the
diagnosis. A study was therefore undertaken to compare the proportion of
patients who underpresented their respiratory symptoms with the proportion of
underdiagnosed cases of asthma by the general practitioner (GP). A secondary
aim was to investigate whether bad perception of dyspnoea by the patient was a
determining factor in the underpresentation of asthma symptoms to the GP.
METHODS: A random sample of 1155 adult subjects from the general population in
the eastern part of the Netherlands was screened for respiratory symptoms and
lung function and the results were compared with the numbers of asthma related
consultations registered in the medical files of the GP. In subjects with
reduced lung function the ability to perceive dyspnoea was investigated during
a histamine provocation test in subjects who did and did not report their
symptoms to their GP. RESULTS: Of the random sample of 1155 subjects 86 (7%)
had objective airflow obstruction (forced expiratory volume in one second
(FEV(1)) below the reference value corrected for age, length, and sex minus 1.64SD on two occasions) and had
symptoms suggestive of asthma. Of these 86 subjects only 29 (34%) consulted the
GP, which indicates underpresentation
by 66% of patients. Of all subjects with objective airflow obstruction who
presented to their GP with respiratory symptoms, 23 (79%) were recorded in the
medical files as having asthma, indicating underdiagnosis by the GP in 21% of
cases. Of the subjects with objective airflow obstruction who visited the GP
with respiratory symptoms 6% had bad perception of dyspnoea compared with 26%
of those who did not present to the GP in spite of airflow obstruction (chi(2)
= 3.02, p = 0.08). CONCLUSIONS: Underpresentation to GPs of respiratory
symptoms by asthmatic patients contributes significantly to the problem of
underdiagnosis of asthma. Underdiagnosis by the GP seems to play a smaller
role. Furthermore, there are indications that underpresentation of symptoms by
the patient is at least partly explained by a worse perception of dyspnoea.
1212.
No Abstract
1213. Ward
S. Heyneman LE. Flint JD.
Leung AN. Kazerooni EA. Muller NL. Bronchocentric granulomatosis:
computed tomographic findings in five patients. Clinical Radiology.
55(4):296-300, 2000 Apr.
Abstract
AIM: The aim of this study was to assess the CT manifestations
of bronchocentric granulomatosis.
SUBJECTS AND METHODS: The CT results of five patients with bronchocentric
granulomatosis were retrospectively analysed. The patients ranged from 20 to 72
years of age and included three men and two women. The diagnosis of
bronchocentric granulomatosis was made at lobectomy (n = 2), open lung biopsy
(n = 2), and transbronchial biopsy (n = 1). Only one of the five patients had
asthma. RESULTS: The main findings consisted of a spiculated mass lesion (n =
3) or lobar consolidation with associated mild volume loss (n = 2). One of the
two patients with consolidation had extensive mucoid impaction. The
abnormalities involved predominantly an upper lobe in four patients and a lower lobe in one patient. In the four
resected specimens, the macroscopic
pathological appearance was consolidation (n = 2) and mass lesion (n =
2). Microscopically, the typical
histology of airway-centred necrotizing
granulomata was present in all cases. Aspergillus hyphae were
identified in two cases. Nocardia sp.
was cultured from the biopsy specimen in one case. CONCLUSION: The CT
manifestations of bronchocentric granulomatosis consist of a focal mass or
lobar consolidation with atelectasis. These reflect the presence of granuloma
formation with or without associated
bronchial obstruction.
1214.
Weissman DN. Lewis DM. Is specific antibody determination
diagnostic for asthma attributable to low-molecular-weight agents?. [Review]
[44 refs] Occupational Medicine. 15(2):385-98,
2000 Apr-Jun.
Abstract
It is important to understand a medical testis performance
characteristics, so that it can be used appropriately. Performance
characteristics of tests for antibodies specific to low-molecular-weight (LMW)
agents in predicting asthma caused by these agents differ in the study
population. In general, currently published data supporting the use of tests to
detect specific IgE and IgG to LMW agents in the diagnosis of occupational
asthma is limited and inconclusive. However, a few general statements can be
made. The most promising results have been achieved for agents such as acid
anhydrides and platinum salts, where specific IgE responses appear to play a
significant pathogenic role in causing
occupational asthma. Results have been less promising for agents such as isocyanates and plicatic acid, for which
antibody responses do not appear to underlie the development of asthma in most
individuals. In the case of
isocyanates, determination of antigen-specific IgG might have some
utility as a biomarker of exposure. [References: 44]
1215.
Wood-Baker R. Walters EH. Corticosteroids for acute
exacerbations of chronic obstructive pulmonary disease. [Review] [7 refs]
Cochrane Database of Systematic Reviews [computer file]. (2):CD001288, 2000.
Abstract
BACKGROUND: Acute exacerbations occur quite commonly in patients
with chronic obstructive pulmonary disease (COPD). Corticosteroid drugs, either
parenteral or oral, are used commonly in this setting. OBJECTIVES: To determine
the effect of corticosteroids, administered either parenterally or orally, on
the outcome in patients with acute exacerbations of COPD. SEARCH STRATEGY: An
initial search was carried out using the Cochrane Airways Group COPD register
with additional studies sought in the bibliographies of randomised controlled
trials and review articles. Abstract of identified randomised controlled trials
were contacted for other published and
unpublished studies. SELECTION CRITERIA: Randomised controlled trials comparing corticosteroids, administered either
parenterally or orally, with appropriate placebo. Other interventions were
standardised e.g. bronchodilators, antibiotics. Studies of acute asthma were
excluded. DATA COLLECTION AND ANALYSIS: Data was extracted by one reviewer and
sent to Abstract for verification. All trials were combined for analysis where
possible. MAIN RESULTS: We identified 7 studies that fulfilled the inclusion
criteria. Outcomes were varied and few were common to all studies. The most
commonly reported outcome, the FEV1 between 6 - 72 hours after treatment,
showed no significant difference between corticosteroid and placebo treatment.
Treatment failure (defined as re-attendance in the emergency department, need
for oral steroids or hospitalisation)
and quality of life did show a statistically significant benefit for corticosteroid treatment, but
the number of studies reporting these
outcomes was small and there was significant heterogeneity between them
REVIEWER'S CONCLUSIONS: Treatment with oral or parenteral corticosteroids in
outpatients may decrease the number of patients requiring further treatment or
hospitalisation, but otherwise it has no significant effect on the outcome of
acute exacerbations of chronic obstructive airways disease. Further research is
required to determine the place of corticosteroid treatment in acute exacerbations
of chronic obstructive airways disease. [References: 7]
1216. Wu
W. Samoszuk MK. Comhair SA.
Thomassen MJ. Farver CF. Dweik RA. Kavuru MS. Erzurum SC.
Hazen SL. Eosinophils generate brominating oxidants in allergen-induced
asthma [see comments]. Journal of Clinical Investigation. 105(10):1455-63, 2000
May.
Abstract
Eosinophils promote tissue injury and contribute to the
pathogenesis of allergen-triggered
diseases like asthma, but the chemical basis of damage to eosinophil targets is
unknown. We now demonstrate that eosinophil activation in vivo results in
oxidative damage of proteins through bromination of tyrosine residues, a
heretofore unrecognized pathway for covalent modification of biologic targets
in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine
serves as a specific "molecular fingerprint" for proteins modified
through the eosinophil peroxidase-H(2)O(2) system in the presence of plasma
levels of halides. We applied a localized allergen challenge to model the
effects of eosinophils and brominating oxidants in human lung injury.
Endobronchial biopsy specimens from allergen-challenged lung segments of
asthmatic, but not healthy control, subjects demonstrated significant
enrichments in eosinophils and eosinophil peroxidase. Baseline levels of
3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic
asthmatic individuals were modestly but not statistically significantly
elevated over those in control
subjects. After exposure to segmental allergen challenge, lung segments of
asthmatics, but not healthy control subjects, exhibited a >10-fold increase
in BAL 3-bromotyrosine content, but only two- to threefold increases in
3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived
myeloperoxidase. These results identify reactive brominating species produced
by eosinophils as a distinct class of oxidants formed in vivo. They also reveal
eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory
tissue injury in humans.
1560. Allakhverdi
Z. Lamkhioued B. Olivenstein R. Hamid Q. Renzi PM. CD8
depletion-induced late airway response is characterized by eosinophilia,
increased eotaxin, and decreased IFN-gamma expression in rats. American Journal
of Respiratory & Critical Care Medicine.
162(3 Pt 1):1123-31, 2000 Sep.
Abstract
There is an emerging body
of knowledge defining the role of CD8(+) cells in the pathogenesis of allergic
asthma. We have previously demonstrated in sensitized Sprague-Dawley (SD) rats
that depletion of CD8(+) cells caused an increase in the late airway response
(LAR) and cellular infiltration after antigen challenge. To better delineate
the mechanism of CD8(+) cell involvement in the development of the LAR and
airway inflammation, we investigated the pattern of chemokine and cytokine
production after antigen challenge. SD rats were sensitized to ovalbumin (OA)
and subsequently treated with anti-CD8 (OX-8) monoclonal antibody (mAb) for the
depletion of CD8(+) cells or with control mouse anti-rat IgG(1) mAb as a
control procedure. After OA challenge, CD8- depleted SD rats developed an
increased LAR when compared with control rats (area under the curve: 16.65 +/-
6.6 in CD8- depleted rats versus 5.39 +/- 2.0 in control animals; p < 0.05).
Compared with the control animals, the increase in the LAR was accompanied by a
significantly increased eosinophilic infiltration of the airways and was
associated with increased eotaxin expression (both messenger RNA [mRNA] and protein)
in the CD8-depleted group. There were no
differences between the groups in RANTES or monocyte chemoattractant
protein-1 (MCP-1) expression. In addition, we found a significantly lower
interferon gamma (IFN-gamma) mRNA expression in the CD8-depleted rats, without
any effects on interleukin (IL)-4 and IL-5 mRNA expression when measured either
by semiquantitative reverse transcriptase/polymerase chain reaction (RT-PCR) or
by in situ hybridization for the number of cells expressing these cytokines. Taken
together, these results suggest that CD8(+) cells from sensitized SD rats
exhibit the functional capacity to suppress the LAR, possibly through downregulation of eotaxin expression and
increased expression of IFN-gamma mRNA.
1561. Azuara
V. Pereira P. Genetic mapping of two
murine loci that influence the development of IL-4-producing Thy-1dull gamma
delta thymocytes. Journal of Immunology.
165(1):42-8, 2000 Jul 1.
Abstract
IL-4-producing gamma
delta cells belong to a novel subset of gamma delta lymphocytes that expresses a very restricted repertoire of TCRs.
To gain a deeper insight into the
development and in vivo functions of these cells, we have analyzed the genetic
control of their representation in the thymus. Using an intercross between C57BL/6
and DBA/2 mice we found two loci on chromosomes 13 and 17-named LadT1 and
LadT2, respectively-with marked influence in their development. The LadT2 locus
does not appear to be the MHC locus. The region identified on mouse chromosome
13 contains the structural genes for TCR gamma as well as the IL-9 gene, which
has been suggested as a candidate gene influencing the complex pathogenesis of
asthma.
1562.
Bai TR. Cooper J.
Koelmeyer T. Pare PD. Weir TD. The effect of age and duration of
disease on airway structure in fatal asthma. American Journal of Respiratory
& Critical Care Medicine. 162(2 Pt
1):663-9, 2000 Aug.
Abstract
We hypothesized that if
airway remodeling is related to duration of asthma, that when matched for
severity, the airways of older adults should show greater alterations than the
airways of younger adults. Using standard morphometric techniques, we compared
airways with basement membrane perimeters (Pbm) between 2 and 10 mm from young
individuals who died of asthma (n = 14, range 17-23 yr), and older individuals
with fatal asthma (n = 13, range 40-49 yr). Comparisons were also made with
normal airways from age-matched adults. Wall area was increased in old
individuals with fatal asthma compared with young individuals with fatal asthma,
primarily due to greater adventitial area, whereas wall area in young
individuals with fatal asthma was not different from control subjects. Within
muscle bundles the connective tissue matrix was increased around individual
cells in individuals with asthma, unrelated to age. After adjustment for this
change, smooth muscle area in both asthma groups was still greater than in
age-matched control subjects, in old individuals with fatal asthma 4-fold
greater (p = 0.04), and in young individuals with fatal asthma 2-fold greater
(p = 0.03). Airway narrowing was increased in old versus young individuals with
fatal asthma, with both groups more narrowed than control subjects.
Intralumenal obstruction and subepithelial collagen in the two asthma groups
were significantly greater than in control subjects, but there was no age
effect. These data provide support for the hypothesis that there is an increase
in airway wall area, including smooth muscle, and airway narrowing with
increasing duration of severe asthma or with older age. The observation that
total wall thickness was not greater in young individuals with young fatal
asthma than in control subjects
suggests that factors other than airway wall geometry contribute to the
pathogenesis of fatal attacks in this age group.
1563. Barnes
PJ. New directions in allergic diseases: mechanism-based anti-inflammatory
therapies. [Review] [121 refs] Journal of Allergy & Clinical
Immunology. 106(1 Pt 1):5-16, 2000 Jul.
Abstract
Advances in our
understanding of allergic inflammation have led to the development of several novel
anti-inflammatory drugs that target specific
aspects of the inflammatory process. These treatments are based on improvements
in existing therapies or on a better understanding of the cellular and
molecular mechanisms involved in atopic diseases. Although most attention has
been focused on asthma, treatments that inhibit the atopic disease process
would have application to all atopic diseases, which often coincide. Specific
agents that are now in development for the treatment of allergic inflammation
include inhibitors of eosinophilic inflammation (eg, anti-IL-5, CCR3
antagonists, and very late antigen 4 inhibitors), drugs that may inhibit
allergen presentation, and inhibitors of T(H)2 cells. More general
anti-inflammatory approaches include novel cortico-steroids, phosphodiesterase
inhibitors, and mitogen-activated
protein kinase inhibitors. Most of the new therapies in development are
aimed at inhibiting or suppressing components of the allergic inflammatory
response, but in the future, there are possibilities for development of
preventive and curative treatments. [References: 121]
1564. Bhathena
PR. Comhair SA. Holroyd KJ.
Erzurum SC. Interleukin-9 receptor expression in asthmatic airways In vivo.
Lung. 178(3):149-60, 2000.
Abstract
Inflammation of the
airway wall is a defining feature in asthma and is likely the cause of the
hyperreactivity and variable airflow limitation found in asthma. Immune
response biased toward production of Th2 cytokines has been proposed as a
mechanism in the pathogenesis of airway inflammation in asthma. The Th2
cytokine interleukin-9 (IL-9) is one candidate gene for asthma on the basis of
position cloning and animal models of airway inflammation. To determine whether
IL-9 is involved in the chronic inflammation of the asthmatic airway, we
investigated the expression of IL-9 and the IL-9 specific receptor chain in
asthmatic airways compared with healthy airways. IL-9 and IL-9 receptor
expression in airway epithelial cells and bronchoalveolar lavage cells obtained
at bronchoscopy of healthy (n = 9) and mild intermittent asthmatic individuals
(n = 7) were studied by Northern analyses and reverse-transcription polymerase
chain reaction technique. Primary and transformed human airway epithelial cells
were also evaluated for IL-9 specific receptor chain expression in vitro. IL-9
was not detected in airways of healthy or mild asthmatic individuals. In
contrast, IL-9 specific receptor chain expression was found in asthmatic airway
samples but not in healthy controls. In vitro, airway epithelial cells did
not Expres s IL-9 specific receptor
chain until stimulation with interferon gamma. Our results support that IL-9
may play a role in the mechanism leading to chronic airway inflammation and
asthma.
1565.
Bianco S. Robuschi M.
Vaghi A. Fumagalli A. Sestini P. Inhaled transmembrane ion
transport modulators and non-steroidal anti-inflammatory drugs in asthma.
[Review] [26 refs] Thorax. 55 Suppl
2:S48-50, 2000 Oct.
1566.
Bircher AJ. Bigliardi P. Zaugg T. Makinen-Kiljunen
S. Delayed generalized allergic reactions to corticosteroids. Dermatology. 200(4):349-51, 2000.
Abstract
A 37-year-old patient
presented with a severe allergic local reaction upon inhalation of budesonide for asthma. Skin tests were positive for
budesonide and amcinonide (group B) and elicited a strong local reaction and a
disseminated macular exanthema. Corticosteroids from other groups were well
tolerated. A 38-year-old male patient had first an allergic contact dermatitis
to topically applied prednisolone acetate and then a disseminated eczematous
exanthema upon oral intake of prednisone. A delayed-type sensitization to
corticosteroids from group A such as hydrocortisone, prednisone and tixocortol pivalate
was identified. A detailed diagnosis in patients with allergic reactions to
corticosteroids is crucial with regard to their use in emergency therapy.
Copyright 2000 S. Karger AG, Basel
1567. Bosse
M. Audette M. Laflamme G. Ferland
C. Boulet LP. Laviolette M. Eosinophil activation status and corticosteroid
responsiveness in severe asthma. International Archives of Allergy &
Immunology. 122(3):200-8, 2000 Jul.
Abstract
BACKGROUND: Since
eosinophils are implicated in asthma pathogenesis, we investigated whether
these cells were activated in severe asthma. METHODS: Twenty-six asthmatics with different clinical responses to oral
corticosteroid (CS), i.e. sensitive [change in forced expiratory volume in 1 s
(DeltaFEV(1)) >/= 25% after oral methylprednisolone, 40 mg daily, for 14
days, n = 7], resistant (DeltaFEV(1) </= 15%, n = 9) and dependent (>/=
20 mg oral prednisone daily for acceptable asthma control, n = 10), were
studied. RESULTS: Calcium ionophore-induced leukotriene (LT) C(4) release of
purified blood eosinophils was similar in the three groups. Cell incubation
with granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced
ionophore-induced LTC(4) release, and this effect was higher in CS-sensitive
(5-fold) than in CS-resistant subjects (1.7-fold) (p = 0.02). CS treatment
decreased blood eosinophil counts in these two groups of subjects (p </=
0.02) and decreased GM-CSF-enhanced LTC(4) release in CS-sensitive asthmatics
only (p = 0.04). In contrast, despite a high mean daily dose of oral CS (35 +/-
8 mg), blood counts of eosinophils from CS-dependent subjects were higher (p =
0.03) and GM-CSF enhancement of LTC(4)
release was greater (2.8-fold) than in CS-sensitive (2. 1-fold) and CS-resistant
(1.7-fold) subjects (p = 0.04). Interestingly, serum from CS-resistant subjects
reduced GM-CSF enhancement of LTC(4) release by eosinophils of CS-sensitive
asthmatics (p = 0.001). CONCLUSIONS:
Eosinophils from CS-dependent asthmatics have an impaired response to
CS, whereas serum from CS-resistant subjects contains an inhibitor of
eosinophil response to GM-CSF. Copyright 2000 S. Karger AG, Basel.
1568. Christian
Virchow J. Prasse A. Naya I.
Summerton L. Harris A.
Zafirlukast improves asthma control in patients receiving high-dose inhaled
corticosteroids.
American Journal of Respiratory & Critical Care Medicine. 162(2 Pt 1):578-85, 2000 Aug.
Abstract
Not all asthma can be
adequately controlled, despite the use of high-dose inhaled corticosteroids.
Because cysteinyl-leukotrienes (Cys-LT) have been implicated in the pathogenesis of asthma, we hypothesized that
the leukotriene receptor antagonist zafirlukast, in combination with high-doses
of inhaled corticosteroids, might be efficacious in severe asthma. In a
double-blind, parallel group study, 368 chronic adult asthmatic patients
treated with inhaled corticosteroids (1,000 to 4,000 microgram/d), who had a
predefined level of asthma symptoms during the run in period of the study, were
randomly assigned to receive additional treatment with a high dose of
zafirlukast (80 mg twice daily) (n = 180) or placebo (n = 188) for 6 wk.
Compared with placebo, zafirlukast produced a significant improvement over
baseline in the primary study endpoint of mean morning peak expiratory flow
rate (PEFR) (18.7 L/min versus 1.5 L/min, p < 0.001), as well as in evening
PEFR (p < 0.01), FEV(1) (p < 0.05), daytime symptom score (p < 0.001),
and beta(2)-agonist use (p < 0.001). Furthermore, zafirlukast significantly
reduced the risk of an exacerbation of asthma (odds ratio [OR]: 0.61; 95%
confidence interval [CI]: 0.38 to 0.99) and the risk of patients requiring a
further increase in asthma controller therapy (OR: 0.4; 95% CI: 0.2 to 0.8). In
conclusion, in patients taking high-dose inhaled corticosteroids, zafirlukast
improves pulmonary function and asthma symptoms, and reduces the risk of an
asthma exacerbation, suggesting that the contribution of leukotrienes to asthma
symptoms and exacerbations is not adequately controlled by high-dose inhaled
corticosteroids.
1569. Chung
KF.Airway smooth muscle cells: contributing to and regulating airway mucosal
inflammation?. [Review] [85 refs] European Respiratory Journal. 15(5):961-8, 2000 May.
Abstract
In addition to its
contractile properties, airway smooth muscle may contribute to the pathogenesis of asthma by increased
proliferation, and by the expression and secretion of pro-inflammatory
cytokines and mediators. Studies of airway smooth muscle cells in culture have
shown that many mitogenic mediators can induce proliferation, and that these
may therefore, contribute to the increase in airway smooth muscle mass observed
in asthma. Other mechanisms for airway smooth muscle proliferation include the
interaction with inflammatory cells such as T-cells and eosinophils. Airway
smooth muscle cells may also be a source of inflammatory mediators and
cytokines, in particular chemokines, thus
implicating airway smooth muscle cells as contributors to the
inflammatory mechanisms of asthma. The
pro-activating signals for converting airway smooth muscle cells into a
proliferative and secretory cell in asthma are unknown, but may include viruses
and immunoglobulin E. Airway smooth muscle contractility may also be altered in
response to inflammation. Airway smooth muscle cells may play an important
interactive role with inflammatory and other structural cells, contributing to
inflammation, injury and repair of the airways. Such a recognition makes it
imperative to consider the airway smooth muscle as a target of therapeutic
drugs for suppressing not only the contractile but also the proliferative and
secretory effects of asthma. [References: 85]
1570. Cimerman
N. Brguljan PM. Krasovec M.
Suskovic S. Kos J. Serum
cystatin C, a potent inhibitor of cysteine proteinases, is elevated in
asthmatic patients.
Clinica
Chimica Acta. 300(1-2):83-95, 2000 Oct.
Abstract
The effect of asthma
pathogenesis on serum cystatin C, a potent inhibitor of cysteine proteinases
and a newly proposed marker of the renal function, has not been yet determined.
The objectives were to determine the 24-h pattern of cystatin C and creatinine
concentrations in sera of asthmatic patients in order to test whether their
concentrations might reflect circadian rhythms, the disease severity and the
effect of therapy. Serum concentrations of cystatin C and creatinine were
determined in steroid-independent and steroid-dependent asthmatics before and
after 1 week of treatment with methylprednisolone and cyclosporin A,
respectively. Samples were collected every 4 h during a 24-h period. Little or
no significant effects of time on cystatin C and creatinine concentrations over
a 24-h period were observed in healthy and asthmatic sera. However,
significantly higher cystatin C concentrations were found in asthmatic Patients compared to controls which suggests
its role in the pathogenesis of asthma. Methylprednisolone increased and
cyclosporin A decreased serum cystatin C concentrations after 1 week of
therapy. Additionally these results support the need for the evaluation of cystatin
C as a marker of glomerular filtration rate determination in asthma.
1571.Crim
C. Clinical practice guidelines vs actual clinical practice : the asthma paradigm. Chest. 118(2 Suppl):62S-64S, 2000 Aug.
Abstract
In recent years, a
multitude of practice guidelines, statements, position papers, and "best practices" have
been promulgated for a number of disease
entities by a variety of medical societies and managed care
organizations. In the case of asthma, for example, the National Heart, Lung, and
Blood Institute of the National Institutes of Health (NIH) initially published
guidelines for the diagnosis and management of asthma in 1991; these
recommendations were updated in 1997. However, health-care providers have not
widely and consistently adhered to these guidelines. Several recent
publications suggest that this underutilization of the NIH asthma guidelines
may in part be related to a lack of understanding. This lack of understanding
appears to span the spectrum of physicians in private practice, physicians
working in health maintenance organizations, as well as university-affiliated
physicians. Moreover, both primary-care physicians and "asthma
specialists" share deficits in their knowledge base. To compound the
problem, patients with asthma also demonstrate poor adherence to the
guidelines. This poor adherence is evident irrespective of the patient's socioeconomic status. These
types of data clearly indicate a need for further educational programs directed
to both physicians and patients. However, as with the development and
promulgation of any practice guideline, physicians need to be convinced that
there exists compelling evidence from well-controlled clinical trials, for
example, or from evidence-based medicine, to substantiate implementation of
these guidelines.
1572. Eaton
T. Garrett J. Milne D. Frankel A. Wells AU. Allergic bronchopulmonary
aspergillosis in the asthma clinic. A prospective evaluation of CT in the
diagnostic algorithm [see comments]. Chest.
118(1):66-72, 2000 Jul.
Abstract
OBJECTIVE: Allergic
bronchopulmonary aspergillosis (ABPA) occurs in cases of atopic asthma and may
result in important lung disease. Early diagnosis is essential as this disease
is responsive to steroids. However, while asthma is common, ABPA is infrequently
diagnosed. CT allows precision in the diagnosis of central bronchiectasis
(which is virtually pathognomonic of ABPA) and may enable earlier diagnosis.
DESIGN: A prospective evaluation of 255 patients with asthma for ABPA, using
skin prick testing (SPT) for Aspergillus fumigatus (AF) as a screening tool and
incorporating CT into the diagnostic algorithm. SETTING: Asthma clinic, Green
Lane Hospital, Auckland, New Zealand. PARTICIPANTS: Patients with asthma.
INTERVENTIONS: ABPA was diagnosed using "essential" criteria (ie,
asthma, SPT positivity to AF, elevated serum total IgE, elevated serum
AF-specific IgE, and pulmonary infiltrates seen on chest radiography or central
bronchiectasis seen on CT scan) and "minimal essential" criteria
(ie, Asthma, SPT positivity, and
central bronchiectasis). MEASUREMENTS AND RESULTS: Two hundred fifty-five
consecutive patients with asthma who consented to SPT were studied: 218 of 255
patients (86.8%) were atopic; and 47 of 255 patients (21.6%) were AF-positive,
of whom 35 accepted further evaluation including CT scanning. A secure
diagnosis of ABPA, satisfying all essential criteria, was evident in 9 of 35
patients (25.7%), a proportion that increased to 13 of 35 patients (37.1%) by
using the minimal essential diagnostic criteria. CONCLUSIONS: SPT positivity to
AF was present in approximately 20% of patients in the asthma clinic. A
diagnosis of ABPA is disclosed by CT in 25 to 40% of SPT-positive patients,
depending on the selection of diagnostic criteria. These findings support the use of SPT as a
screening tool in the asthma clinic and indicate that a routine CT scan is
warranted in SPT-positive patients.
1573.
Ek A. Palmberg L. Larsson K. Influence of fluticasone and
salmeterol on airway effects of inhaled organic dust;an in vivo and ex vivo
study. Clinical & Experimental Immunology.
121(1):11-6, 2000 Jul.
Abstract
Inhalation of dust from
swine confinement buildings induces airway inflammation with an increase in
both inflammatory cell numbers and secretion of proinflammatory cytokines in
the lungs. It is not known whether anti-asthma drugs, which influence airway
inflammation in asthma, also influence the airway reaction to inhaled organic
dust. In the present study we examined the effects of a ss2-agonist (salmeterol)
and an inhaled steroid (fluticasone) on the swine dust-induced cell and
cytokine content of the lower airways, and cytokine release in cultured
alveolar macrophages. Healthy volunteers were pretreated with inhaled
salmeterol (n = 8), fluticasone propionate (n = 8) or placebo (n = 8) for about
2 weeks and exposed to dust in a pig house. Bronchoalveolar lavage was
performed both before medication and after dust exposure. Cell differential
counts and cytokine analyses in bronchoalveolar lavage fluid (BALF) were
examined. Alveolar macrophages were cultured and cytokine release was studied,
both in unstimulated cells and after lipopolysaccharide (LPS) stimulation.
Unstimulated alveolar macrophages from swine dust-exposed individuals released
less IL-6, IL-8 and tumour necrosis factor-alpha (TNF-alpha) after, than
before, exposure (P < 0.01). Medication did not influence basal cytokine
production. Fluticasone inhibited LPS-induced IL-6 and IL-8 release (P <
0.05). There was no significant difference between the groups. There was a
large and significant increase (P < 0.05) in alveolar macrophage,
granulocyte, lymphocyte numbers, and IL-6 and TNF-alpha content in BALF in all
three groups following dust exposure,
with no significant difference between the groups. These findings
suggest that drugs which are known to influence and control airway inflammation
in asthma do not have major effects on airway inflammation induced by the
inhalation of organic dust.
1574. Eldridge
MW. Peden DB. Airway response to concomitant
exposure with endotoxin and allergen in atopic asthmatics. [Review] [38 refs]
Journal of Toxicology & Environmental Health. Part A. 61(1):27-37, 2000 Sep 15.
Abstract
Epidemiological and in
vivo studies suggest that inhaled endotoxin may be an important environmental
factor associated with the increases in asthma-related morbidity and mortality.
Recent studies by our group and others provide a rationale for the hypothesis
that airway exposure of atopic asthmatics to both allergen and endotoxin might
result in greater inflammatory responses than those observed with either
stimulus alone. Moreover, these studies may provide further evidence that
concomitant exposure to allergen and endotoxin is an important factor in asthma
pathogenesis. [References: 38]
1575. Falcao
AC. Rocha MJ. Almeida AM. Caramona MM.
Theophylline pharmacokinetics with concomitant steroid and gold therapy.
Journal of Clinical Pharmacy & Therapeutics. 25(3):191-5, 2000 Jun.
Abstract
BACKGROUND: Theophylline
has been used for several decades in the treatment of asthma. In recent years,
however, with the appreciation of the importance of inflammation in the
pathogenesis of asthma, new therapeutic approaches have arisen, including
beta2-agonists, steroid and nonsteroidal anti-inflammatory drugs, such as gold
salts. OBJECTIVE: In the present work we studied the kinetic behaviour of
theophylline administered concomitantly with methylprednisolone (steroid
compound) and auranofin (oral gold) in six adult female patients. METHOD: Drug
concentration data for patients under routine care were collected. The kinetic
analysis (Bayesian Approach) was done using two different commercial software
packages, PKS (Abbott Diagnostics) and CAPCIL (SIMKIN Inc., courtesy of
Dade-Behring). A one-compartment open model with first-order absorption (ka for
PKS=0. 5/h; ka for CAPCIL=0.3/h ) and first- order elimination. Default CL,
t1/2 and Vd values were used for each program was assumed. The measured and
predicted theophylline concentrations were used to calculate percentage
prediction errors defined as %PE=[(predicted conc. - measured conc.)/measured
conc.] x 100. A linear regression analysis was also carried out for the
observed concentrations and those
predicted by each method (PKS vs. CAPCIL). RESULTS: The predicted
concentrations indicating persistently over-predicted the observed theophylline
serum levels (results expressed as median and interquartile range; %PE for
PKS=58.1 [37.1-126.0]; %PE for CAPCIL=34.0 [12.5-93.8]). The regression
analysis confirmed the same tendency, showing an intercept significantly
different from zero using both PKS and CAPCIL. CONCLUSION: The results suggest
a possible interaction between theophylline and auranofin. Both PKS and CAPCIL
failed to predict theophylline serum levels based exclusively on population
pharmacokinetic parameters. The lower
observed concentrations than expected have obvious implications in practice.
Periodic theophylline serum determinations are advisable until further studies
provide the necessary clarification about the kinetic profile of theophylline
in patients taking concomitant steroids and gold salts.
1576.
Fauroux B. Sampil M.
Quenel P. Lemoullec Y. Ozone: a
trigger for hospital pediatric asthma emergency room visits. Pediatric
Pulmonology. 30(1):41-6, 2000 Jul.
Abstract
A time-series study was
carried out in Paris from January 1 to December 31, 2023 with the aim of
investigating the association between urban air pollution and daily emergency
room visits for asthma in a pediatric hospital. Levels of black smoke, sulfur
dioxide, nitrogen dioxide, and ozone were monitored throughout the study area,
and meteorological data were collected. Influenza epidemics and pollen periods
were identified. Health data were collected from a pediatric hospital emergency
room. Case definition of asthma attacks was based on clinical diagnosis.
Children were included in the study if: 1) they were 1 to 15 years old; 2) they
had doctor-diagnosed asthma and were followed in our asthma outpatient clinic;
and 3) they were residents in the Paris region. The relation between daily
asthma visit counts and air pollution levels was assessed, using a multiple
linear regression model and taking into account temporal variations and
autocorrelation in the data. A thousand and twenty visits for asthma were
observed during the study period. A positive statistical association was found between daily asthma
visits and daily variations of ozone levels (1 day after exposure, relative
risk = 1.52 [95% confidence interval: 1. 06-2.19]) after controlling for
monthly and weekly variations, influenza epidemics, periods of pollen exposure,
and daily mean temperature (2 days' lag). This study underlines the significant
role of ozone as a trigger for asthma attacks in children. Copyright 2000
Wiley-Liss, Inc.
1577. Forbes
L. Jarvis D. Bumey P. Is pre-menstrual asthma related to use of aspirin or
non-steroidal anti-inflammatory drugs?. Respiratory Medicine. 94(8):828-9, 2000 Aug.
1578. Grunberg
K. Sharon RF. Hiltermann TJ. Brahim JJ. Dick EC.
Sterk PJ. Van Krieken JH. Experimental rhinovirus 16 infection increases
intercellular adhesion molecule-1 expression in bronchial epithelium of
asthmatics regardless of inhaled steroid treatment. Clinical & Experimental
Allergy. 30(7):1015-23, 2000 Jul.
Abstract
BACKGROUND: Rhinovirus
infections in airway epithelial cells in vitro have been shown to upregulate intercellular adhesion molecule-1
(ICAM-1) expression. Epithelial ICAM-1, in its dual role as the major
rhinovirus receptor and as adhesion molecule for inflammatory cells may be
involved in the pathogenesis of rhinovirus-induced exacerbations of asthma.
OBJECTIVE: We aimed to investigate the effect of experimental rhinovirus 16
(RV16) infection on ICAM-1 expression in bronchial mucosal biopsies in asthma.
In addition, the effect of 2 weeks pretreatment with inhaled budesonide (800
microg b.d.) on RV16-associated changes in ICAM-1 expression was studied.
METHODS: The study had a parallel, placebo-controlled
design in 25 steroid-naive nonsmoking atopic asthmatic subjects. After 2 weeks budesonide (BUD) or
placebo (PLAC) pretreatment
bronchoscopy was performed 2 days before (day -2) and 6 days after (day
6) RV16 inoculation (on days 0 and 1).
Immunohistochemical staining for ICAM-1 was performed on snap-frozen bronchial
biopsies. ICAM-1 staining intensity on the basal epithelial cells was scored
semiquantitatively from 1 (weak) to 3 (intense). Similarly, epithelial
intactness was noted (1 = basal cells only, 2 = basal and parabasal cells, 3 =
intact epithelium). RESULTS: ICAM-1 scores were not significantly different
between the groups at day -2 (P > or = 0.08). Subsequent RV16 infection was
associated with a trend towards an increase in ICAM-1 expression in the
BUD-group (P = 0.07), whereas the increase was significant in the PLAC-group (P
= 0.03). However, the increase was not significantly different between the
groups (P = 0.74). Epithelial intactness score was not different between the
groups before RV16 infection (P > or = 0.07), and no significant changes
were observed in either group (P > or = 0.59). Moreover, ICAM-1 score did
not correlate significantly with epithelium score in either group, at any
time-point (P > or = 0.27). CONCLUSION: We conclude that an RV16 common cold
in atopic asthmatic subjects is associated with increased ICAM-1 expression in
the bronchial epithelium, which is not related to epithelial intactness. Glucocorticoid treatment does
not appear to prevent the RV16-associated increased ICAM-1 expression. This
suggests that other treatment modalities are required to protect against the
spreading of infection during rhinovirus-induced exacerbations in asthma.
1579. Helms
PJ. Issues and unmet needs in pediatric asthma. Pediatric Pulmonology. 30(2):159-65, 2000 Aug.
Abstract
Asthma is common and
becoming more so in childhood. Although mild asthma may incur low average
annual costs per child, these estimates need to be viewed in the context of the
very large numbers of affected individuals. Whereas asthma and wheezing illness
in childhood had in the past been broadly subdivided into asthma (often
associated with atopy) and wheezy bronchitis (wheeze only, with associated
upper respiratory tract infection), this distinction was lost during the 1970s
in view of the demonstrated underdiagnosis and undertreatment of symptomatic
school-age children. The acceptance of asthma as a chronic inflammatory disease
and evidence for airway remodeling and
progressive deterioration in airway function in association with symptoms and
atopy have led to earlier use of topical steroids at higher starting doses
delivered by improved age-appropriate devices. Treating all children as if they
were destined to become atopic asthmatics and at risk of airway remodeling may
not be rational, particularly in those whose symptoms will subsequently
resolve. However, there are as yet no
screening tests which can clearly identify
individuals at risk of long-term chronic airway inflammation and
airway remodeling. The large number of
infants and young children with current
symptoms suggestive of asthma and in whom resolution is likely in the
majority poses problems for the clinician in deciding the best initial therapy.
There is an urgent need to develop simple and reliable measures that can identify
the early manifestations of atopic airway sensitization and to establish the
place of early intervention with nonsteroidal drugs, including leukotriene
antigonists. Copyright 2000 Wiley-Liss, Inc.
1580. Holloway
JW. Dunbar PR. Riley GA.
Sawyer GM. Fitzharris PF. Pearce N. Le Gros GS. Beasley R. Association of beta2-adrenergic
receptor polymorphisms with severe asthma. Clinical & Experimental
Allergy. 30(8):1097-103, 2000 Aug.
Abstract
BACKGROUND: There is
considerable interest in the role of different candidate loci in the
development of asthma. This study investigates the association between asthma
severity and previously identified polymorphisms at two sites within the
beta2-adrenergic receptor (beta2AR) gene: the Arg16-->Gly16 and Gln27-->Glu27
alleles. METHODS: Restriction enzyme analysis of amplified beta2AR gene
products (PCR-RFLP) was used to analyse the frequency of the Arg16-->Gly16
and Gln27-->Glu27 polymorphisms within the beta2AR gene in 95 severe
asthmatic patients (with a markedly increased risk of death from asthma), 59
mild asthmatic patients, and a control group of 92 nonasthmatic subjects.
RESULTS: The Gly16 polymorphism was significantly associated with asthma
severity with odds ratios (95% CI) for the Gly16 allele being 1.56 (1.02-2.40,
P = 0.04) and 0. 98 (0.61-1.57, P = 0.92) for the severe and mild asthma
groups, respectively. The corresponding
odds ratios (95% CI) for Gly16 homozygotes were 1.91 (0.82-4.41, P = 0.13) and
0.82 (0.35-1.92, P = 0.65) for the severe and mild asthma groups, respectively.
There was no significant association between either polymorphism at amino acid
27 and asthma or asthma severity. CONCLUSIONS: We conclude that the
polymorphisms of amino acids 16 and 27 of the beta2AR gene are not associated with
the development of asthma per se, but that the Gly16 polymorphism may play a
role in the pathogenesis of asthma severity.
1581. Holt
PG. Sly PD. Prevention of adult asthma
by early intervention during childhood: potential value of new generation immunomodulatory
drugs. [Review][44 refs] Thorax. 55(8):700-3, 2000 Aug.
1582. Houston
EC. Cunningham CC. Metcalfe E.
Newton R. The information needs and understanding of 5-10-year old
children with epilepsy, asthma or diabetes. eizure. 9(5):340-3, 2000 Jul.
Abstract
This exploratory study
compared the information needs and understanding of 25 5-10-year olds with
epilepsy with those of 10 children with asthma and 10 with diabetes (of the
same age range). The children were interviewed whilst attending specialist
clinics by the first author and were unaware of her professional status. All
the children had access to specialist nurses and their families had received
literature about their condition. The interview covered five main areas:
knowledge of their condition, psychological effects, medication, restrictions
on lifestyle, where they obtained their information and if they had unanswered
questions. The children with epilepsy had far more unanswered questions and
felt excluded from discussions with doctors. They also appeared reluctant to
tell their friends their diagnosis and, at such a young age, felt stigmatized
by their condition. The results highlight a contrast in the understanding of
children with epilepsy when compared with those with asthma or diabetes. It is
proposed that if a simple biological model were used to explain epilepsy this could aid children's
understanding and reduce their reluctance to disclose their diagnosis.
Copyright 2000 BEA Trading Ltd.
1583. Jaffuel
D. Demoly P. Gougat C. Balaguer
P. Mautino G. Godard P. Bousquet J.
Mathieu M. Transcriptional potencies of inhaled glucocorticoids.
American Journal of Respiratory & Critical Care Medicine. 162(1):57-63, 2000 Jul.
Abstract
Glucocorticoids (GC) are
the most effective anti-inflammatory drugs used in asthma. By a process called
trans-activation, they increase the transcription of genes involved in either
beneficial processes or certain side effects. Through trans-repression, they
inhibit the transcription factors nuclear factor kappa B (NF-kappaB) and
activator protein-1 (AP-1), thereby decreasing the expression of many genes
encoding inflammatory mediators such as the cytokine RANTES. We have measured
the trans-activation and trans-repression potencies of the five currently
available inhaled GC using reporter gene assays. The rank order of trans-activation potencies in HeLa cells
stably transfected with a GC-inducible luciferase gene was fluticasone
propionate > budesonide and triamcinolone acetonide > beclomethasone
dipropionate and flunisolide. For all GC except beclomethasone dipropionate,
there was a highly significant correlation between their potency to
trans-activate in HeLa cells and their capacity to induce the gluconeogenic
enzyme tyrosine aminotransferase in hepatoma tissue culture (HTC) cells. The
rank order of trans-repression potencies in A549 lung cells transiently
transfected with an AP-1- or NF-kappaB-dependent luciferase gene was
fluticasone propionate > budesonide > beclomethasone dipropionate, triamcinolone
acetonide, and flunisolide. The same rank order was found for inhibition of
RANTES release. Thus, determination of trans-repression and
trans-activation potencies of GC may
help to predict their capacity to produce anti-inflammatory and side effects, respectively.
1584. Kabra
SK. Pandey RM. Singh R.
Seth V. Ketotifen for asthma in children aged 5 to 15 years: a
randomized placebo-controlled trial. Annals of Allergy, Asthma, &
Immunology. 85(1):46-52, 2000 Jul.
Abstract
BACKGROUND: The
prophylactic agent ketotifen has been studied in mild-to-moderate asthma.
Various trials showed benefit from 10 to 12 weeks of therapy, but no trial in
children with followup beyond 12 weeks of the drug is available. OBJECTIVES: We
studied the efficacy of ketotifen, 1 mg twice a day, orally as a prophylactic
drug in children with asthma. METHODS: The double-blind, placebo-controlled
trial studied 120 asthmatic children of either sex between the ages of 5 to 15
years at a tertiary care hospital. After an observation period of 4 weeks,
children were randomly assigned to receive either ketotifen, 1 mg twice a day,
or placebo for 6 months. Antiasthma drugs were continued as required. Main outcome measures included average duration
for regular antiasthma drugs, average symptom scores, symptom free days, peak
expiratory flow rate, FEV1, and need for emergency room visits. RESULTS: Of the
120 children enrolled, 13 could not complete the trial. Thus 58 children
remained in the treatment group and 49 were in the placebo group. Both groups
were comparable in their baseline characteristics. The average number of days
that required antiasthma drugs were significantly less in the treatment group:
salbutamol (27+/-4.7 versus 37+/-3.5 P < .05), theophylline (37+/-4.7 versus
51+/-4.8 P < .05), oral steroids (2+/-0.4 versus 5+/-1.6 P < .05), and
inhalation steroids (18+/-2.7 versus 16+/-10.8 P < .05). The average symptom
scores and symptom free days for cough, wheeze, and breathlessness also favored
the ketotifen group. Emergency room visits
were also significantly lower in the ketotifen group (20 versus 10 P
< .05). Statistically significant improvement in all the above parameters
were observed after 14 weeks of therapy. The mean PEFR, FEV1 and side effects
of medications were comparable between the two groups. CONCLUSIONS: Ketotifen,
1 mg twice a day, is an effective prophylaxis for asthma in children between 5
to 15 years. Significant clinical improvement is evident after 14 weeks of
therapy.
1585. Kallay
N. Crim L. Dunagan DP. Kavanagh
PV. Meredith W. Haponik EF. Massive left diaphragmatic
separation and rupture due to coughing during an asthma exacerbation. [Review]
[5 refs] Southern Medical Journal.
93(7):729-31, 2000 Jul.
Abstract
We report a case of
herniation of abdominal contents into the left hemithorax in a patient
hospitalized with an acute exacerbation of asthma accompanied by paroxysms of
coughing. There was no history of trauma. We believe this is the first reported
case of diaphragmatic rupture complicating an asthma exacerbation. We review
clinical features, pathophysiology, diagnosis, and treatment of diaphragmatic
rupture in its most common setting, trauma, and discuss its occasional
"spontaneous" occurrence. [References: 5]
1586. Kemp
JP. Role of leukotriene receptor antagonists in pediatric asthma. Pediatric
Pulmonology. 30(2):177-82, 2000 Aug.
Abstract
During the past decade,
the inflammatory mechanisms that result in the clinical syndrome we call asthma
have been emphasized in research, publications, and the various asthma
management guidelines. This information clearly emphasizes the treatment of
asthma with maintenance controller therapies early after the onset of symptoms
in all but the very mildest of patients. Until the advent of the leukotriene receptor
antagonists, nearly all of these maintenance therapies needed to be
administered by inhalation through a variety of devices and spacers. Inhalation
of medication was necessary to either increase the amount of drug reaching the
airways or to increase the therapeutic index of drugs such as corticosteroids.
Even under the best circumstances, this route of administration is difficult and expensive for many parents whose
children have asthma. Now that oral controller therapies (leukotriene receptor
antagonists) are available for children, their role in clinical practice needs
to be examined. The latest asthma management guidelines classify asthma into
four groups of severity, and base treatment recommendations on the intensity of
symptoms, need for rescue medications, and pulmonary function as measured by
peak expiratory flow and forced expiratory volume in 1 sec (FEV(1)). The
categories of mild intermittent, mild persistent, moderate persistent, and
severe asthma in children will be addressed in this presentation by reviewing
the available data on the use of the leukotriene receptor antagonist
montelukast in children. Mild intermittent asthma can be typified by
exercise-induced asthma, a common pediatric condition. In this often
troublesome condition, montelukast demonstrated effectiveness at the end of a
once a day dose by blocking the effects of this naturally occurring challenge.
Drug regulatory approval of a new drug also includes patients with more regular
symptoms who are usually classified as having persistent or moderate asthma. In
these montelukast pediatric studies,
approximately 40% of patients were already taking inhaled corticosteroids.
Patients had improvements in FEV(1), symptoms, and rescue medication use,
clearly showing an effect with once a day dosing. Pediatric data in severe
asthma patients are more limited, but in such patients a therapeutic trial of
montelukast would seem preferable to using systemic corticosteroids or
increasing inhaled steroids to a level where adverse effects have an increasing
potential of occurring. Montelukast has been available in the United States
since March 1998 and has received excellent acceptance by physicians, parents,
and patients. The 5-mg chewable tablet administered once a day in the evening
in children aged 6-14 years apparently
fills a previously unmet need in the
treatment of pediatric asthma. Copyright 2000 Wiley-Liss, Inc.
1587. Kips
JC. Pauwels RA. Use of induced sputum
in the diagnosis and follow-up of asthma and chronic obstructive pulmonary disease
[editorial]. Monaldi Archives for Chest Disease. 55(2):93-5, 2000 Apr.
1588. Koshino
T. Takano S. Kitani S. Ohshima N. Sano Y.
Takaishi T. Hirai K. Yamamoto K.
Morita Y. Novel polymorphism of the 5-lipoxygenase activating protein
(FLAP) promoter gene associated with asthma.
Molecular Cell Biology Research Communications. 2(1):32-5, 1999 Jul.
Abstract
The human 5-lipoxygenase
activating protein (FLAP) gene is one of the key genes involved in the production of the cysteinyl-leukotrienes.
We studied novel polymorphism of the
FLAP promoter gene and attempted to clarify the relationship between this polymorphism and asthma. We sequenced
the FLAP promoter region, containing
the -170 to +46-bp sequence from the translational start codon, and found two
homozygotes of novel alleles in the polyadenyl region which showed 21 A repeats
and 18 A repeats, respectively. The frequency of the 21 A repeats was 52/71
(73.2%) in asthmatics and 39/71 (54.9%) in control subjects. The difference
between these frequencies was statistically significant (P = 0.035). This is
the first report of FLAP promoter gene polymorphism associated with asthma. Our
data suggest that FLAP promoter gene polymorphism might play a crucial role in
the pathogenesis of asthma.
1589. Kulig
J. Advances in medical management of asthma, headaches, and fatigue. [Review]
[36 refs] Medical Clinics of North America.
84(4):829-50, vi, 2000 Jul.
Abstract
The 1990s in medicine
have been characterized by the development of various clinical guidelines to
assist in the diagnosis, classification, and management of common disorders.
Among the most frequent presenting complaints of adolescent patients are
asthma, headaches, and fatique. In an era of managed care and brief clinical
encounters, application of standardized guidelines, modified appropriately for
adolescents, is likely to improve clinical outcomes, including patient and
parent satisfaction. In each of these disorders, engaging the adolescent
patient as a partner in planning and implementing management is crucial to
success. [References: 36]
1590. Luxenberger
W. Posch U. Berghold A. Hofmann
T. Lang-Loidolt D. HLA patterns in
patients with nasal polyposis. European Archives of Oto-Rhino-Laryngology. 257(3):137-9, 2000.
Abstract
The etiology of nasal
polyposis is still unknown, although risk factors include Aspirin intolerance, asthma, cystic fibrosis and primary
ciliary dyskinesia. We studied frequencies
of HLA A, B, DR and DQ in patients with
nasal polyposis in order to determine a possible genetic component in
the multifactorial pathogenesis of
nasal polyps. Previous work has suggested an association of HLA-A1B8 with nasal
polyposis and Aspirin intolerance. We investigated 89 patients with nasal
polyposis, 11 of whom had Aspirin-intolerance, 19 asthma and 22 allergies to
inhalation allergens. HLA patterns of these patients were compared to the ones
of 1,070 healthy controls. No significant association of HLA-A1B8 was found
with nasal polyps in the Aspirin-sensitive subgroup of our patients, but a
significant association was seen with HLA-A74 and nasal polyposis.
1591. Mathison
DA. Koziol JA. Persistent asthma:
patient characteristics, courses of asthma, and utility of salmeterol. Journal
of Asthma. 37(5):441-50, 2000 Aug.
Abstract
Applications of National
Asthma and Education and Prevention Program (NAEPP) guidelines for the
diagnosis and management of asthma may reduce the morbidity of this disorder.
Medical records and questionnaires from a series of 177 outer-city adolescents
and adults with persistent asthma were audited according to NAEPP guidelines
and for utility of salmeterol (Serevent). Allergic sensitivity and exposure to
indoor allergens house-dust mite (66% of patients), fungi (42%), cat (20%)
and/or dog (14%) were of dominant importance to persistent asthma. Patients who
continued salmeterol over 1 year had reduced severity of disease, improved
forced expiratory flow at 25%-75% of vital capacity, and reduced usage of
systemic, but not inhaled, corticosteroid.
1592. Mazur
LJ. de Ybarrondo L. Miller J. A guide to the pediatric patient
with "difficult" asthma. [Review] [29 refs] Journal of Pediatric
Health Care. 13(6 Pt 1):284-7, 1999
Nov-Dec.
Abstract
Patients whose asthma
symptoms are poorly controlled with the therapies usually recommended for this disease are considered to have
"difficult" asthma. Although such patients represent a small
proportion of patients with asthma, children who have difficult asthma are at
increased risk for morbidity and mortality. Once the diagnosis of asthma is
established, caregivers must appropriately categorize and treat the asthma
according to the patient's level of symptom severity. The purpose of this
article is to present an approach to the management of patients with difficult
asthma by (a) searching for alternative diagnoses or conditions that are often
associated with asthma, (b) investigating environmental issues, (c) reviewing
inhalation techniques, and (d) determining the patient's level of compliance
with the prescribed treatment plan and simplifying it whenever possible.
[References: 29]
1593. Morice
AH. Andrews B. Taylor M. Comparison of the effect on
bronchial hyperresponsiveness of beclomethasone dipropionate administered via a
novel multidose dry-powder inhaler or a conventional pressurised metered dose
inhaler [see comments]. Respiration.
67(3):298-305, 2000.
Abstract
BACKGROUND: Treatment
with inhaled corticosteroids improves symptoms and reduces bronchial hyperresponsiveness (BHR) associated with
asthma. Delivery of drugs into the lung is dependent on the inhaler device.
Furthermore, environmental concerns regarding the use of chlorofluorocarbon
propellants in pressurised inhalers and patient acceptability of inhaler
devices both influence the extent of use of different delivery systems.
OBJECTIVES: To compare the efficacy of beclomethasone dipropionate (BDP)
administered via a novel multidose
dry-powder inhaler (DPI) and a conventional pressurised metered-dose
inhaler (pMDI) with spacer in patients with BHR. METHODS: A randomised,
double-blind, crossover study was carried out in a group of 27 patients (aged
19-55 years) with a clinical diagnosis of reversible airway disease, who
demonstrated BHR to methacholine (PD(20) < or =6.4 mg). Each patient received
BDP (< or =2 mg/day) via the DPI or pMDI, for periods of 4 weeks. The
randomised treatment periods were preceded by 3-week washout periods when no
corticosteroid was used. Five clinic visits marked the start and end of each
study phase. The primary efficacy endpoint was BHR as defined by the
pharmacodynamic parameter, PD(20), which was determined at the start and end of
each treatment period. Clinical endpoints including lung function, symptoms and
adverse events were also evaluated. RESULTS: Both treatments caused a
significant decrease in BHR (p<0.05 vs. pre-treatment values). Mean +/- SD
changes in log PD(20) were: DPI 0.59+/-1.29; pMDI 0.59+/-0.94 mg. There was no statistically significant difference
between treatments and no evidence of a
carry-over effect between treatments on BHR. Clinical efficacy and safety
parameters also demonstrated no statistically significant treatment
differences, and patients found the DPI easier to use. CONCLUSION: Efficacy of
BDP in reducing BHR is comparable via the DPI and pMDI plus spacer. Copyright
2000 S. Karger AG, Basel.
1594. Motala
C. Kling S. Gie R. Potter PC. Manjra A.
Vermeulen J. Weinberg EG. Green R. Guideline for the management of
chronic asthma in children--2000 update. Allergy Society of South Africa
Working Group. South African Medical Journal.
90(5 Pt 2):524-8, 530, 532 passim, 2000 May.
Abstract
OBJECTIVE: To increase
awareness of asthma and diagnose asthma early in children. To make recommendations regarding management of chronic
childhood asthma in a country with diverse cultural, socio-economic and
educational characteristics. The guideline should be used by health
professionals involved in the treatment of asthma at all levels of care.
OPTIONS: Various management options were considered. Ideal treatment includes
use of the new generation inhaled corticosteroids (fluticasone, budesonide),
housedust mite intervention for asthma control using impermeable covers for
pillows and mattresses, and if needed use of inhaled long-acting beta 2 agonists
(LABAs) and leukotriene receptor antagonists (LRAs). Alternative therapeutic
approaches for situations where
resources are limited include simple housedust mite control measures (e.g. airing mattresses and bedding),
avoidance of exposure to passive smoking, use of lower doses of beclomethasone
than recommended by other guideline documents and/or sustained-release (SR)
theophylline as preventer treatment and use of plastic bottles as cheap spacer
devices. OUTCOMES: The main potential outcomes considered were: to reduce
morbidity and mortality by correct diagnosis of asthma, to achieve the best
quality of life for the child with asthma, to minimise side-effects from
medication and to prevent development of permanently abnormal lung function.
EVIDENCE: Current international guideline documents for diagnosis and management of childhood asthma
were evaluated. Clinical studies before 1998 pertaining to the various aspects
of management of childhood asthma were reviewed, including controlled studies
on the use of inhaled corticosteroids in children with asthma, randomised
controlled trials on the use of LRAs and two studies evaluating the efficacy of
LABAs. Current data on the anti-inflammatory effects of SR theophylline were
also reviewed as well as a randomised controlled trial on the benefits of SR
theophylline as adjunct treatment in childhood asthma. The benefit of simple
spacer devices, based on well-conducted local studies (published in an
international peer-reviewed journal) was also considered. VALUES: The South
African Childhood Asthma Working Group (SACAWG) committee members, appointed by
the Allergy Society of South Africa (ALLSA), were selected to represent the
interests of health professionals
involved in the care of childhood asthma and to co-opt other colleagues
with expertise relevant to the guideline. The committee was divided into six
task groups headed by a chairperson--each task group had to review critically
the previous SACAWG guideline (for deficiencies and obstacles to
implementation), review current trends in asthma management (evidence-based
where available) and submit proposals and recommendations to their respective
chairperson. The chairperson then compiled a report for discussion by the
SACAWG executive committee. The executive group convened a meeting to discuss
the recommendations and obtain consensus. An editorial board was appointed to
compile the final report. Cultural factors, patient preferences, cost,
availability and education were considered important. BENEFITS, HARMS AND COSTS:
Proper treatment should enable most
children with asthma to lead normal or near-normal lives. The guideline could be implementable at all
levels of care. The risk of systemic effects due to inhaled corticosteroids
should be minimised in children with mild to moderate persistent asthma (risk
of systemic effects is more likely at daily beclomethasone doses exceeding 400
micrograms or the equivalent dose of other inhaled corticosteroids). Promotion
of simple environmental control measures and use of inhaled beclomethasone
and/or SR theophylline should make treatment more widely available and more
affordable and improve adherence to treatment. Alternative cheap plastic bottle
spacer devices will increase availability and assist with overcoming the
problem of incorrect inha
1595. Nizankowska
E. Bestynska-Krypel A. Cmiel A.
Szczeklik A. Oral and bronchial provocation tests with aspirin for
diagnosis of aspirin-induced asthma.
European Respiratory Journal.
15(5):863-9, 2000 May.
Abstract
In 35 asthmatic patients
with acetylsalicylic acid (aspirin; ASA) intolerance (AIA) and 15 asthmatics
tolerating ASA well, the authors compared the diagnostic value of the
placebo-controlled oral ASA versus inhaled L-lysine (L) ASA challenges. All AIA
subjects gave a history of asthmatic attacks following ingestion of ASA and in
all of them the intolerance was confirmed by oral challenge test over the past
10 yrs. Doses of ASA increasing in geometric progression were used in oral
tests 10-312 mg (cumulative dose 500 mg); in bronchial tests 0.18-115 mg
(cumulative dose 182 mg). Either challenge was considered as positive, if
forced expiratory volume in one second (FEV1) dropped at least 20% from the
baseline value and/or strong extrabronchial symptoms of intolerance occurred.
Urinary leukotriene E4 excretion was determined at baseline and following the
challenges. In 24 out of 35 patients the oral test was positive, based on a 20%
decrease in FEV1. When including extrabronchial symptoms this was positive in 31 cases. Bronchial L-ASA challenge
led to > or =20% fall FEV1 in 21 out
of 35 cases, and in 27 cases when including extrabronchial symptoms. No
correlation was observed between ASA provocative dose causing a 20% fall in
FEV1, determined by the oral route compared to the inhalation route. Urinary
LTE4 increased after both challenges the rise being higher following oral as
compared to inhalation provocation (p=0.0001). It is concluded that both tests
had similar specificity whilst the oral test showed a tendency to higher sensitivity
for the clinical diagnosis of acetylsalicylic acid intolerance. The inclusion
of extrabronchial symptoms into the criteria of test positivity enhanced the
diagnostic value of both procedures. In both tests the highest leukotriene E4
increases were found in the presence of
extrabronchial symptoms, suggesting the participation of tissues other
than the lung in aspirin induced leukotriene E4 release to urine.
1596. O'Brien
C. Guest PJ. Hill SL. Stockley RA.
Physiological and radiological characterisation of patients diagnosed with
chronic obstructive pulmonary disease in primary care. Thorax. 55(8):635-42, 2000 Aug.
Abstract
BACKGROUND: Chronic
obstructive pulmonary disease (COPD) is common although often poorly
characterised, particularly in primary care. However, application of guidelines
to the management of such patients needs a clear understanding of the
phenotype. In particular, the British guidelines for the management of COPD
recommend that the diagnosis is based on appropriate symptoms and evidence of
airflow obstruction as determined by a forced expiratory volume in one second
(FEV(1)) of <80% of the predicted value and an FEV(1)/VC ratio of <70%.
METHODS: A study was undertaken of 110 patients aged 40-80 years who had presented
to their general practitioner with an acute exacerbation of COPD. The episode
was treated at home and, when patients
had recovered to the stable state (two months later), they were characterised
by full lung function tests and a high resolution computed tomographic (HRCT)
scan of the chest. RESULTS: There was a wide range of impairment of FEV(1)
which was in the normal range (>/=80%) in 30%, mildly impaired (60-79%) in
18%, moderately impaired (40-59%) in 33%, and severely impaired (<40%) in
19% of patients. A reduced FEV(1)/VC ratio was present in all patients with an
FEV(1) of <80% predicted but also in 41% of those with an FEV(1) of
>/=80% predicted. Only 5% of patients had a substantial bronchodilator
response suggesting a diagnosis of asthma. Emphysema was present in 51% of
patients and confined to the upper lobes in most (73% of these patients). HRCT
evidence of bronchiectasis was noted in 29% of patients and was predominantly tubular; most (81%) were
current or ex-smokers. A solitary pulmonary nodule was seen on 9% of scans and
unsuspected lung malignancy was
diagnosed in two patients. CONCLUSIONS: This study confirms that COPD in
primary care is a heterogeneous condition. Some patients do not fulfil the
proposed diagnostic criteria with FEV(1) of >/=80% predicted but they may
nevertheless have airflow obstruction. Bronchiectasis is common in this group
of patients, as is unsuspected malignancy. These findings should be considered
when developing recommendations for the investigation and management of COPD in
the community.
1597. Ochs
RL. Muro Y. Si Y. Ge H. Chan EK.
Tan EM. Autoantibodies to DFS 70 kd/transcription coactivator p75 in
atopic dermatitis and other conditions. Journal of Allergy & Clinical
Immunology. 105(6 Pt 1):1211-20, 2000
Jun.
Abstract
BACKGROUND: Sera of
patients with atopic dermatitis (AD) were found to have autoantibodies that
reacted with tissue culture cell substrates in immunohistochemistry to display
a characteristic pattern of nuclear distribution of dense fine speckles. The
sera also recognized a 70-kd protein on Western immunoblots, and the antigen
was termed dense fine speckles 70 kd (DSF70). OBJECTIVE: Because spontaneously
occurring autoantibodies could be immune responses to proteins that might be
participating in the disease process, it was of interest to identify the
antigens driving the autoimmune antibody response. METHODS: A serum containing
high-titer antibodies to DFS70 was used to immunoscreen a complementary (c)DNA
expression library to isolate cDNA encoding the antigen. After the cDNA was
isolated, this was used to express recombinant
protein to determine the prevalence of antibody in AD and other
conditions. RESULTS: Thirty percent of patients with AD were found to have
antibody to recombinant DFS70 in Western immunoblots. Sixteen percent of
patients with asthma and 9% of patients with interstitial cystitis had
antibodies of the same specificities. The cDNA encoding DFS70 was identical to
a transcription coactivator called p75, which had been shown to be required for
RNA polymerase II-dependent transcription. Another important finding was that
IgE antibodies to DFS70 were also present in AD sera. CONCLUSION: It is
suggested that a common basis for the presence of autoantibodies to DFS70 might
be related to AD in asthma, interstitial cystitis, and other conditions. A
possible role of this antigen-antibody system in pathogenesis remains to be
demonstrated, but it appears to be a marker for a subset of patients with AD.
1598. Palmer
LJ. Cookson WO. Genomic approaches to
understanding asthma. [Review] [132 refs] Genome Research. 10(9):1280-7, 2000 Sep.
Abstract
Asthma is the most common
chronic childhood disease in developed nations, and it is a complex disease
that has high social and economic costs. Asthma and its associated intermediate
phenotypes are under a substantial degree of genetic control. The genetic
aetiology of asthma offers a means of better understanding its pathogenesis
and, thus, improving preventive strategies, diagnostic tools, and therapies.
Considerable effort and expense have been expended in attempts to detect
genetic loci contributing to asthma susceptibility, and extensive candidate
gene studies and a number of whole-genome screens have been undertaken. This
article reviews the current state of knowledge of the genetics of asthma, with
a focus on genomic approaches to understanding allergic diseases. [References:
132]
1599. Piirila
PL. Nordman H. Keskinen HM. Luukkonen R. Salo
SP. Tuomi TO. Tuppurainen M. Long-term
follow-up of hexamethylene diisocyanate-, diphenylmethane diisocyanate-, and
toluene diisocyanate-induced asthma.
American Journal of Respiratory & Critical Care Medicine. 162(2 Pt 1):516-22, 2000 Aug.
Abstract
In 1976-1992 245 new
cases of asthma induced by diisocyanates were diagnosed, caused by
hexamethylene diisocyanate (HDI) in 39%, diphenylmethane diisocyanate (MDI) in
39%, and toluene diisocyanate (TDI) in 17% of the cases. Our aim was to study
the clinical outcome of diisocyanate-induced asthma. A questionnaire was sent
to the 235 patients alive in 1995, and validated by reexamining clinically 91
of them. The study was carried out on average 10 () yr after the diagnosis. Of
the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients
having displayed immunoglobulin E (IgE) antibodies to isocyanates used less
medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR
0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly
shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and
duration of exposure (p = 0.0008) than the IgE-negative patients. This did not,
however, entirely explain the more favourable outcome of the IgE-positive
patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI
0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results
confirm the generally rather poor medical
outcome of diisocyanate-induced asthma; the persistence of symptoms
and unspecific bronchial reactivity
were pronounced in TDI-induced asthma. A more favourable outcome was associated
with IgE mediation and HDI inducement.
1600. Reid
J. Marciniuk DD. Cockcroft DW. Asthma management in the
emergency department. Canadian Respiratory Journal. 7(3):255-60, 2000 May-Jun.
Abstract
OBJECTIVES: To evaluate
various aspects of the management of adult patients who present to the
emergency department with acute exacerbations of asthma and who are discharged
from the emergency department without hospital admission. Further, to compare
the results with accepted management guidelines for the emergency department
treatment of asthma. DESIGN: A retrospective chart collection and review until
each site contributed 50 patients to the survey. SETTING: Three tertiary care
hospitals in the Saskatoon Health District, Saskatoon, Saskatchewan. The study
period was from July 1, 2023 to November 18, 1997. POPULATION: Patients aged 17
years or older, who were discharged from the emergency department with the
diagnosis of asthma. METHODS: Data were collected on 130 patients from 147
emergency department visits. RESULTS: A number of important physical examination findings were frequently not
documented. In contrast to management
guidelines, peak expiratory flow rates (44%) and spirometry (1%) were not
commonly used in patient assessments. Only 59% of patients received treatment in the emergency departments with
inhaled or systemic corticosteroids.
Furthermore, specific follow-up plans were
infrequently documented in the emergency department charts (37%).
CONCLUSIONS: Adherence with published Canadian guidelines for the emergency
department management of acute asthma exacerbations was suboptimal.
Corticosteroid use in the emergency department was significantly less than recommended. Increased emphasis on
education and implementation of accepted asthma management guidelines is
necessary.
1601. Rodrigo
GJ. Rodrigo C. First-line therapy for
adult patients with acute asthma receiving a multiple-dose protocol of
ipratropium bromide plus albuterol in the
emergency department. American Journal of Respiratory & Critical
Care Medicine. 161(6):1862-8, 2000 Jun.
Abstract
We designed a larger,
double-blind, randomized, prospective trial to test our hypothesis that patients with acute asthma given combination
high dose therapy with ipratropium bromide (IB) and beta(2)-agonists will have
greater improvement in pulmonary function and fewer hospital admissions than
those given beta(2)-agonists alone. One hundred eighty patients (mean age +/-
SD, 34.3 +/- 10.5 yr) who presented to an emergency department (ED) for
treatment of an exacerbation of asthma (baseline FEV(1) < 50% of predicted)
were assigned in a randomized, double-blind fashion to receive albuterol and placebo
(n = 92) or albuterol and IB (n = 88). Both drugs were administered through a
metered-dose inhaler and spacer at 10-min intervals for 3 h (24 puffs or 2,880
microg of albuterol and 504 microg of IB each hour). Primary outcome measures
were improvement in pulmonary function (FEV(1) or peak expiratory flow [PEF]),
and hospital admission rates. In both groups, pulmonary function improved
significantly over baseline values (p
< 0.01). Subjects who received IB had an overall 20.5% (95% CI: 2.6 to
38.4%) (p = 0.02) greater improvement in PEF and a 48.1% (95% CI: 19.8 to
76.4%) (p = 0.001) greater improvement in FEV(1) from the control group. At the
end of protocol (3 h), 39% (n = 36) of patients in the control group and 20% (n
= 18) in the IB group were admitted (p = 0.01). The use of high doses of IB
reduced the risk of hospital admission 49% (relative risk = 0.51, 95% CI: 0.31
to 0.83). Five (95% CI: 3 to 17) patients would need to be treated with high
doses of IB to prevent a single admission. Kaplan-Meier-estimated curves of the
proportion of patients who reached the discharge threshold during the 3 h of
treatment, showed a significant difference in favor of the IB group (log-rank
test = 0.005). A subgroup analysis showed that patients most likely to benefit from the addition of high doses of IB were
those with more severe obstruction (FEV(1) </= 30% of predicted) and long
duration of symptoms before the ED presentation (>/= 24 h). On the contrary,
previous use of inhaled beta(2)-agonists did not modify the admission rate and
the pulmonary function response to IB. In conclusion, our data support a
substantial therapeutic benefit from the addition of IB to albuterol
administered in high doses through MDI plus spacer, particularly in patients
with FEV(1) less than 30%, and with long duration of symptoms before the ED
presentation (>/= 24 h).
1602. Schwartz
DA. Etiology and pathogenesis of airway disease in children and adults from
rural communities. [Review] [150 refs] Environmental Health Perspectives. 107 Suppl 3:393-401, 1999 Jun.
Abstract
Asthma is the most common
chronic disease of childhood and affects nearly 5 million children. The prevalence and severity of childhood
asthma have continued to increase over the past decade despite major advances
in the recognition and treatment of this condition. A comparison of urban and
rural children suggests that the etiology of airway disease is multifactorial
and that unique exposures and genetic factors contribute to the development of
asthma in both settings. The most important environmental exposure that
distinguishes the rural environment and is known to cause asthma is the organic
dusts. However, animal-derived proteins, common allergens, and low
concentrations of irritants also
contribute to the development of airway disease in children and adults
living in rural communities. A fundamental unanswered question regarding asthma
is why only a minority of children who wheeze at an early age develop
persistent airway disease that continues throughout their life. Although
genetic factors are important in the development of asthma, recurrent airway
inflammation, presumably mediated by environmental exposures, may result in
persistent airway hyperresponsiveness and the development of chronic airway
disease. Increasing evidence indicates that control of the acute inflammatory
response substantially improves airflow and reduces chronic airway remodeling.
Reducing exposure to agricultural dusts and treatment with anti-inflammatory
medication is indicated in most cases of childhood asthma. In addition,
children with asthma from rural (in
comparison to urban) America face multiple barriers that adversely affect their
health e.g., more poverty, geographic barriers to health care, less health
insurance, and poorer access to health care providers. These unique problems
must be considered in developing interventions that effectively reduce the
morbidity and mortality of asthma in children from rural communities.
[References: 150]
1603. Sheftell
F. Rapoport A. Weeks R.
Walker B. Gammerman I. Baskin S.
Montelukast in the prophylaxis of migraine: a potential role for
leukotriene modifiers. Headache.
40(2):158-63, 2000 Feb.
Abstract
OBJECTIVE: Clinical
observation of a decrease in migraine frequency in patients with comorbid asthma taking montelukast, a specific D4
leukotriene receptor antagonist, or zafirlukast, another leukotriene receptor
antagonist, prompted us to explore a possible role for leukotriene modifiers in
the treatment of migraine. (A further prompt was a pharmacist colleague's
observation that a number of patients on these agents reported a decreased
sensitivity to perfume triggers and improvement in migraine.) BACKGROUND:
Nonsteroidal anti-inflammatory agents have been used widely in the treatment of
migraine. Another class of anti-inflammatory agents, known as leukotriene
modifiers, have not been studied to date with regard to their possible role in
the treatment of migraine. The name "leukotriene is derived both from the
parent molecule, which was originally isolated from leukocytes, and from its
three double-bond carbon backbone or
triene structure. Both prostaglandins and leukotrienes are derived from the
metabolism of arachidonic acid, with
prostaglandins coming off the cyclooxygenase pathway and leukotrienes
derived via the enzyme 5-lipoxygenase. Both prostaglandins and leukotrienes
mediate inflammatory responses. The latter have been studied with regard to
their role in the pathophysiology of asthma. METHODS: A prospective, open-label
study evaluating the efficacy of montelukast, 10 mg or 20 mg, in the
prophylaxis of migraine in 17 patients is presented in this paper. All 17
patients completed the study that consisted of a 2-month baseline run-in period
and a 3-month treatment phase. RESULTS: Montelukast was extremely well
tolerated, and no adverse events were reported by any of the patients.
Fifty-three percent showed a reduction of greater than 50% (P<.025) in the
frequency of severe attacks, with 41% showing a reduction of greater than 60%.
Responders, including modest
responders, rated the drug as excellent. CONCLUSIONS: We conclude, given
the limitations of an open-label study design and the small sample size, that
montelukast shows potential as an effective, well-tolerated prophylactic agent
in migraine. Double-blinded, placebo-controlled studies are warranted. In
addition, the leukotrienes, as suggested previously in the literature, may play a role in the
pathogenesis of migraine.
1604. Springer
C. Godfrey S. Picard E. Uwyyed K. Rotschild M. Hananya S. Noviski
N. Avital A. Efficacy and safety of
methacholine bronchial challenge performed by auscultation in young asthmatic
children. American Journal of Respiratory & Critical Care Medicine. 162(3 Pt 1):857-60, 2000 Sep.
Abstract
The measurement of
bronchial reactivity is an important aid in the diagnosis of asthma, but the
technique using spirometry is not feasible in young children. The aim of the
present study was to determine the efficacy and safety of a modification of the
chest auscultation method in the assessment of bronchial reactivity to inhaled
methacholine in young asthmatic children. One hundred forty-six young children
with asthma (mean age, 4.3 yr) underwent bronchial challenges with nebulized
methacholine using the auscultation method (PCW). The end point was defined as
the appearance of wheezing, oxygen desaturation, or tachypnea. For comparison,
30 children and young adults with asthma underwent bronchial provocation with
methacholine using spirometry (PC(20)). A positive response using the
auscultation method was observed in 95.9% of the younger children, and wheezes
alone or in combination with other signs appeared in 80.8% of them. The mean
desaturation at the end point was 4.6% (PCW) and 5.0% (PC(20)), with a similar
pattern in the two groups. Cough was not helpful in determining the end point.
We conclude that the modified auscultation method is effective and safe, with
wheeze appearing at the end point in the large majority of the children.
1605. Stach
SL. Improving self-care in adults with asthma using peak expiratory flow rate
home monitoring. [Review] [28 refs] Journal of the American Academy of Nurse
Practitioners. 12(2):59-70; quiz 71-3,
2000 Feb.
Abstract
Asthma management is
based on step therapy incorporated into an individualized patient treatment
plan. Medication selection is based on differing degrees of asthma severity.
With proper assessment of the patient and a severity level incorporating the
patient's needs, a clinician can create a credit card treatment plan for each
patient. The assessment should include both PEFR and symptom monitoring as a
means of incorporating the CDC's severity guidelines and treatment options into
the credit card plan. Evaluation of technique, review of home monitoring outcomes,
and reinforcement during clinic visits is likely to be helpful for those
patients who do home monitoring. Note, however, that not all patients should be treated using this
self-management approach. Asthma associated with comorbidities may be a reason
to manage patients more closely either by clinic visit or telephone. Asthma in
both older and pregnant patients presents issues of drug safety (Evans, Brown,
& Morain, 1997). The common comorbidities of chronic obstructive pulmonary
disease, sinusitis, GERD, cardiovascular disease and diabetes present unique
issues of difficulty of diagnosis and drug safety. By following individualized
asthma management plans, patients should be able to achieve prevention or
reduction of chronic symptoms. They should also notice an improvement in
physical activity, the reduction or elimination of exacerbations and improved
overall satisfaction. [References: 28]
1606. Suissa
S. Ernst P. Benayoun S. Baltzan
M. Cai B. Low-dose inhaled
corticosteroids and the prevention of death from asthma. New England Journal of
Medicine. 343(5):332-6, 2000 Aug 3.
Abstract
BACKGROUND: Although
inhaled corticosteroids are effective for the treatment of asthma, it is
uncertain whether their use can prevent death from asthma. METHODS: We used the
Saskatchewan Health data bases to form a population-based cohort of all
subjects from 5 through 44 years of age who were using antiasthma drugs during
the period from 1975 through 1991. We followed subjects until the end of 1997,
their 55th birthday, death, emigration, or termination of health insurance
coverage; whichever came first. We conducted a nested case-control study in
which subjects who died of asthma were matched with controls within the cohort
according to the length of follow-up at the time of death of the case patient
(the index date), the date of study entry, and the severity of asthma. We
calculated rate ratios after adjustment for the subject's age and sex; the
number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the
year before the index date; the number
of canisters of inhaled beta-adrenergic agonists used in the year before the
index date; and the number of hospitalizations for asthma in the two years
before the index date. RESULTS: The cohort consisted of 30,569 subjects. Of the
562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who
died of asthma for whom there were complete data with 2681 controls.
Fifty-three percent of the case patients and 46 percent of the control patients
had used inhaled corticosteroids in the previous year, most commonly low-dose
beclomethasone. The mean number of canisters was 1.18 for the patients who died
and 1.57 for the controls. On the basis of a continuous dose-response analysis,
we calculated that the rate of death from asthma decreased by 21 percent with
each additional canister of inhaled corticosteroids used in the previous year
(adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The
rate of death from asthma during the first three months after
discontinuation of inhaled
corticosteroids was higher than the rate among patients who continued to use the drugs. CONCLUSIONS: The
regular use of low-dose inhaled corticosteroids is associated with a decreased
risk of death from asthma.
1607. Szczeklik
A. Nizankowska E. Clinical features and
diagnosis of aspirin induced asthma. [Review] [28 refs] Thorax. 55 Suppl 2:S42-4, 2000 Oct.
1608. Takabayashi
A. Ihara K. Sasaki Y. Suzuki Y. Nishima S.
Izuhara K. Hamasaki N. Hara T.
Childhood atopic asthma: positive association with a polymorphism of IL-4
receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I
beta gene. Experimental & Clinical Immunogenetics. 17(2):63-70, 2000.
Abstract
We examined the relative
contributions of three representative candidate genes for atopy (Fc epsilon receptor I beta, IL-4, and IL-4
receptor alpha) to the development of atopic asthma. Four polymorphisms of the
three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor alpha,
-590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta were
studied in 100 patients with atopic asthma and 100 nonatopic controls in the
northern Kyushu area in Japan. Among the four polymorphisms of the three
candidate genes, the Ile50 allele of the IL-4 receptor alpha chain gene
demonstrated an association with atopic asthma subjects (p = 0.044), especially
in patients with onset at 2 years of age or earlier (p = 0.034) and in patients
with moderate to severe atopic asthma (p = 0. 031). Gln551Arg of IL-4 receptor
alpha, -590C/T of IL-4 promoter and
Glu237Gly of Fc epsilon receptor I beta showed no association with atopic
asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms
of the IL-4 receptor alpha chain gene was observed in both patients and
nonatopic controls. The identification of additional atopy genes in areas with
a certain genetic background is essential for genetic diagnosis and to
establish new therapeutic modalities for atopic asthma. Copyright 2000 S.
Karger AG, Basel
1609. Tang
RB. Chen SJ. Evaluation of serum
interleukin-8 as a marker of disease activity in acute asthma in children.
Journal of Asthma. 37(5):409-13, 2000
Aug.
Abstract
Cytokine-mediated
interactions among the inflammatory cells may play a role in the pathogenesis
of bronchial asthma. Interleukin-8 (IL-8) is a major cytokine in the
recruitment of neutrophils to the area of inflammation. Serum IL-8 is a marker
of disease activity and treatment efficacy in bronchial asthma. To understand
the role of IL-8 in disease activity in acute asthma, changes in serum
concentrations of IL-8 elaborated by activated eosinophil before and after
prednisolone therapy with clinical improvement were determined in the present
study. Circulating levels of IL-8 in 15 normal control subjects and in sera
from 20 allergic asthmatic children
with acute exacerbation and in stable condition were determined by using commercially
available assay kits. The mean concentration of serum IL-8 was statistically
significantly higher in asthmatic children with acute exacerbation (63.62 +/-
11.41 pg/mL) and in stable asthmatics (64.22 +/- 10.31 pg/mL) compared to the
control group subjects (50.40 +/- 30.70 pg/mL; p < 0.01). However, the
difference was not statistically significant between the acute exacerbation and
stable asthmatics groups (p > 0.05). Serum IL-8 is a poor indicator of
disease activity in acute asthma; therefore, monitoring by serum IL-8
concentration is of limited value. The clinical value of serum IL-8 as a marker
of disease activity remains to be established.
1610. Tang
RB. Tsai LC. Chao PL. Hung MW.
Significance of specific IgG subclass antibodies to house dust mites in
asthmatic children. Chung Hua i Hsueh Tsa Chih - Chinese Medical Journal. 63(6):440-6, 2000 Jun.
Abstract
BACKGROUND:
Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df), the
major components of house dust, are considered to be etiologic factors of
extrinsic asthma. The relationships between immunoglobulin (Ig) G subclass
antibodies specific for Dp (or Df) were compared in specific IgE-positive and
-negative asthmatic children. METHODS: Serum levels of IgG and IgE subclass
antibodies specific for Dp and Df were studied in 52 children (age, 3-13 years;
mean age, 8.4 years) with asthma using enzyme-linked immunosorbent assays. The
skin prick test was also used in diagnosis of the reactivity of allergic
disease. RESULTS: The levels of serum-specific IgG1 and IgG2 to Dp and Df in
mite-specific IgE-(or skin-test) positive asthmatic children were significantly
higher than those in mite-specific IgE- (or skin test) negative children (p
< 0.01). Significant correlations
between the level of the specific IgE and IgG1 (r = 0.6067; p = 0.0001) or IgG2
(r = 0.5851; p = 0.0002) to Dp, and IgG1 (r = 0.3823; p = 0.0214) or IgG2 (r =
0.5057; p = 0.0017) to Df were found. The specific IgE level and skin test
reactivity showed a high correlation of greater than 96% (50/52). CONCLUSIONS:
The levels of mite-specific IgG subclasses were partially compatible to
specific IgE levels and skin test reactivity. We conclude that house dust mite
allergy is significantly associated with specific IgG1, IgG2 and IgE responses.
1611. Teel
GS. Engeler CE. Tashijian JH. duCret RP.Imaging of small airways disease. [Review] [39
refs]Source Radiographics. 16(1):27-41,
1996 Jan.
Abstract
High-resolution computed
tomography (HRCT) is the most useful modality for imaging of small airways disease. Direct signs of small airways
disease that appear on HRCT scans are the result of changes in the airway wall
or lumen. Abnormal small airways can be seen as tubular, nodular, or branching
linear structures on HRCT scans. Indirect signs of small airways disease result
from changes in the lung parenchyma distal to the diseased small airway and
include air trapping, subsegmental atelectasis, centrilobular emphysema, and
air-space nodules. Diverse inflammatory and infectious processes, such as
bronchiolitis obliterans (BO), bronchiolitis obliterans with organizing
pneumonia (BOOP), smoking-related diseases, and asthma affect the small airways
of the lungs. HRCT findings of BO include air trapping and bronchiectasis. The
predominant findings of BOOP are consolidation and ground-glass attenuation.
HRCT can show abnormalities such as small nodules and areas of ground-glass
attenuation even in asymptomatic smokers, but emphysema predominates in smokers
with moderate or severe obstructive
disease. Patients with asthma can have thickened airway walls, plugged large
and small airways, subsegmental atelectasis, and air trapping, but emphysema is
rarely seen even in severe asthma patients. HRCT scans can often accurately
depict disease processes in the small airways and can occasionally lead to a
specific diagnosis from among several clinically relevant possibilities.
[References: 39]
1612. Terwindt
GM. Ferrari MD. Tijhuis M.
Groenen SM. Picavet HS. Launer
LJ. The impact of migraine on quality of life in the general population:
the GEM study [see comments]. Neurology.
55(5):624-9, 2000 Sep 12.
Abstract
OBJECTIVE: To assess
health-related quality of life (HRQOL) in migraineurs in the general population. DESIGN: Cross-sectional study within
the context of a population-based study monitoring health characteristics of
the Dutch adult population in two municipalities representative of the general
population in the Netherlands. Migraine was assessed in a multistaged procedure
that included a semistructured clinical interview by telephone. Final diagnosis
met 1988 International Headache Society criteria. HRQOL was measured with the
self-administered RAND 36-item Health Survey (RAND-36), including physical
functioning, social functioning, role limitations, and physical perception.
HRQOL of migraineurs was compared with that of nonmigraineurs. To compare and
study the effect of comorbidity, the authors also identified subjects with asthma or chronic musculoskeletal pain.
There were 5998 people with complete data, 620 of whom had migraine in the last
year. RESULTS: Compared with nonmigraineurs, significantly more migraineurs had
asthma (OR = 1.6; 95% CI 1.1, 2.4) or chronic musculoskeletal pain (OR = 1.7;
95% CI 1.5, 2.1). Migraineurs reported diminished functioning and well-being on
all eight domains as compared with nonmigraineurs. HRQOL was inversely related
to attack frequency (p < 0.0002). Migraineurs had a poorer HRQOL than did
those reporting asthma, except for dimensions concerning physical functioning
and general health perception, but they had a better HRQOL than did subjects
with chronic musculoskeletal pain. Comorbidity of asthma or chronic
musculoskeletal pain in migraine further reduced HRQOL. CONCLUSIONS:
Migraineurs report more asthma and chronic musculoskeletal pain. Compared with
nonmigraineurs and to others with chronic conditions, migraineurs report
compromised physical, mental, and social functioning, particularly those with a
high frequency of attack.
1613. Tukiainen
H. Taivainen A. Majander R.
Poussa T. Svahn T. Puolijoki H. Terho EO. Comparison of high and low dose of the inhaled steroid,
budesonide, as an initial treatment in newly detected asthma. Respiratory
Medicine. 94(7):678-83, 2000 Jul.
Abstract
The importance of early
initiation of inhaled steroids even in mild asthma has been documented in several studies. It is not, however, clear
whether the treatment should be started with a high or a low dose of the
inhaled steroid. We have compared the effects of high and low dose inhaled
steroid, budesonide, in patients with newly detected asthma. We studied 101
adult patients with newly detected bronchial asthma who were without inhaled
steroid or any regular pharmacological treatment for their asthma. The patients
were randomly allocated to two treatment groups: one to receive 800 microg
inhaled budesonide per day and the other to receive 200 microg inhaled
budesonide per day. The drugs were given with a Turbuhaler dry powder inhaler.
During the 3-month treatment period, no significant differences between the
treatment groups were noted in morning or evening PEF values, in spirometric
parameters, in asthmatic symptoms or in the use of rescue beta2-agonists. The
decrease in bronchial hyperresponsiveness
was, however, more marked in the high dose budesonide group, reaching
a borderline significance (P=0.10 high
vs. low dose budesonide). In addition, in serum markers of asthmatic
inflammation significant differences were shown between the treatment groups.
The decrease in the number of blood eosinophils during the treatment was more
marked in the high dose budesonide group (P=0.02; high vs. low dose
budesonide). In serum ECP no change was observed in the low dose budesonide
group, but a marked decrease in the high-dose budesonide group (P=0.008; high
vs. low dose budesonide). The change was even more marked with regard to serum
EPX (P=0.005; high vs. low dose budesonide). Our results support the view that
the treatment of newly detected asthma should be started with a high dose of
inhaled steroid. The low dose may not be enough to suppress asthmatic
inflammation despite good clinical primary response.
1614. Van
den Berg NJ. Ossip MS. Hederos CA.
Anttila H. Ribeiro BL. Davies PI. Salmeterol/fluticasone propionate
(50/100 microg) in combination in a Diskus inhaler (Seretide) is effective and
safe in children with asthma. Pediatric Pulmonology. 30(2):97-105, 2000 Aug.
Abstract
The aim of this study was
to compare the efficacy and safety in children of salmeterol (50 microg twice
daily) plus fluticasone propionate (100 microg twice daily) when delivered
together via a single Diskus inhaler (Seretide; combination therapy) or
concurrently using two separate Diskus inhalers (concurrent therapy). In a
multicenter, randomized, double-blind, double-dummy, parallel-group study, 257
children with reversible airways obstruction who remained symptomatic on
inhaled corticosteroids (200-500 microg daily) alone were randomized to
combination or concurrent therapy for 12 weeks. Efficacy was assessed by
measuring daily peak expiratory flow (PEF), symptom scores, and rescue
salbutamol use. In addition, lung function tests were performed at each clinic
visit. Safety assessments included monitoring of adverse events and morning
serum cortisol concentrations. The primary efficacy parameter (mean morning
PEF) increased during treatment in both groups; adjusted mean changes were 33
and 28 L/min for the combination and concurrent therapies, respectively. The 90% confidence interval for the
difference in mean morning PEF between treatment groups was within the +15
L/min criterion for clinical equivalence. Similarly, there were improvements in
pulmonary function, symptom score, and rescue salbutamol use during treatment
in both groups, with no significant differences between the combination and
concurrent therapy groups for any of these secondary efficacy parameters. Both
treatment regimens were well-tolerated and had comparable adverse event
profiles. Mean morning serum cortisol levels increased similarly in both groups
during the study. In conclusion, salmeterol and fluticasone propionate therapy
given as a new combination product is as safe and effective in children with
asthma as the same drugs given concurrently via separate inhalers. Copyright 2000 Wiley-Liss, Inc.
1615. Warman
KL. Management of asthma exacerbations: home treatment. [Review] [32 refs]
Journal of Asthma. 37(6):461-8, 2000
Sep.
Abstract
Asthma is a major cause
of morbidity in children. Delays in care and
inappropriate home management practices can contribute to morbidity
and mortality. Guidelines for the
diagnosis and management of asthma were developed in 1991 and revised in 1997
by The National Heart, Lung and Blood Institute. In this article we review the
recommended pharmacological protocol for home treatment of asthma
exacerbations, and then discuss in more detail behavioral components of asthma
management, including monitoring of symptoms, seeking medical care, developing
clinician-patient partnerships, and practical issues in equipment and medication
usage. Discrepancies between guideline recommendations and current management
practices are also discussed. [References: 32]
1616. Waserman
S. Dolovich J. Conway M.
Marshall JS. TNF-alpha dysregulation in asthma: relationship to ongoing
corticosteroidtherapy. Canadian Respiratory Journal. 7(3):229-37, 2000 May-Jun.
Abstract
BACKGROUND: Tumour
necrosis factor-alpha (TNF-alpha) is a major proinflammatory cytokine that is
thought to be important in the pathogenesis of asthma. However, alterations in
systemic regulation of this cytokine in asthma have not been examined in the
context of corticosteroid therapy. OBJECTIVES: To examine the ability of
peripheral blood mononuclear cells (PBMC) from three different groups of
patients with asthma requiring varying amounts of inhaled corticosteroids (ICS)
for clinical control, and to examine cells from age- and sex-matched
nonasthmatic patients to produce TNF-alpha. DESIGN: All patients with asthma
had a positive methacholine challenge test. 'High dose' ICS patients with asthma required ICS greater
than or equal to 800 microg/day.
'Medium dose' patients with asthma were on less than or equal to 500
microg/day of ICS, whereas 'no ICS' patients with asthma had received no ICS
for at least three months. Each patient with asthma was examined in parallel
with an age- and sex-matched, nonasthmatic, nonatopic control subject. Cells
were cultured (with or without the addition of potential stimulators
phytohemagglutinin, lipopolysaccharide, formyl-methionine-leucine-phenylalanine
or antihuman CD3), and TNF-alpha production was assessed by ELISA. MAIN
RESULTS: PBMC from both high dose ICS (n=8) and no ICS (n=11) patients with
asthma produced more than twice the amount of TNF-alpha than cells from matched
nonasthmatic control patients
(P<0.01) when cultured alone or in the presence of each stimulus (P<0.05). In contrast, there was no
significant difference in TNF-alpha
production between medium dose ICS patients with asthma and control
patients. A group of asymptomatic atopic patients (n=6) did not have an
increased level of TNF-alpha production. CONCLUSIONS: Increases in TNF-a
production within the PBMC compartment can be observed in both patients with
asthma receiving high dose ICS and in a group of patients with mild asthma
receiving no ICS therapy, but not in patients with asthma receiving a medium
dose of ICS or atopic patients.
1617. Williams
S. Sehgal M. Falter K. Dennis R. Jones D.
Boudreaux J. Homa D. Raskin-Hood C. Brown C. Griffith M. Redd S. Effect of asthma on the quality of
life among children and their caregivers in the Atlanta Empowerment Zone.
Journal of Urban Health. 77(2):268-79,
2000 Jun.
Abstract
BACKGROUND AND OBJECTIVE:
Asthma is the most common chronic pediatric disease and exacts a toll on the
health-related quality of life of
affected children and their primary caregivers. This investigation
describes the relationship between the clinical severity of asthma among
inner-city children and their quality of life and that of their primary adult
caregivers. METHODS: Telephone interview data were collected from individual
adult caregivers of 5-12-year-old children with asthma. Questions addressed the
history, diagnosis, and management of the child's asthma, the child's family
and social background, the family's
socioeconomic status, the caregiver's knowledge and attitude about
asthma, and the health-related quality of life of both the child and the
caregiver. An asthma severity score was calculated from the caregiver's
responses to questions about their child's wheezing frequency, nocturnal and
early morning symptoms, and speaking during an asthma attack, as well as the
impact of the disease on their child's physical activity and breathing during
the prior 4-month period. A clinical asthma triage score was determined from
information collected at the emergency department about the child's oxygen
saturation, alertness, use of accessory respiratory muscles, extent of
breathlessness, and peak expiratory flow. Spearman correlation coefficients were
used to identify association between
quality of life and disease severity, caretaker's asthma knowledge, and
functional impact of asthma symptoms. RESULTS: Data from 240 of 755 eligible
children were analyzed. Most children were younger than 11 years, male, black,
and non-Hispanic. The children's median duration of asthma diagnosis was 86% of
their life (range less than 1 to 11.3 years, median 5.0 years). Of the primary
caregivers, 69% had at least completed high school, and 90% reported a total
monthly household income of $1,600 or less. The maximum possible
quality-of-life score and the median for caregivers were 91 and 70,
respectively; for children, the same scores were 69 and 58, respectively. In
addition, there was significant
negative correlation of the quality-of-life scores of both the
caregivers and children with the number of schooldays the children missed (r =
-0.24 and r = -0.26, respectively, P < .001 for both) and the caregivers'
and children's asthma severity scores (r = -0.39 and r = -0.47, respectively, P
< .001 for both). The quality-of-life scores of the children and caregivers
did not correlate significantly with the asthma triage scores. CONCLUSIONS: The
questionnaires captured baseline quality-of-life information about this urban
population and will facilitate longitudinal monitoring. The fact that the
quality-of-life scores of children with asthma correlated with those of their
adult caregivers, but not with their clinical triage scores, highlights the
impact of asthma on families and the importance of having a long-term
comprehensive management plan that is not based on exacerbations, but that
includes both the children and their primary caregivers.
1618. Wilson
AM. Dempsey OJ. Sims EJ.
Lipworth BJ. Subjective and objective markers of treatment response in
patients with seasonal allergic rhinitis [see comments]. Annals of Allergy,
Asthma, & Immunology. 85(2):111-4,
2000 Aug.
Abstract
BACKGROUND: Although
there is a recognized association between upper and lower allergic airways disease, it is unknown how seasonal
allergic rhinitis (SAR) therapy will effect sensitive markers of airway
function in patients with no history of asthma. OBJECTIVE: To prospectively
evaluate subjective and objective markers of treatment response in 26 patients
with SAR who have been screened to exclude a diagnosis of asthma. METHODS: The
patients' usual treatment, with antihistamine alone (n = 13) or in combination
with intranasal corticosteroid (n = 13), was withheld for 1 week to achieve a
baseline and then resumed. Measurements were made after baseline and after 2
and 4 weeks of treatment for nasal peak inspiratory flow rate (nPIFR); airways
resistance (Raw) and specific conductance (sGaw); and nasal nitric oxide (NO).
Patients reported their symptom (nasal, throat and eye) scores, daily activity
scores, and ocular sodium cromoglycate usage over the preceding 24 hours.
RESULTS: Compared with baseline, there
were significant (P < .05) improvements with nPIFR, symptom scores and
cromoglycate usage at 2 and 4 weeks of treatment. There was no significant
suppression for NO at 2 or 4 weeks. There was a significant correlation between
nPIFR and nasal symptoms (r = -0.52, P < .001). After 4 weeks of treatment
there were significant (P < .05) improvements in sGaw (143.3% predicted) and
Raw (91.6% predicted) compared with baseline (sGaw: 111.8%, Raw: 104.2%
predicted). CONCLUSION: Treatment of SAR improves upper and lower airway
parameters but not NO. Nasal PIFR correlates significantly with nasal symptoms.
1619. Wuthrich
B. Lethal or life-threatening allergic reactions to food. [Review] [53 refs]
Journal of Investigational Allergology & Clinical Immunology. 10(2):59-65,
2000 Mar-Apr.
Abstract
Fatal or life-threatening
anaphylactic reactions to food occur in infants, children and adults. Atopic individuals with bronchial asthma and
prior allergic reactions to the same food are at a particularly high risk,
whereby even the mere inhalation of the allergenic food can be fatal. Not only
peanuts, seafood and milk can induce severe, potentially lethal anaphylaxis,
but indeed a wide spectrum of foods, according to the different patterns of
food sensitivity in different countries. Foods with "hidden"
allergens and meals at restaurants are particularly dangerous for patients with
food allergies. Similarly, schools, public places and restaurants are the major
places of risk. However, the main factor contributing to a fatal outcome is the
fact that the victims did not carry their emergency kit with adrenaline
(epinephrine) with them. In cases of
death where food anaphylaxis is suspected, it is important for forensic
reasons to preserve uneaten portions of the food in order to identify (hidden)
allergens. It is also important to determine postmortem specific serum IgE,
tryptase and histamine levels to document the anaphylaxis. There is a need to
raise awareness of the diagnosis and treatment of anaphylaxis among doctors,
those called upon to administer emergency medical care, and the public, and
also to provide increased support for those with potentially fatal food
allergies through the help of patients' organizations, and national and
international medical societies. The food industry should ensure a policy of
comprehensive labelling of ingredients so that even the smallest amount of
potentially lethal foodstuffs can be clearly identified. Finally, the
pharmaceutical industry should be persuaded to reintroduce an adrenaline
inhaler onto the market. [References:
53]
1620. Yanni
JM. Sharif NA. Gamache DA.
Miller ST. Weimer LK. Spellman JM. A current appreciation of sites
for pharmacological intervention in allergic conjunctivitis: effects of new
topical ocular drugs. [Review] [31 refs] Acta Ophthalmologica Scandinavica
Supplement. (228):33-7, 1999.
Abstract
Two important
realizations about pathophysiological mechanisms involved in allergic conjunctivitis have led to novel
drug discovery efforts and new topical ocular medications for prevention and
treatment of this prevent allergic disease. The first of these, interspecies
and intraspecies mast cell heterogeneity, was established in the mid-1980's by
investigators working in the field of asthma. It is now appreciated that
secretory responses as well as effects of pharmacological agents differ
depending upon the mast cell population studied. Two types of human mast cells,
the tryptase containing (T) and the tryptase/chymase containing (TC) mast
cells, have been characterized in a variety of tissues. Significantly, Irani et
al. (1) demonstrated by immunohistochemical staining that the mast cells
present in conjunctival tissues from patients with allergic conjunctivitis were
100% TC. Functional responses of human conjunctival mast cells to a variety of
secretagogues (2) were consistent with their classification as TC or connective
tissue type mast cells. Importantly, the studies by Miller et al. mentioned
above allowed the harvesting and preparation of human conjunctival mast cells
for use in drug screening studies.
Utilization of these cells has led to the identification of Patanol, the most
effective human conjunctival mast cell stabilizer available for topical use in
allergic conjunctivitis (3). These same studies demonstrated the lack of mast
cell stabilizing activity for cromolyn and nedocromil in these connective tissue
type, TC containing, human conjunctival mast cells. Similar lack of effect was
noted with these drugs on human skin mast cell degranulation (4). The second
important discovery in the area of allergic conjunctivitis has been the demonstration that conjunctival epithelial
cells may contribute to the perpetuation of the allergic response. A report
from Gamache et al. (5) identified cytokines produced by human conjunctival
epithelial cells following treatment with a number of stimuli. Significantly,
Sharif et al.(6) subsequently identified functional histamine H1 receptors on
these same cell types. Recently, Weimer et al. (7) have shown that exposure of
human conjunctival epithelial cells to histamine leads to the production of
pro-inflammatory cytokines IL-6 and IL-8. Importantly, treatment of the
epithelial cells with drugs that possess histamine H1 antagonist properties
prevents cytokine production. It is noteworthy that first generation
anti-histamines antazoline and pheniramine are not potent inhibitors of
histamine-stimulated cytokine synthesis in intact epithelial cells, while newer
anti-histamines Emadine and levocabastine are more potent. Surprisingly, Patanol was more potent as an inhibitor of
histamine-stimulated cytokine production by the epithelial cells than would be
predicted from its histamine H1 antagonist affinity. These inhibitory effects
on conjunctival epithelial cell production of pro-inflammatory cytokines may
contribute to enhanced clinical activity noted with these recently approved drugs.
[References: 31]
1621. Zarkovic
JP. Marenk M. Valovirta E. Kuusela
AL. Sandahl G. Persson B. Olsson H. One-year safety study
with bambuterol once daily and terbutaline three times daily in 2-12-year-old children with asthma. The
Bambuterol Multicentre Study Group.
Pediatric Pulmonology. 29(6):424-9,
2000 Jun.
Abstract
The aim of this study was
to compare bambuterol oral solution (10 mg)
administered once daily in the evening with terbutaline oral solution
(0.075 mg/kg body weight) administered three times daily in 2-5-year-old
children and to compare bambuterol tablets (10 mg or 20 mg) administered once
daily in the evening with terbutaline tablets (2.5 mg) administered three times
daily in 6-12-year-old children with asthma. The study was of an open,
randomized, parallel-group design, and lasted 1 year. The primary objective was
to evaluate safety (pulse rate, blood pressure, adverse events, hematology, and
clinical chemistry). Plasma terbutaline concentrations were also measured.
Evaluation of efficacy (FEV(1)) was a
secondary objective. A total of 141 patients (83 boys, 58 girls) were
randomized and treated with the study drugs, i.e., 43 patients in the
terbutaline group (30 on oral solution and 13 on tablets) and 98 patients in the bambuterol group (62 on oral solution
and 36 on tablets). A total of 11 patients discontinued the study: 3 were on
terbutaline, and 8 were on bambuterol. There were no clinically important
differences between treatment groups regarding pulse rate, or systolic or
diastolic blood pressure. There were no clinically important findings in the
laboratory tests (hematology and clinical chemistry). Both terbutaline and
bambuterol were well-tolerated, and the reported adverse events were mostly
mild or moderate. Mean steady state plasma terbutaline concentrations at the
visits ranged between 8.0-11.5 nmol/L in the bambuterol tablet group and
between 10.6-15.2 nmol/L in the terbutaline tablet group. The corresponding
values in children on oral solution were 10.3-11.3 nmol/L in the bambuterol
group and 7.5-9.7 nmol/L in the terbutaline group. FEV(1) measured in the
6-12-year-old children increased by more than 0.2 L in both treatment groups during the year in the
study. In conclusion, bambuterol tablets or oral solution once daily and
terbutaline tablets or oral solution three times daily showed a comparable and
favorable safety profile. Copyright 2000 Wiley-Liss, Inc.
2081 Anis AH. Lynd LD. Wang XH. King G. Spinelli JJ. Fitzgerald M. Bai T. Pare P. Double trouble: impact of inappropriate use of asthma medication on the use of health care resources. CMAJ. 164(5):625-31, 2001 Mar 6.
Abstract
BACKGROUND: There is considerable controversy about the regular use of short-acting beta-agonists for the treatment of asthma. Although case-control studies have suggested that excessive use of these drugs may worsen asthma control and increase the risk of fatal or near-fatal asthma, the controversy remains unresolved because of the confounding that exists among disease control, disease severity and the use of short-acting beta-agonists. Whatever the cause-and-effect relation between the use of short-acting beta-agonists and disease severity, we hypothesized that their excessive use, in conjunction with underuse of inhaled corticosteroids, would be a marker for poorly controlled asthma and excessive use of health care resources. METHODS: To characterize the pattern of health services utilization among asthmatic patients taking various doses of inhaled beta-agonists and corticosteroids in British Columbia, we linked the relevant health administrative databases. All patients between 5 and 50 years of age for whom a prescription for a short-acting beta-agonist was filled in 1995 and whose prescription data were captured through the provincial drug plan were included in a retrospective analysis of prescriptions for asthma drugs, physician prescribing patterns and health services utilization. Patients' use of asthma medication was classified as appropriate (low doses of short-acting beta-agonist and high doses of inhaled corticosteroid) or inappropriate (high doses of short-acting beta-agonist and low doses of inhaled corticosteroid), and the 2 resulting groups were compared, by means of logistic, Poisson and gamma regression, for differences in prescribing patterns, physician visits and use of hospital resources. RESULTS: A total of 23,986 patients were identified as having filled a prescription for a short-acting beta-agonist (for inhalation) in 1995. Of these, 3069 (12.8%) filled prescriptions for 9 or more canisters of beta-agonist, and of this group of high-dose beta-agonist users, 763 (24.9%) used no more than 100 micrograms/day of inhaled beclomethasone. On average, those with inappropriate use of beta-agonists visited significantly more physicians for their prescriptions (1.8 v. 1.4), and each of these physicians on average wrote significantly more prescriptions for asthma medications per patient than the physicians who prescribed to appropriate users (5.2 v. 2.5 prescriptions). Patients with inappropriate use were more likely to be admitted to hospital (adjusted relative risk [RR] 1.68, 95% confidence interval [CI] 1.25-2.26), were admitted to hospital more frequently (adjusted RR 1.81, 95% CI 1.41-2.32) and were more likely to require emergency admission (adjusted RR 1.93, 95% CI 1.35-2.77). INTERPRETATION: Despite the widespread distribution of guidelines for asthma pharmacotherapy, inappropriate use of asthma medications persists (specifically excessive use of inhaled short-acting beta-agonists combined with underuse of inhaled corticosteroids). Not only are patients who use medication inappropriately at higher risk for fatal or near-fatal asthma attacks, but, as shown in this study, they use significantly more health care resources than patients with appropriate medication use.
2084. Crystal RG. Research opportunities and advances in lung disease. JAMA. 285(5):612-8, 2001 Feb 7.
Abstract
Lung diseases cause morbidity, mortality, and economic burden. Susceptibility to pathogenesis of most lung diseases result from a complex interaction of a relevant challenge from the environment, genetic background, and the nature of the host responses. Cutting-edge research in lung disease now centers on understanding the lung as a genetically determined biological organ that functions to mediate gas exchange and defend against a hostile environment. A major challenge is to determine the hierarchy of gene expression that integrates the function of multiple cell types in this complex anatomy. Emerging therapies that will play a major role in the future treatment of lung disease include the use of recombinant proteins, including monoclonal antibodies, cell therapy (including stem cells), and gene therapy. Future advances will include the cure of the major hereditary lung disorders by gene therapy, new treatment for asthma, chronic obstructive pulmonary disease, and interstitial lung disease; development of vaccines to protect the lung from major lung pathogens; and pathogen-specific "designer" therapies to eradicate chronic lung infections.
2085. Gani F. Pozzi E. Crivellaro MA. Senna G. Landi M. Lombardi C. Canonica GW. Passalacqua G. The role of patient training in the management of seasonal rhinitis and asthma: clinical implications. Allergy. 56(1):65-8, 2001 Jan.
Abstract
BACKGROUND: Allergic rhinitis is an inflammatory disease often associated with bronchial asthma. Intranasal corticosteroids and oral antihistamines are the first-choice drugs. Patient training is relevant to asthma management, but little is known about its impact on rhinitis. We evaluated the role of patient training in the treatment of allergic rhinitis and its effects on nasal and bronchial symptoms. METHODS: One hundred and one patients (M/F = 62/39, age range 12-62 years) with pollen-induced rhinitis (32 with concomitant mild asthma) were enrolled. They were randomized into three groups: A (n = 30) with drug therapy alone, B (n = 35) with drug therapy plus training on the use of nasal spray, and C (n = 36) the same as B plus a lesson on rhinitis and asthma. All patients received mometasone furoate nasal spray for 8 weeks as regular therapy, plus rescue medications on demand. Symptoms and drug consumption were evaluated during the pollen season. RESULTS: The rate of noncompliance/dropout was highest in the untrained patients (P = 0.001). No difference in nasal symptoms was seen among the three groups. On the other hand, group C had significantly fewer asthma symptoms (P = 0.02) and less albuterol use (P = 0.005) than group A. Moreover, the trained group globally used less rescue medication than the other groups (P = 0.02). CONCLUSIONS: Detailed training of patients seems to improve compliance with treatment, reduce concomitant asthma symptoms, and reduce the use of symptomatic drugs.
2087. Grennan DM. Gray J. Loudon J. Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Annals of the Rheumatic Diseases. 60(3):214-7, 2001 Mar.
Abstract
OBJECTIVES: To determine whether continued methotrexate treatment increases the risk of postoperative infections or of surgical complications in patients with rheumatoid arthritis (RA) within one year of elective orthopaedic surgery. DESIGN: A prospective randomised study of postoperative infection or surgical complications occurring within one year of surgery in patients with RA who underwent elective orthopaedic surgery. SUBJECTS: 388 patients with RA who were to undergo elective orthopaedic surgery. Patients who were receiving ethotrexate were randomly allocated to groups who either continued methotrexate (group A) or who discontinued methotrexate from two weeks before surgery until two weeks after surgery (group B). Their complication rates were compared with complications occurring in 228 patients with RA (group C) who were not receiving methotrexate and who also underwent elective orthopaedic surgery. MAIN OUTCOME MEASURES: Signs of postoperative infection were recorded, including rubor, discharge, systemic infection, and frequency of wound dehiscence as well as the incidence of any surgical complication requiring a secondary revision procedure that occurred within one year of surgery. The frequencies of flare up activity of RA at six weeks and six months after surgery were also recorded. A flare of rheumatoid disease was defined as an increase in joint pain in two or more joints notified by the patient as well as by an increase in articular index of at least 25% after surgery. RESULTS: Signs of infection or surgical complications occurred in two of 88 procedures in group A (2%), 11 of 72 procedures in group B (15%), and 24 of 228 (10.5%) procedures in group C. The surgical complication or infection frequency in group A was less than that in either group B (p<0.003) or group C (p=0.026). At six weeks after surgery there were no flares in group A, six flares in group B (8%), and six flares in group C (2.6%). Logistic regression analysis of the overall surgical complication rate in all the patients with RA studied showed that methotrexate, whether continued or discontinued before surgery, did not increase the early complication rate in the patients with RA who underwent elective orthopaedic surgery. Other drugs-penicillamine, indometacin, cyclosporin, hydroxychloroquine, chloroquine, and prednisolone-all did significantly increase the risk of infection or surgical complication after elective orthopaedic surgery. The risk of surgery was also increased in the presence of intercurrent chronic diseases-diabetes, hypertension, bronchiectasis, psoriasis, asthma, and ischaemic heart disease. CONCLUSION: Continuation of methotrexate treatment does not increase the risk of either infections or of surgical complications occurring in patients with RA within one year of elective orthopaedic surgery. Thus methotrexate treatment should not be stopped in patients whose disease is controlled by the drug before elective orthopaedic surgery.
2089. Holgate ST. Lackie PM. Howarth PH. Roche WR. Puddicombe SM. Richter A. Wilson SJ. Holloway JW. Davies DE. Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma. International Archives of Allergy & Immunology. 124(1-3):253-8, 2001 Jan-Mar.
Abstract
BACKGROUND: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. METHODS: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. RESULTS: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme - the epithelial mesenchymal trophic unit - leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. CONCLUSIONS: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-betaRs provide targets against which to develop novel therapies for chronic asthma. Copyright 2001 S. Karger AG, Basel
2091. Hoshino M. Takahashi M. Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. Journal of Allergy & Clinical Immunology. 107(2):295-301, 2001 Feb.
Abstract
BACKGROUND: Angiogenesis is a prerequisite for airway remodeling in bronchial asthma. Several growth factors may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization. OBJECTIVE: We sought to compare bronchial vascularity and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin in bronchial biopsy specimens from asthmatic and healthy control subjects. METHODS: Bronchial biopsy specimens were obtained from 16 asthmatic subjects and 9 normal control subjects. The number of vessel profiles and the vascular area per unit area on a histologic section were estimated by using computerized image analysis after staining for type IV collagen in vessel walls. Numbers of VEGF+, bFGF+, and angiogenin+ cells were determined by means of immunoreactivity. RESULTS: The airways of asthmatic subjects had significantly more vessels (P < .05) and greater vascular area (P < .001) than that observed in control subjects. Asthmatic subjects exhibited higher VEGF and bFGF and angiogenin immunoreactivity in the submucosa than did control subjects (P < .001, respectively). Significant correlations were detected between the vascular area and the numbers of angiogenic factor-positive cells (VEGF: rs = 0.93, P < .001; bFGF: rs = 0.83, P < .001; angiogenin: rs = 0.88, P < .001) within the asthmatic airways. Furthermore, the degree of vascularity was inversely correlated with airway caliber and airway responsiveness. Colocalization analysis revealed that the angiogenic factor-positive cells were CD34+ cells, eosinophils, and macrophages. CONCLUSION: Our results suggest that increased vascularity of the bronchial mucosa in asthmatic subjects is closely related to the expression of angiogenic factors, which may then contribute to the pathogenesis of asthma.
2094. Kanazawa S. Tsunoda T. Onuma E. Majima T. Kagiyama M. Kikuchi K.VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. American Journal of Gastroenterology. 96(3):822-8, 2001 Mar.
Abstract
OBJECTIVE: Inflammatory bowel disease (IBD), the precise etiology of which remains unknown, is comprised of two forms of chronic intestinal inflammation; ulcerative colitis (UC) and Crohn's disease (CD). Recent evidence increasingly suggests that IBD is the result of dysfunctional immunoregulation manifested by inappropriate production of mucosal cytokines. An abnormal microcirculatory system has also been implicated in its pathogenesis. To elucidate the mechanism of ischemic change in IBD, we assesse serum concentration levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and plasma level of endothelin-1 (ET-1). We also investigated the expression of VEGF, b-FGF, and transforming growth factor-beta1,2,3 (TGF-beta1,2,3) in tissue by immunostaining. METHODS: Blood samples were obtained from 11 patients with UC, 11 patients with CD, and 10 patients as controls. Paraffin-embedded samples were used for an immunohistochemical study. RESULTS: The concentration levels (in picograms per milliliter) were as follows: for ET-1, UC: 127+/-47.0, CD: 167.3+/-35.1, and controls (asthma: 38.5+/-23.8, p < 0.01; diverticulitis: 40.5+/-25.6, p < 0.01), for b-FGF, UC: 9.2+/-1.9, CD: 9.1+/-1.5, and controls (asthma: 5.0+/-0, p < 0.01; diverticulitis: 5.0+/-0, p < 0.01), for VEGF, UC: 659.8+/-181.0, CD: 740.0+/-182.3, and controls (asthma: 193.7+/-58.7, p < 0.01; diverticulitis: 199.6+/-59.7, p < 0.01). The levels of VEGF and b-FGF were significantly higher in active IBD than those in the controls. There was a significant positive correlation among the serum levels of VEGF and b-FGF and the plasma level of ET-1; that is, elevated VEGF, b-FGF, and ET-1 levels correlated well with each other. Immunohistochemical studies showed increased venula in the submucosa and lamina propria. Overexpression of VEGF and b-FGF in endothelial cells was revealed and TGF-beta2 and TGF-beta3 were found in inflammatory cells of active IBD, but no change was observed around the vessels in the controls. CONCLUSIONS: It is suggested that the reciprocal reaction of these cytokines may contribute to angiogenesis in IBD b inducing intestinal ischemia through vasoconstriction.
2095. Kotaru C. Coreno A. Skowronski M. Ciufo R. McFadden ER Jr. Exhaled nitric oxide and thermally induced asthma. American Journal of Respiratory & Critical Care Medicine. 163(2):383-8, 2001 Feb.
Abstract
The purpose of the present study was to determine if nitric oxide (NO) is involved in the pathogenesis of thermally induced asthma. To provide data on this issue, 10 normal and 13 asthmatic subjects performed isocapnic hyperventilation with frigid air while the fractional concentration of NO in the expirate air (FENO) was serially monitored with a chemiluminescence analyzer. FEV1 was measured before and after hyperpnea. Prior to and throughout the challenge, the asthmatics had significantly larger values for FENO (baseline FENO normal, 11 +/- 2 ppb; asthma, 16 +/- 1; p = 0.03). Posthyperpnea, the normal subjects had little change in bronchial caliber (deltaFEV1 baseline to 5 min posthyperpnea, -3.5 +/- 1.5%; p = 0.06), whereas the patients with asthma developed significant airway obstruction (deltaFEV1, -27.7 +/- 2.9%; p = 0.0001). During hyperventilation, the volume of NO rose in both groups. The asthmatic subjects, however, generated approximately 55% more NO/min than did the normal control subjects even though their level of ventilation was approximately 66% less. In contrast to the normal subjects, NO production in the asthmatics continued into the recovery period after the challenge stopped and FENO rose temporally as the airflow limitation developed. These results suggest that NO plays an intimate role in the development of airway obstruction that follows hyperpnea.
2096. Kuo ML. Huang JL. Yeh KW. Li PS. Hsieh KH. Evaluation of Th1/Th2 ratio and cytokine production profile during acute exacerbation and convalescence in asthmatic children. Annals of Allergy, Asthma, & Immunology. 86(3):272-6, 2001 Mar.
Abstract
BACKGROUND: Th2-type cytokines, such as IL-4 and IL-5, are generally believed to play an important role in the pathogenesis of allergic asthma. In contrast, Th1-type cytokine, especially interferon (IFN)-gamma, is thought to have a downregulatory effect on Th2 immune response cells. Thus, the imbalance of Th1 and Th2 cells may be a key factor in relation to disease severity. OBJECTIVE: The aim of this study is to examine the changes in the Th1/Th2 ratios and cytokine production profiles of asthmatic children at acute attacks and convalescent stages. METHODS: Twelve asthmatic patients were included in this study. The percentages of IFN-gamma- or IL-4-producing cells were determined with a flow-cytometric method of intracellular protein detection. Fresh whole blood obtained from normal controls and patients at two stages was stimulated with brefeldin A, phorbol myristate acetate, and ionomycin for 4 hours. Cells were fixed and stained intracellularly with fluorescein isothiocyanate- or phycoerythrin-conjugated antibody specific to each cytokine in combination with anti-CD4. ELISA assays were applied to measure cytokine concentrations of supernatant from peripheral blood mononuclear cells (PBMC) activated with phorbol myristate acetate and ionomycin for 24 hours. RESULTS: Among CD4+ cells, the percentage of IL-4+ cells decreased significantly from 8.18 +/- 4.77% at acute attacks to 4.18 +/- 1.26% (P < .020) at convalescence. The percentage of IFN-gamma+ cells also decreased from 13.49 +/- 4.21% to 9.03 +/- 5.42% (P < .052). The Th1/Th2 ratios of patients at the two stages were similar, and both were lower than the normal controls. Significantly higher IL-5 and lower IFN-gamma production were detected from activated PBMC of asthmatic patients than normal controls. CONCLUSIONS: The decrease of IFN-gamma+ and IL-4+ cells detected at the single-cell level may explain the potential mechanism of convalescence from acute asthma attacks. High Th1/Th2 ratio and low IL-5 production from the PBMC of normal controls support the idea of a biased Th2 immune response in asthmatic patients.
2097. Larsen GL. Differences between adult and childhood asthma. [Review] [43 refs] Disease-A-Month. 47(1):34-44, 2001 Jan.
Abstract
During the last 2 decades, we have gained new insights into the pathogenesis of asthma; consequently, new therapeutic agents and approaches to therapy have emerged. Nevertheless, significant gaps remain in our understanding of this disease. Important new treatment issues affect childhood (the usual time of asthma onset), and researchers have recently described increases in asthma incidence in children. Yet, most clinical studies have been performed with adults, and our knowledge about major determinants of childhood asthma remains incomplete. Major challenges in pediatric asthma include methods of easily assessing lung function and noninvasive methods of assessing asthma's inflammatory nature. Research that addresses the mechanisms responsible for disease onset is also critical to decrease the prevalence of asthma. What we know about adult asthma cannot be used in the treatment of children without further study, but it is now clear that effective treatment should begin during childhood. (J Allergy Clin Immunol 2000;106:S153-7.) [References: 43]
2098. Lazzeri N. Belvisi MG. Patel HJ. Yacoub MH. Fan Chung K. Mitchell JA. Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells. Relevance to asthma therapy. American Journal of Respiratory Cell & Molecular Biology. 24(1):44-48, 2001 Jan.
Abstract
Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.
2099. Leff AR. Regulation of leukotrienes in the management of asthma: biology and clinical therapy. [Review] [64 refs] Annual Review of Medicine. 52:1-14, 2001.
Abstract
Leukotrienes (LTs) are the ultimate synthetic product resulting from the intracellular hydrolysis of membrane phospholipid at the nuclear envelope in inflammatory cells. Activated cytosolic phospholipase (cPLA2) catalyzes the production of arachidonic acid, which is converted by cyclooxygenases into leukotriene A4 (LTA4) and subsequently into the chemotaxin LTB4,which has no direct bronchoconstrictor activity. In certain inflammatory cells, LTA4 is converted into the cysteinyl leukotriene (cysLT) LTC4, which is converted into LTD4 and finally to LTE4 after extracellular transport. All cysLTs occupy the same receptors and are extremely potent bronchoconstricting agents that are pathogenetic in both asthma and allergy. With the identification of the structure of the cysLT receptor, antileukotriene therapies have been developed that either (a) inhibit synthesis of leukotriene (through 5-lipoxygenase inhibition) or (b) block the cysLT receptor. Preliminary investigations indicate that corticosteroids also may partially block the synthesis of cysLT and that cysLTs may be chemotactic for other inflammatory cells, e.g. eosinophils, by a mechanism that has not yet been defined. Currently, anti-LT therapies are approved by the US Food and Drug Administration (FDA) only for patients with asthma. These drugs generally are moderately efficacious agents, although they are highly efficacious in aspirin-induced asthma (AIA). In other forms of asthma, inhaled corticosteroid (ICS) therapy has been more effective than anti-LT therapy in improving air flow obstruction. However, anti-LT agents are additive to beta-adrenoceptor and ICS in their effects. Accordingly, anti-LT therapies are used frequently as supplemental treatments in asthmatic patients whose asthma is not optimally controlled by a combination of other drugs, including long-acting beta-adrenoceptor drugs and ICS agents. The growth of leukotriene receptor antagonists (LTRAs) has been extraordinary in the United States. The exceptional safety of these agents and their ease of administration as tablets taken once or twice daily has spurred this growth. In the past year, the high-affinity cysLT receptor has been cloned. This holds forth the promise of a second generation of LTRA agents of even greater efficacy and possibly greater duration of action. [References: 64]
2101. Lewis SA. Pavord ID. Stringer JR. Knox AJ. Weiss ST. Britton JR. The relation between peripheral blood leukocyte counts and respiratory symptoms, atopy, lung function, and airway responsiveness in adults. Chest. 119(1):105-14, 2001 Jan.
Abstract
STUDY OBJECTIVES: Eosinophils and neutrophils play major roles, respectively, in the pathogenesis of asthma and COPD, and it is well recognized that levels of these cells in peripheral blood are increased in relation to their pulmonary involvement. However, the relation between peripheral blood cell counts of the other major leukocyte groups and these lung diseases or markers of allergy or airflow obstruction is less clear. We have therefore investigated the association between peripheral blood levels of eosinophils, neutrophils, basophils, monocytes, and lymphocytes and the occurrence of chronic respiratory symptoms, atopy, lung function, and bronchial hyperresponsiveness, and the modifying effect of age, in adults. DESIGN: A cross-sectional general population study. SETTING: Data on > 2,000 British adults, who originally participated in a study of diet and lung health, were analyzed using multiple linear and logistic regression to adjust for potential confounders, including age, sex, and smoking history. RESULTS: We found that, like eosinophils, the peripheral basophil count was increased in relation to asthma and associated symptoms, and to airway hyperreactivity and increased total IgE, but differed from eosinophils in that basophils were unrelated to atopy. Monocytes were predominantly associated with symptoms indicative of obstructive airway disease, in similar relation to neutrophils, but both of these leukocyte counts were also increased in asthma patients in older age groups. Lymphocyte counts were unrelated to any objective or subjective marker of disease. CONCLUSIONS: If peripheral blood cell counts reflect pulmonary involvement of these leukocyte groups, basophils and monocytes may play a distinct role in the pathogenesis of allergic and nonallergic respiratory disease.
2102 Marks F. Harrell K. Fischer R. Successful use of cyclooxygenase-2 inhibitor in a patient with aspirin-induced asthma. Southern Medical Journal. 94(2):256-7, 2001 Feb.
Abstract
We describe the case of an aspirin-sensitive asthma patient with a history of anaphylactic reactions to nonsteroidal anti-inflammatory drugs. The patient was subsequently diagnosed with rheumatoid arthritis and treated with a cyclooxygenase (COX)-2 inhibitor without an adverse response. Current prescribing information warns to avoid using COX-2 inhibitors in aspirin-sensitive asthma patients. New evidence suggests that aspirin sensitivity may be linked to the COX-1 pathway, and COX-2 inhibitors, as a result of their selectivity, may be beneficial in patients with aspirin-induced asthma.
2105. Nicosia S. Capra V. Rovati GE. Leukotrienes as mediators of asthma. [Review] [210 refs] Pulmonary Pharmacology & Therapeutics. 14(1):3-19, 2001.
Abstract
This review describes the aspects of leukotriene (LT) pharmacology and biology that are relevant to their important role in asthma. The biosynthesis and metabolism, including transcellular metabolism, of LTB4 and the cysteinyl-LTs (i.e. LTC4, LTD4 and LTE4) are described, and their transport is briefly outlined. The existence, distribution and pharmacological characterization of the receptors (BLT, CysLT1, CysLT2), as well as the transduction mechanisms triggered, are discussed in detail. We also describe their effects on airway smooth muscle tone, hyperresponsiveness and proliferation, on vascular tone and permeability, on mucus secretion, on neural fibers and inflammatory cell functions. Finally, the evidence supporting their role as asthma mediators is reviewed, including the effects of anti LT drugs (both biosynthesis inhibitors and receptor antagonists) in experimental and clinical asthma. [References: 210]
2107. Oettgen HC. Geha RS. IgE regulation and roles in asthma pathogenesis. [Review] [155 refs] Journal of Allergy & Clinical Immunology. 107(3):429-40, 2001 Mar.
Abstract
Asthma and the predisposition to produce IgE are inherited as linked traits in families. In patients IgE levels correlate with asthma severity and bronchial hyperresponsiveness. The concept that IgE plays a critical role in asthma pathogenesis has driven the development of IgE blockers, which are currently being introduced into clinical use. This review focuses on the mechanisms whereby IgE participates both in immediate hypersensitivity responses in the airways and in the induction of chronic allergic bronchial inflammation. The molecular genetic events that give rise to IgE production by B cells and the cellular and cytokine factors that support IgE production in the bronchial mucosal microenvironment are discussed. It is clear that much remains to be learned regarding the roles of IgE in asthma and the genetic and environmental influences that lead to its production. Over the next few years, the emerging experience with anti-IgE in patients will provide a more complete understanding of the mechanisms whereby IgE contributes to disease, as well as the therapeutic potential of its inhibition. [References: 155]
2109. Roland M. Bhowmik A. Sapsford RJ. Seemungal TA. Jeffries DJ. Warner TD. Wedzicha JA. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax. 56(1):30-5, 2001 Jan.
Abstract
BACKGROUND: Endothelin (ET)-l is a bronchoconstrictor peptide produced in the airways. It has been implicated in the pathogenesis of asthma and virally mediated airway inflammation and may play a role in exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: Seventy one patients with COPD were followed prospectively and sampled for plasma and sputum ET-1 levels when stable and during an exacerbation. Sputum was also examined for cytokines, human rhinovirus, and Chlamydia pneumoniae. RESULTS: Plasma ET-1 levels were available for 67 patients with stable COPD (mean (SD) 0.58 (0.31) pg/ml); 28 pairs of stable-exacerbation plasma samples had a mean stable ET-1 level of 0.54 (0.30) pg/ml rising to 0.67 (0.35) pg/ml at exacerbation (mean difference 0.13, 95% confidence interval (CI) 0.04 to 0.21, p = 0.004). Plasma ET-1 levels in the 67 patients with stable COPD were inversely correlated with baseline forced expiratory volume in one second (FEV(1); r = -0. 29, p = 0.022) and forced vital capacity (FVC; r = -0.38, p = 0.002). The change in plasma ET-1 levels during an exacerbation correlated with the change in oxygen saturation (SaO(2); r = -0.41, p = 0.036). In 14 stable-exacerbation pairs of sputum samples median stable ET-1 levels were 5.37 (0.97-21.95) pg/ml rising to 34.68 (13.77-51.95) pg/ml during an exacerbation (mean difference 25.14, 95% CI 3.77 to 46.51, p = 0.028). This increase in sputum ET-1 levels correlated with the increase in plasma ET-1 levels (r = 0.917, p = 0.001) and sputum interleukin (IL)-6 levels (r = 0.718, p =0.013). CONCLUSIONS: Sputum levels of ET-1 rise in COPD patients during an exacerbation and this is reflected by a smaller rise in plasma ET-1 levels. ET-1 may have a role in mediating airway inflammatory changes during exacerbations of COPD.
2112. Tang RB. Chen SJ. Soluble interleukin-2 receptor and interleukin-4 in sera of asthmatic children before and after a prednisolone course. Annals of Allergy, Asthma, & Immunology. 86(3):314-7, 2001 Mar.
Abstract
BACKGROUND: Cytokine-mediated interactions among inflammatory cells may play a role in the pathogenesis of bronchial asthma. OBJECTIVE: To understand the role of soluble interleukin-2 receptor (sIL-2R) and interleukin-4 (IL-4) in the disease activity of acute asthma, changes in serum concentrations of sIL-2R and IL-4 elaborated by activated T-lymphocyte before and after prednisolone therapy with clinical improvement were determined in the present study. METHODS: Circulating levels of sIL-2R and IL-4 in sera from 15 normal control subjects and in sera from 20 allergic asthmatic children with acute exacerbation and in a stable condition were determined by using commercially available ELISA kits. RESULTS: The mean concentration of serum sIL-2R was significantly higher in acute exacerbation than in children with stable asthma (368.9 +/- 395.4 pg/mL vs 291.2 +/- 361.0 pg/mL; P < .01) or in control subjects (124.6 +/- 17.8 pg/mL; P < .001). The mean concentration of serum IL-4 was higher in acute exacerbation (5.82 +/- 1.10 pg/mL) and in stable asthmatic patients (6.73 +/- 2.83 pg/mL) versus control group subjects (5.54 +/- 1.20 pg/mL). However, the difference was not statistically significant among the three study groups. CONCLUSIONS: This study provides further evidence that changes in serum IL-2R may serve as an objective indicator for clinical outcome of allergic asthmatic patients.
2115. Wickens K. Crane J. Kemp T. Lewis S. D'Souza W. Sawyer G. Stone L. Tohill S. Kennedy J. Slater T. Rains N. Pearce N.A case-control study of risk factors for asthma in New Zealand children. Australian & New Zealand Journal of Public Health. 25(1):44-9, 2001.
Abstract
OBJECTIVE: As in other English-speaking countries, asthma is a major and increasing health problem in New Zealand. This study examined the risk factors for asthma in children aged 7-9. METHODS: Cases and controls were randomly selected from participants in the Wellington arm of the International Study of Asthma and Allergies in Childhood (ISAAC). Cases were children with a previous diagnosis of asthma and current medication use (n=233), and controls were children with no history of wheezing and no diagnosis of asthma (n=241). RESULTS: After controlling for confounders, factors significantly associated with asthma were maternal (OR=3.36, 95% CI 1.88-5.99) and paternal asthma (OR-2.67, 95% CI 1.42-5.02), and male sex (OR=1.81, 95% CI 1.17-2.81). Children from social classes 5 and 6 or with unemployed parents (OR=2.32, 95% CI 1.22-4.44) were significantly more likely to have asthma than children in social classes 1 and 2. There was no significant association between having polio vaccination (OR=2.48, 95% CI 0.83-7.41), hepatitis B vaccination (OR=0.66, 95% CI 0.42-1.04) or measles/mumps/rubella vaccination (OR=1.43, 95% CI 0.85-2.41) and asthma. CONCLUSIONS: This study has confirmed the associations of family history and lower socio-economic status with current asthma in 7-9 year old children. The role of vaccinations requires further research.
2615-2676 No Abstract.