Transcript Asthma Update Suneel Kumar MD Definition of Asthma • National Asthma Education and Prevention Program (NAEPP) defined as: – Airway obstruction that is reversible (but not.

Asthma Update
Suneel Kumar MD
Definition of Asthma
• National Asthma Education and
Prevention Program (NAEPP) defined
as:
– Airway obstruction that is reversible (but
not completely so in some subjects), either
spontaneously or with treatment
– Airway inflammation
– Increased airway responsiveness to a
variety of stimuli
WHO Definition of Asthma
• "A chronic inflammatory disorder of the
airways in which many cells play a role, in
particular mast cells, eosinophils, and T
lymphocytes. In susceptible individuals this
inflammation causes recurrent episodes of
wheezing, breathlessness, chest tightness,
and cough particularly at night and/or in the
early morning. These symptoms are usually
associated with widespread but variable
airflow limitation that is at least partly
reversible either spontaneously or with
treatment. The inflammation also causes an
associated increase in airway responsiveness
to a variety of stimuli."
Symptoms
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Cough
Wheezing
Chest tightness
Shortness of breath
Update in Asthma
• Current guidelines for treatment of
asthma
• Beta agonist use
• Inhaled corticosteroids
• Leukotriene modifiers
• Chromones
• Anti-IgE therapy
• Use of exhaled nitric oxide in
monitoring asthma
• Asthma during pregnancy
Current Guidelines for Treatment
Mild Intermittent Asthma
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Symptoms < 2 days/week
Symptoms < 2 nights/month
PEF or FEV1 > 80%
PEF variability < 20%
No daily medication needed
PRN beta agonists
Course of systemic steroids for
exacerbations
Mild Persistent Asthma
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Symptoms > 2 days/wk but < 1x/day
> 2 nights/month
PEF or FEV1 > 80%
PEF variability 20-30%
Preferred treatment low dose inhaled
corticosteroids
• Alternatives include cromolyn,
leukotriene modifiers, necromodil, or
sustained release theophylline
Moderate Persistent Asthma
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Symptoms daily
> 1 night/week
PEF or FEV1 > 60% and < 80%
PEF variability > 30%
Preferred treatment is low to medium
dose inhaled corticosteroid and a long
acting inhaled beta 2 agonist
• Alternative includes increasing ICS
within moderate dose range, or low to
medium dose ICS with either
leukotriene modifier or theophylline
Severe Persistent Asthma
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Continual symptoms
Frequent nocturnal attacks
PEF or FEV1 < 60%
PEF variability > 30%
Preferred treatment is high dose
inhaled corticosteroid and long acting
beta 2 agonists
• If needed, can add systemic
corticosteroids
Goals of Therapy
• Minimal or no chronic symptoms day
or night
• Minimal or no exacerbations
• No limitations on activities; no
school/work missed
• Maintain (near) normal pulmonary
function
• Minimal use of short-acting inhaled
beta 2 agonist
• Minimal or no adverse effects from
medications
Stepwise Approach
• Review treatment every 1 to 6 months,
and gradually step down treatment
• If asthma controlled not maintained,
then a step up in treatment may be
warranted
Reasons for Poor Asthma Control
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Inhaler Technique
Compliance
Environment
Also assess for an alternative diagnosis
“All that wheezes is not asthma, and
not all asthma wheezes”
Factors Affecting Compliance
• Support of health care professional
and family
• Route of drug administration (inhaled
vs. oral)
• Complexity of drug regimens
• Side effects of medications
• $$ Cost $$
Beta 2 Agonists
Beta 2 Agonists
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Most potent and rapidly acting
bronchodilators currently available
for clinical use
Given in different forms:
– short acting = isoproterenol
– intermediate acting = albuterol,
metaproterenol, pirbuterol, levalbuterol,
terbutaline (IV only), fenoterol [not
available in the US]
– long acting = salmeterol, formoterol
Mechanism of Action
• Beta 2 agonists interact with beta 2
receptors on the surface of a variety of
cells that may play a role in asthma
pathogenesis
• Beta agonists have the potential to
relax bronchial smooth muscle,
decrease mast cell mediator release,
inhibit neutrophil, eosinophil, and
lymphocyte functional responses,
increase mucociliary transport, and
affect vascular tone and edema
formation
MDI with Spacer vs. Nebulizer
• Equivalent bronchodilation can be
achieved by giving beta 2 agonist with
a spacer/holding chamber or by
nebulizer therapy
• Continuous administration with a
nebulizer may be more effective in
severely obstructed adults and in
those who have difficulty with an MDI
plus spacer
Chronic Use of Beta Agonists
• Arguments against chronic use:
– Mortality may be increased
– Control of asthma may worsen
– Equal or superior efficacy can be achieved
with inhaled corticosteroids
Increased Mortality with Chronic Use?
• A case-control study using linked
health insurance databases in
Saskatchewan, Canada*
• Increased risk of death or near-death
from asthma was associated with the
regular use of inhaled beta agonists,
especially fenoterol (adjusted OR 6.1;
4.1 for albuterol)
• Did not appear to be confounded by
asthma severity, and there was no
relation to non–asthma mortality
*Spitzer et al, NEJM Feb 1992;326(8):501-6
Increased Mortality with Chronic Use?
• However, increased odds ratios were
also noted for theophylline (OR 2.4)
and oral corticosteroids (OR 2.5)
• The case-control design precludes the
establishment of causality
*Spitzer et al, NEJM Feb 1992;326(8):501-6
Increased Mortality with Chronic Use?
• A subsequent analysis demonstrated a
relationship between CV death and use
of beta agonists taken orally or by
nebulizer (RR = 2.4) but not when
taken by MDI (RR = 1.2)
• Risk of CV death was also greater in
patients who used theophylline (RR =
2.7)
• Most of CV deaths in patients with
underlying CV disease, including acute
coronary insufficiency and congestive
cardiomyopathy*
*Suissa et al, Am J Respir Crit Care Med 1996 Dec;154(6 Pt 1):1598-602
Increased Mortality with Chronic Use?
• A similar case-control study design
demonstrated no evidence of any
adverse effects on mortality with
prolonged use of long-acting beta
agonists
• Use of short-acting beta agonists in
the 12 months prior to an index event
was not associated with an increased
risk of death from asthma, suggesting
a direct causal relationship was
unlikely*
*Anderson et al, BMJ 2005 Jan 15;330(7483):117
Long Acting Beta Agonist Monotherapy
• Prolonged treatment with long-acting
beta agonists and without inhaled
corticosteroids has been associated with
increased mortality
• 28-week placebo-controlled trial
assessing the safety of the long-acting
beta agonist salmeterol enrolled over
25,000 patients, but was stopped early
when interim analysis revealed a
significantly increased risk of death in
those not taking concomitant inhaled
corticosteroids and, independent of
steroid therapy, in African-American
patients*
*"The Pink Sheet" FDC Reports. Chevy Chase, MD. 2003; 65(4):10
Tolerance to Beta Agonists
• More frequent in chronic use
• Induced more with oral rather than
inhaled preparations
• Tolerance to long acting beta agonists
may or may not occur (conflicting
data)
Corticosteroids
Glucocorticoids
• Most potent antiinflammatory agents
available for the treatment of asthma
• More effective than beta agonists,
theophylline, and cromolyn sodium in
reducing airway hyperresponsiveness
during maintenance therapy
Glucocorticoid Mechanisms
• Alleviating airway inflammation
• Reducing collagen and tenascin
deposition, two features associated
with airway remodeling
• Inhibit the synthesis of almost all
known cytokines
• Alteration of the number and
availability of circulating leukocytes
• Reduction in vascular permeability
• Inhibition of mediator synthesis and
release
Steroids and Long Acting Beta Agonists
• Results in greater improvements in
lung function and symptom control
than monotherapy with escalating
doses of inhaled glucocorticoid
• Act synergistically to activate
transcription factors, decrease smooth
muscle proliferation, and impair
eosinophil adhesion
Potency of Inhaled Corticosteroids
Can ICS Cause Osteoporosis?
• Three year prospective study looked at
dose of inhaled triamcinolone and rate
of bone loss in premenopausal women
with asthma
• There was a dose-related decline in
bone density in the total hip and
trochanter
• No dose-related decline in the femoral
neck or spine*
*Israel et al, NEJM Sept 2001;345:941-47
Leukotriene Modifiers
Leukotriene Modification
• 5-lipoxygenase pathway is a series of
biochemical reactions that result in the
transformation of arachidonic acid into
leukotrienes
• Produced by eosinophils and mast cells
when appropriately activated
Leukotriene Modifiers
• Zafirlukast (Accolate) and montelukast
(Singulair) are inhibitors of the action
of LTD4 at its receptor
• Zileuton (Zyflo) is an inhibitor of 5lipoxygenase
• All are oral
Leukotriene Modifiers
• Superior effect when compared to
placebo in the treatment of patients
with mild to moderate asthma
• Associated with both a significant
decrease in the need for rescue beta
agonist therapy and improved asthma
symptoms, especially at night
• Similar in magnitude to those achieved
with inhaled steroids given at
recommended doses
Montelukast vs. Beclomethasone
• Both agents demonstrated similar
efficacy with respect to preventing
asthma exacerbations in moderate
persistent asthma
• However, beclomethasone was
significantly superior to montelukast
in its capacity to improve objective
measures of lung function as
measured by average responses
Cause of Churg-Strauss?
• Rarely (1 out of 25,000 to 150,000
patient-years of treatment) ChurgStrauss vasculitis has been seen in
patients started on leukotriene
modifiers who were on systemic
steroids
• It is unlikely that this is a direct effect
of leukotriene inhibition in these
patients, and is more probably due to
preexisting CSS unmasked as a result
of steroid withdrawal
Chromones
Chromones
• Cromolyn sodium and nedocromil
• Act as mast cell stabilizers by
inhibiting chloride channels (thereby
stopping degranulation)
• Remarkably favorable therapeutic
indices
Use of Chromones
• Children and young adults with mild to
moderate asthma requiring an
antiinflammatory agent
• Patients with a strong allergic
component to their asthma
• Patients with exercise-induced
bronchospasm
• Patients who require an
antiinflammatory agent but for whom
ICS are contraindicated or undesirable
Anti-IgE Therapy
Anti-IgE Therapy
• Most asthmatic patients have elevated
circulating IgE concentrations when
levels are adjusted for age
• IgE is produced by B lymphocytes
Anti-IgE Therapy
• Recombinant humanized antibody
omalizumab (Xolair) binds IgE with
high affinity
• Developed for the treatment of allergic
diseases
• Binds to the C-epsilon-3 domain of
circulating IgE but does not bind to Fcepsilon-RI, and therefore does not
activate mast cells or basophils
• Specific to IgE; does not bind to IgG or
IgA
Omalizumab
• SQ injection every 2 to 4 weeks
• Dose determined by levels of serum
IgE
• Considered as an add-on therapy to
reduce or discontinue treatment with
oral corticosteroids
• May also be indicated in patients who
have severe allergic symptoms of
asthma and rhinitis and who have very
high circulating levels of IgE
Omalizumab
• Circulating IgE-omalizumab complexes
are small
• No evidence of immune complex
formation
• Elimination half-life is 1 to 4 weeks
• Aerosolized omalizumab (10 mg) is
ineffective in protecting against
allergen challenge and has no effect on
circulating IgE
Asthma Control During ICS Withdrawl
Omalizumab and ICS Therapy
US sites alone
US and international sites
Omalizumab
• Necessary to obtain almost complete
disappearance of circulating IgE in
order to achieve clinical efficacy
• Dose of 150 to 375 mcg every 2 to 4
weeks
• Peak serum concentration is reached
in 7 to 8 days
• Should be treated for a minimum of 12
weeks
• Cost is $10,000 to $12,000 per year
• Well tolerated
Exhaled Nitric Oxide
Nitric Oxide Effects in the Lung
• Regulates vascular and bronchial
tone, promoting dilation of both
vessels and airway
• Helps to facilitate the coordinated
beating of ciliated epithelial cells
• Important neurotransmitter for
non-adrenergic, non-cholinergic
neurons which run in the bronchial
wall
Isoforms of NOS
NO Formation
• nNOS and eNOS are usually
constitutively active and produce
low amounts of NO
• iNOS has the capacity to generate
large quantities of NO when
transcriptionally upregulated by
the inflammatory cytokines TNF
alpha, IL-1 beta, and IFN-gamma
FENO in Asthma
Red = normals
Blue = asthmatics
FENO
• Asthmatics have higher FENO than
do similar non-asthmatic subjects
• The magnitude of FENO in increased in
proportion to bronchial wall
inflammation, induced-sputum
eosinophils, and airway
hyperresponsiveness
FENO
• Increased FENO levels are associated
with deterioration in asthma control
• FENO is reduced in a dose-dependent
manner with antiinflammatory
treatment
• Prospective randomized single-blind
placebo controlled trial showed tha
following FENO levels can significantly
decrease the dose of ICS without a
significant change in rate of asthma
exacerbations, use of oral steroids, or
in level of airway inflammation*
*Smith et al, NEJM May 2005; 352(21):2163-73
Pregnancy and Asthma
Beta 2 Agonists
• Beta agonists are safe
• More experience with older
medications
• Also used as tocolytic agents
Theophylline
• Methylxanthines, especially
theophylline and aminophylline, are
considered safe
• Clinical use is limited
• Decreased protein binding during
pregancy; should use levels 8 to 12
µg/mL
• Fetal serum levels same as maternal
• Decreased drug clearance during the
third trimester
• Can inhibit uterine contraction
Inhaled Anticholinergics
• Safe, especially ipatropium
• No adverse development in fetus
Corticosteroids
• Small risk during pregnacy, and should
be withheld unless indicated
• Three potential areas of concern have
been raised: congenital malformations,
primarily cleft palate; low birth
weight; and neonatal adrenal
insufficiency
• No data in humans to show increased
risk of cleft palate in humans
• Palatial closure in 12th week
Corticosteroids
• Some studies show a slight decrease in
birth weight with systemic steroids
• Slight increased risk of prematurity in
studies, but may be related to severity
of asthma rather than use of steroids
Inhaled Corticosteroids
• ICS, especially beclomethasone,
triamcinolone, and budesonide, have
been studied
• The only randomized, controlled trial
assessed 105 asthma exacerbations in
84 pregnant women who were
managed with or without inhaled
beclomethasone
• Associated with a decreased rate of
readmission for asthma (12 vs 33%),
and no adverse events or outcomes
were noted*
*Wendel et al,Am J Obstet Gynecol 1996 Jul;175(1):150-4
Inhaled Corticosteroids
• Registry-based cohort study of 2,014
Swedish women who used inhaled
budesonide during early pregnancy
• Rate of congenital malformations was
no different from that of the general
population (3.8 vs 3.5%)*
• Based largely upon these findings,
budesonide is currently the only
inhaled corticosteroid with a
pregnancy category B rating
*Kallen et al, Obstet Gynecol 1999 Mar;93(3):392-5
Chromones
• Animal data and experience in 296
human pregnancies have not
demonstrated an increase in fetal
malformations or other adverse effects
with cromolyn sodium
• Human data are not available for
nedocromil, although preclinical
animal studies suggest that this drug
is also safe
Leukotriene Modifiers
• Animal data on zafirlukast have shown
no teratogenicity at oral doses up to
160 times the maximum human daily
oral dose on a mg/m2 basis
• No teratogenicity has been observed
with montelukast given to rats or
rabbits at doses greater than 300
times the maximum human daily oral
dose on a mg/m2 basis
• Adequate studies in pregnant human
women have not been performed
Conclusion
Horse hospitals