Internal Medicine Board Review Asthma

Emily DiMango, MD
Internal Medicine Board Review
Asthma
Emily DiMango, MD
Director
John Edsall/John Wood Asthma Center
Columbia University Medical Center
Asthma prevalence
(Increased from 7.3% in 2001 to 8.2% in 2009)
Objectives
• Review asthma epidemiology
• Asthma pathophysiology/definition
• NIH National Asthma Education and
Prevention Program (NAEPP) Guidelines
• Treatment
• Novel therapies
Asthma Is Prevalent:
Significant Morbidity and Mortality
32.6 Million People Have Had an Asthma Diagnosis in
Their Lifetime
25 Million People Are Currently
Diagnosed With Asthma
12.2 Million People Suffer From
Asthma Attacks Annually
Approximately 3500 AsthmaRelated Deaths Occur Annually
Approximately 11 People Die From Asthma Each Day
Center for Disease Control, MMWR 2011
Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma/asthma.htm. Accessed 2011
Risk factors for development of asthma
-Family history
-Sensitization to common allergens
early in life
-Maternal smoking
-Obesity
-Western lifestyle
?? Diet, pollution
Busse, W., NEJM 2001; 344:5
Emily DiMango, MD
Percentage of Children with Asthma According to the Number of Older Siblings
and the
Age at Entry into Day Care
Asthma - Definition
• Chronic inflammatory disorder of the airways,
(eosinophil and lymphocyte mediated)
• Usually associated with atopy (IgE mediated)
• Obstruction to airflow (bronchospasm) which is
reversible (either spontaneously or with use of
medications).
• Airway hyperresponsiveness and narrowing in
response to a variety of environmental stimuli.
Ball M NEJM 2000
Airway inflammation - Early and late
Response
Accelerated decline in lung function among asthmatics
Airway inflammatory changes
Lange, et al, NEJM 1998
Emily DiMango, MD
Diagnostic Criteria For Asthma
Physiologic features of asthma
• Cough, dyspnea, wheeze, chest tightness
• Waxing and waning symptoms
• Heightened airway reactivity – exacerbations
upon exposure to stimuli
• Episodic airflow limitation in response to
antigenic triggers.
• Reduced FEV1 and FEV1/FVC ratio (obstructive
defect)
• Reversible airflow limitation with a significant (>12%
or 200ml) increase in FEV1 in response to inhaled
bronchodilator.
• response to bronchoprovocation testing (methacholine, histamine, cold air) which provokes
bronchial narrowing (decrease of 20%in FEV1) in
sensitive individuals. (Clinical trials, professional
athletes)
Flow Volume loop appearance
Airway obstruction
Normal
Pathologic targets in asthma
Treatment
• Airway smooth muscle (b2 agonists, anticholinergics, phosphodiesterase inhibitors)
• Airway inflammatory cells and mediators
(glucocorticoids, leukotriene modifiers,
anti-IgE, phosphodiesterase inhibitors)
Emily DiMango, MD
Reliever vs. controller medicines
Reliever medicines
• Short acting
bronchodilators (b2
agonists, ipatropium)
Controller medicines
• Inhaled corticosteroids
• Leukotriene modifiers
(sythesis inhibitors and
receptor antagonists)
• long acting beta agonists
• theophylline
• cromyln
• Omalizumab (Xolair)
Inhaled glucocorticoids
• First line controller therapy for all but very
mild asthma
• Reduce exacerbations, hospitalizations and
death from asthma
• Improve lung function and quality of life
• ? Prevent or delay airway remodeling
• Inhaled glucocorticoid use inversely
correlates with asthma mortality
Inhaled steroid use inversely correlates with asthma exacerbation
Busse, W, NEJM 2001; 344: 5
Williams LK, JACI 2011
Time Course of Improvements in ACQ and MiniAQLQ Scores and Peak Expiratory Flow over a 2-Year
Period in Patients with Asthma.
b2-agonists
•
•
•
•
Most effective bronchodilator for asthma
bind to b2 receptors on airway smooth muscle cells
useful as “rescue” for acute symptom relief
Side effects are due to overlap b1 activity in other
organs (cardiac) and activation of non-airway b2
receptors (skeletal muscle, metabolic)
• no effect on inflammation
• Polymorphisms in b2-receptor gene may modify
response?????
Price D et al. N Engl J Med 2011;364:1695-1707.
Emily DiMango, MD
Long acting beta agonists
• Inhaled salmeterol (component of Advair®) and formoterol
(Symbicort®);duration of action 12 hours
• Delayed onset of action (30 minutes) for salmeterol, rapid onset for
formoterol
• Efficacious in moderate to severe asthma
• In patients not well controlled on ICS, addition of LABA is more
effective than increasing steroid dose. Use of LABA may be associated
with increased asthma risk.
• Preferred add-on therapy in patients not adequately controlled on
inhaled corticosteroids (STEROID SPARING).
• Not monotherapy
Salmeterol Multi-center Research
Trial (SMART)
• Initiated 1996
• 28-week safety study comparing salmeterol
(Serevent®) and placebo in addition to usual asthma
therapy in the treatment of asthma. (47% of patients
enrolled were taking inhaled steroids)
• Primary endpoint: number of respiratory-related
deaths and life-threatening events (intubations)
• interim analysis performed once half of the patients
(25,800) were recruited.
• Black box warning: Increased mortality and serious
events in some patients taking long acting beta agonists,
particularly African Americans
Are Long Acting Beta agonists
dangerous in some people with
asthma?
Occurrence of asthma-related deaths by phase and study year
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Nelson, H. S. et al. Chest 2006;129:15-26
Question
• A 78 year old woman with glaucoma and
osteopenia has been treated with fluticasone
110mcg, two puffs bid. She reports asthma
symptoms and need for short acting
bronchodilators 5 times per week and awakens
once per week with asthma symptoms.
All of the following are acceptable changes in
treatment EXCEPT:
Improve asthma control
Improve lung function
Reduce exacerbations
Some individuals may be at increased risk
for asthma related deaths and asthma related
events such as intubation.
• NOT CLEAR YET
Possible answers
a. Increase fluticasone to 220mcg, two puffs
bid
b. Change medication to combination
fluticasone/salmeterol 250mcg/50mcg,
one puff bid.
c. No change in therapy is necessary
d. Discuss environmental triggers with
patient
Emily DiMango, MD
Monoclonal Ab – IgE (omalizumab,
xolair®)
Effect of treatment with anti-IgE on
corticosteroid requirement
• Approved for treatment of moderate and severe atopic
asthma (positive skin test or RAST), dose is weight and
IgE dependent. Elevated IgE not necessary.
• Effective in reducing asthma exacerbation rate and
reducing required corticosteroid dose
• Subcutaneous injections 1-2x/month
• BLACK BOX: Associated with anaphylaxis, even with
long term use, requires 2 hour observation
Milgrom H NEJM 1999
Assessment of asthma severity in
initiation of therapy
NAEPP GUIDELINES FOR
DIAGNOSIS AND TREATMENT
OF ASTHMA 2007
Assessment of asthma impairment
and risk during office visits
• Nocturnal awakenings from asthma
symptoms
• Days per week with symptoms
• Need for rescue bronchodilators
• Activity limitation because of asthma
• Peak flow variability > 20%
• Frequency of exacerbations, loss of lung
function,urgent care visits to assess risk
• Consider level of asthma “impairment” and
“risk”
NAEPP Severity classification
• Mild intermittent: symptoms < 2x/week,
nocturnal symptoms < 2x/month, normal
FEV1
• Mild persistent: symptoms 3-6x/week, 3-4
awakenings/month, normal FEV1
• Moderate persistent: daily symptoms, >5
nocturnal awakenings, FEV1 60-80%
• Severe persistent: continual symptoms,
FEV1 < 60%
Emily DiMango, MD
Well controlled asthma
Classification of Control
•
•
•
•
• Well controlled
• Not well controlled
• Very poorly controlled
Symptoms < 2 days per week
< 2 nocturnal awakenings per month
FEV1 > 80% predicted
0-1 exacerbations per year
Overview of Guidelines
Long term control of asthma
- Classify asthma severity to initiate therapy (assess
impairment and risk)
– Assess control to monitor and adjust therapy (every 1-6
months) – STEP UP OR DOWN.
– Patient education, environmental control and management of
comorbidities (rhinitis, sinusitis, allergies) at every visit
– Consider asthma specialist if more than medium dose ICS is
needed for control
– Consider subcutaneous allergen immunotherapy for patients
who have moderate to severe allergic asthma.
– Re-assess patients every 1-6 months, PFTs once yearly
Stepwise Approach for Managing Asthma
NAEPP 2007
Intermittent
Sx < 2x/week
< 2 awaken/mo
FEV1 > 80%
Step 1
Preferred:
SABA prn
Mild
Persistent
Sx 3-6x/week
Awaken 3-4x
FEV1 > 80%
Severe Persistent
Sx daily
Awaken > 5x
FEV1 60-80%
Step 6
Step 5
Preferred:
High-Dose ICS +
Preferred:
LABA
High-Dose ICS +
Preferred:
+ Oral
LABA
Medium-Dose
Corticosteroid
ICS + LABA
and
and
Alternative:
Consider
Consider
Medium-Dose
Omalizumab
Omalizumab for
ICS
for Patients
Patients Who
and either
Who Have
Have Allergies
LTRA ,
Allergies (>12 yrs)
Theophylline,
or Zileuton
Add LTRA,
theophylline
Step 4
Preferred:
Medium-Dose
ICS
or
Alternative:
Cromolyn,
Nedocromil,
LTRA ,
or
Theophylline
Time to asthma exacerbation based on symptom based,
FeNO based or guideline based controller therapy
Continual sx
Frequent awakening
FEV1 < 60%
Moderate
Persistent
Step 3
Step 2
Preferred:
Low-Dose ICS
•Symptoms occurring more than twice per
week is an indication for daily antiinflammatory therapy (ICS preferred).
“Well-controlled”
• Step up anti-inflammatory therapy or add second
controller based on need for bronchodilators and
frequency of symptoms (LABAs are preferred
add-on, though increase in ICS now being
recommended because of risk issues for LABAs)
Low-Dose ICS +
LABA
Alternative:
Low-Dose ICS
and either
LTRA,
Theophylline,
or Zileuton
Calhoun, W JAMA 2012
Emily DiMango, MD
Mean monthly dose of ICS based
on different treatment strategies
Tiotropium versus salmeterol or doubling dose of ICS
• Guideline based 1610 ug/ml
• Biomarker (FeNO) based: 1,617 ug/ml
• Symptom based: 832 ug/ml (p < 0.012
compared with guideline and biomarker
based).
Peters, S, NEJM 2010
Tiotropium versus salmeterol or doubling dose of ICS
Guidelines for treatment of
asthma in pregnancy
• Inadequate control of asthma is a greater risk to
the fetus than is use of asthma medications
(premature birth, low birth weight).
• Monthly evaluations during pregnancy including
asthma history and lung function (PF or
spirometry)
• Albuterol is the preferred bronchodilator
Peters, S, NEJM 2010
• Budesonide is the preferred ICS – no risk to fetus
Guiding asthma management during pregnancy using
exhaled nitric oxide
Case 2
• 58 year old woman with asthma since age 42,
usually treated with budesonide two puffs bid.
• Comorbidities: osteoporosis, “early cataracts”
• URI 4 days ago, now with persistent cough, using
albuterol 5 times per day, short of breath climbing
stairs in her home
• Past two nights has awakened with asthma
symptoms requiring use of rescue therapy
Powell; Lancet 2011
• WHAT IS THE BEST TREATMENT?
Emily DiMango, MD
Treatment Options
A. Increase budesonide to four puffs bid
B. Add a long acting beta agonist
C. Add a leukotriene modifier
D. Treat with oral corticosteroids for 10 days.
E. Trial of anti-reflux medication
Bronchial thermoplasty
-performed in bronchoscopy suite
-thermal energy to destroy bronchial smooth muscle cells in airways
-improves asthma quality of life, reduces exacerbations.
Thermoplasty improves asthma related quality of life
Asthma Triggers
Effect of high fat versus low fat diet on bronchodilator response
What’s new in Asthma treatment
• Macrolides – not effective
• Bronchial thermoplasty
• Tiotropium as add-on controller
Wood LG, JACI 2011
• Prn rather than regular use of ICS
• Attention to pragmatic (CER) study results
Emily DiMango, MD
Summary
• Asthma prevalence is high and increasing
• Asthma mortality is slowly decreasing
• Clinical diagnosis with PFTs as
confirmatory
• Rescue versus controller medication
• Goal of treatment is very well controlled
(same as mild intermittent symptoms)
• ICS first line for all but mild intermittent
READING
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Busse, W., NEJM 2001; 344:5 (Review article)
Fanta, C., NEJM 2009 (Review of asthma medication)
Badrul A. NEJM 2010 (discussion of FDA warning on LABAs)
Eder, W, etal NEJM 2007 (Changing asthma epidemiology)
Boushey, H etal, NEJM 2005 (asthma therapies)
Milgrom H NEJM 1999 (anti-IgE)
Nelson, H. S. et al. Chest 2006;129:15-26 (safety of LABA)
Castro, M. Am J Respir Crit Care Med 2010 (thermoplasty)
http://www.nhlbi.nih.gov/guidelines/asthma/epr3/resource.pdf.
Peters, S, etal. NEJM 2010 (tiotropium)