Acute and Severe Asthma

Bob Lanier M.D.

Clinical Professor
University of North Texas
Guest Professor:
Peking Union Medical Colle
Beijing
 Make sure it’s severe asthma
100 patients : severe intractable asthma
12% did not have asthma
8% had additional diagnosis ( GERD etc)
55% had reversible airways
20% had no reversablity
Non-compliance with steroids common in the 55
Non-compliance not common in the 20
10% major psychiatric disease
Overall 32% re- classified

Robinson DS, Barnes et al et al Eur Respir J. 2003 Sep;22(3):478-

83.Systematic assessment of difficult-to-treat asthma.
Definition of severe asthma
• Major ( 1 or 2) Minor (2 or >)

1. Daily controller
• continuous high 2. SABA daily
dose inhaled 3. FEV1 < 80%
corticosteroids 6. 1+ Urgent visits
7. 3 or more steroid "bursts" /yr
6. Deterioration with < 25%
• oral reduction in oral or inhaled
corticosteroid dose.
corticosteroids 7. Near fatal asthma event in the
for >50% of the past year
previous year
ATS Workshop Consensus for Definition of Severe/Refractory Asthma 2000
 How big a problem ?
2 million ED visits each year in the United States-

2% of all ED visits – in cities asthma up to 10% of

all ED visits.

5-10% of all asthma hospitalizations = ICU

0.4% patients succumb

8% mortality in admissions requiring ventilation

10% death after near fatal episode

 How it begins…..
Acutely as with RSV – or as genetic time bomb?

Who is at risk for progression – FeV1 is only studied factor

Children with decreased FeV1 = adults with (modest)

decreased FeV1 (Australia and New Zealand
studies 17-35 years in length)

NJH 2/3 severe asthma had onset in early childhood, 1/3 by

12 years or later. Later onset = worse

2 European suggest that late/adult onset asthma = more

rapid
decline
 Genetic factors

• No single gene Mutations in promoter region of

the IL-4 gene or the promoter/coding regions of
the IL-4 receptor
• “non-Th2” factors- transforming growth factor
(TGF)-ß1 and monocyte chemotactic protein
(MCP)-1 \ promote fibrotic reactions
• polymorphisms in ADAM-33 associated with
rapid declines in lung function
• Polymorphisms in the beta-2 receptor, arginine
substitutions at position 16 (Arg/Arg) ~15% of
the Caucasian population and ~25% of the
African American population …….
 Environmental factors
>Allergy = > severe asthma

Severe asthmatics in the ENFUMOSA study were

less atopic than a milder asthma control group,

Role of cigarettes unclear

A cross-sectional European multicentre study of the clinical phenotype of

chronic severe asthma. European Network for Understanding Mechanisms
of Severe Asthma. Eur Respir J 2003;22(3):470-7
 Steroid-unresponsive asthma
Maybe
Two types of Trueyou need
steroid-resistant a bigger
asthma.

dose – expression of glucocorticoid receptor beta, a less active

Type I steroid-resistant (SR) asthma is cytokine induced and is associated
with increased
glucocorticoid receptor isoform.
maybe prednisilone
Type II SR asthma is due to low numbers of glucocorticoid receptors.
maybe by injection –
“An important distinction between these two types of SR asthma is
that the glucocorticoid receptor defect in Type I, but not Type II,
SR asthma - I is reversible in culture and is sustained by
incubation with combination interleukin (IL)-2 and IL-4.”
Type lll ?

Leung DY, Spahn JD, Szefler SJ..

Steroid-unresponsive asthma
Semin Respir Crit Care Med. 2002;23(4):387-98
 GRE- steroid resistance
Blood monocytes: asthmatic patients
Effect of dexamethasone 1µM
cytoplasm 75 Anti-GR antibody

Nuclear localisation (%)

*
50

**
25

nuclei 0
Mild Steroid Steroid
dependent resistant
 HOW STEROIDS WORK
Recruit histone
deacetylases
(HDACs)
Steroidtomolecules
the site
of active Cell membrane
inflammatory gene
transcription and
Inactive steroid
inhibit the
receptor acetylation of core
histones necessary
Active steroid - receptor
Primed steroid for inflammatory
complex
receptor
gene transcription.
Dimer formation

Nucleus Increased
Gene binding anti-inflammatory
activity

DNA strand

GRE GRE GRE

 Role of Histone Deacetylase
HDACs Key enzymes in chromatin remodeling

T
complexes.
Asthma = increased HAT - decreased HDAC
HDACs HDACs
Decreased HDACInjury
HDACs HDACs
Impaired HDAC
(histone deacetylases)

s s Transcription

ss Severe Asthma
Acetlylation

Young-Koo Jee Presentation: KCAAI Novermber 2006

Phenotypes of severe asthma

Early Late
• Atopy ++++ ++
• Allergic symptoms ++++ ++
• Family history +++ +
• Hx atopic dermatitis +++ +
• Persistent eosinophilia ++ +++
• Urinary cysteinyl leukotrienes ++ +++

Adapted from the work of Sally Wenzel M.D. University of Pittsburg

 Airway remodeling in
Severe asthma
• Worse remodeling ( SBM) = severe with persistant eosinophila
>TGF-ß + cells in the submucosa

Activates Fibroblasts – increase collagen

• Stimulated with TGF-ß and a Th2 cytokine, (IL-4 or IL-13) = > eotaxin-1

• increase in collagen MMP-9,,

deposition
TGF-ß break it down.
 Omalizumab, anti-IgE recombinant
humanized monoclonal antibody, for the
treatment of severe allergic asthma

( n=525) Omalizumab treatment resulted in significantly

fewer asthma
BACKGROUND: A recombinantexacerbations per subject
humanized anti-IgE mAb, omalizumab, andwithinfreelower
forms complexes
IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in
thepercentages of subjects
treatment of asthma. OBJECTIVE: The purpose experiencing
of this study was to evaluatean the exacerbation
efficacy and
safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In
thisthan
phase III,placebo treatment.trial,Beclomethasone
double-blinded, placebo-controlled 525 subjects with severe allergicreduction
asthma
requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab
and discontinuation
subcutaneously was
every 2 or 4 weeks, depending significantly
on baseline IgE level and bodygreater
weight. Inhaled
corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a
with
omalizumab
further treatment
12-week treatment period. than treatment
RESULTS: Omalizumab with placebo.
resulted in significantly fewer
asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation
thanImprovements
placebo treatment during thein asthma
stable steroid phasesymptoms and
(0.28 vs 0.54 [P =.006] pulmonary
and 14.6% vs 23.3%
[P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs
function
32.3% occurred
[P =.004], respectively). alongdipropionate
Beclomethasone with areductionreduction in greater
was significantly
omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone
rescue with

beta-agonist
dipropionate
Improvements use.
discontinuation was
in asthma symptoms
more likely with omalizumab (39.6% vs 19.1% [P <.001]).
and pulmonary function occurred along with a reduction in
rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to
that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces
asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

Busse W, Corren J, Lanier BQ, et Omalizumab is effective in the

long-term control of severe allergic asthma.
 Profile of responders to
Omalizumab
Patients who benefit most when omalizumab is
Pooled analysis of two multicenter, double-blind, randomized, placebo-controlled phase III studies with omalizumab. PATIENTS:

administered asINTERVENTIONS:
add-onOmalizumab therapy (n = 542) orare those
One thousand seventy allergic asthma patients symptomatic despite moderate-to-high doses (mean, 725 micro g/d) of inhaled
beclomethasone dipropionate (BDP). placebo (n = 528) were administered at a 4-
weekly subcutaneous dose of at least 0.016 mg/kg/IgE (IU/mL) for 16 weeks in addition to stable BDP therapy. MEASUREMENTS

receiving high doses ofusageBDP, those with a history

AND RESULTS: Univariate logistic regression was performed to explore baseline variables predictive of best response. Various
aspects of response (reduced symptom scores, reduced of rescue medication, improved lung function, improved quality of
life [QoL]) were explored as well as a composite definition of response (response in at least one of these four aspects with no

of
were frequent
also determined for theemergency asthma treatment,
of predictive covariates and
asthma exacerbation during 16 weeks of treatment). Time to onset of response as well as the ability to predict eventual response
composite definition of response. A consistent pattern was seen over all
definitions of response (except for QoL). For the composite definition, a history of emergency asthma treatment in the past year was

those with poor lungwithout a function. Patients

were 63% and 54%, should be
the factor most predictive (p = 0.015) of best response on active treatment (response rate for those with such history was 67% for
omalizumab and 42% for placebo; for those history the response rates respectively). Another factor
predictive of best response on active treatment was high BDP dose (p = 0.037; response rate for those treated with >or= 800 micro

treated with omalizumab forratesaforminimum duration

g/d was 65% for omalizumab and 40% for placebo; for those treated with < 800 micro g/d, the response rates were 63% and 55%,
respectively). A low FEV(1) was also predictive (p = 0.072; response those with FEV(1) <or= 65% predicted were 60% for
omalizumab and 40% for placebo; for those with FEV(1) >or= 65% predicted, the response rates were 67% and 53%, respectively).

of 122.25weeks.
Seventy-six percent of patients had at least one of these factors. This subgroup showed odds of being a responder (composite
definition) times higher (95% confidence interval, 1.68 to 3.01) than placebo. Some 38% of patients treated with omalizumab
showed a response (composite definition) at the first evaluation time point at 4 weeks, increasing to 64% at week 16 (vs 48% for
placebo; p < 0.001). Among omalizumab responders at 16 weeks, only 61% had responded at 4 weeks whereas 87% had
responded at 12 weeks. CONCLUSIONS: Patients who benefit most when omalizumab is administered as add-on therapy are
those receiving high doses of BDP, those with a history of frequent emergency asthma treatment, and those with poor lung function.
Patients should be treated with omalizumab for a minimum duration of 12 weeks.

Bousquet J, Wenzel S, et al Predicting response to omalizumab, an anti-IgE antibody, in

patients with allergic asthma. Chest. 2004 Apr;125(4):1378-86.
 How it’s dosed
Target IgE
↓
IgEIgEIgE
<10 IU/mL
IgE IgE IgE
IgE IgEIgE
IgEIgE IgE
IgE
IgE IgE
+ Omalizumab IgE
IgE

Theophylline in reverse

Persistent skin testing

and dosage and danger
Evaluation of severe asthma and
therapeutic options
• Confirmation of diagnosis
– Lung volumes and diffusing capacity
– Hi resolution CT scan
– Methacholine challenge with laryngoscopy
• Evaluation of confounding/exacerbating factors
– ph probe
– Sinus CT
– IgE level/allergen skin testing
– AM cortisol for patients on oral steroids (NJH Protoco)
Via Sally Wenzel
– Evaluation of pharmacy records for refills
• Evaluation of asthma phenotype
– Determination of age at onset/allergic phenotype
• Skin testing
• Questions regarding asthma symptoms in response to allergic stimuli
– Determination of eosinophilic phenotype
• Bronchoscopy at selected centers
• Sputum analysis
• Exhaled nitric oxide
 Initial assessment
Take a brief history and perform a rapid
physical give oxygen and inhaled short-
acting beta2 agonist immediately.

Take a more detailed history and do a

complete physical examination once therapy
has been initiated.

Wheeze is an unreliable indicator of the

severity of an asthma attack and may be
absent in severe asthma.
 Summary:
Hallmarks of severe asthma
• Polymorphisms in the beta-2 receptor,
arginine substitutions at position 16
(Arg/Arg)
~15% Caucasian population ~25% Black
• severe asthma more common in women
• 25% aspirin sensitivity
• Worse with later onset
• Diminished perception of dyspnea
• Steroid resistance ( dose response shift)