This document discusses the optimal management of severe or refractory asthma. It defines refractory asthma based on medication requirements, symptoms, exacerbations, and airflow limitation. The pathology of refractory asthma involves persistent airway inflammation often with neutrophils and structural changes like increased smooth muscle mass. Treatment involves confirming the diagnosis, treating exacerbating factors, and optimizing standard pharmacotherapy with inhaled corticosteroids and additional controllers. For uncontrolled cases, alternative options like macrolide antibiotics, antifungals, omalizumab, and bronchial thermoplasty may be considered.

3. Reference
Optimal Management of
Severe/Refractory Asthma
Clinical Medicine Insights: Circulatory,
Respiratory and Pulmonary Medicine
2011:5 37–47
Optimal Management of
Severe/Refractory Asthma
Clinical Medicine Insights: Circulatory,
Respiratory and Pulmonary Medicine
2011:5 37–47

4. 1.Definition
2.Diagnosis
3.Risk factors.
4.The Pathology of Refractory
Asthma
5.Treatment

5. .A chronic inflammatory disorder of the airways
.Many cells and cellular elements play a role
.Chronic inflammation is associated with airway hyper
responsiveness that leads to recurrent episodes of
wheezing, breathlessness, chest tightness, and
coughing particularly at night or in the early
morning
.Widespread, variable, and often reversible airflow
obstruction
GINA 2011

6. Refractory Asthma” should be defined
on the basis of
.med-ication requirements,
.asthma symptoms,
.frequency of asthma exacerbations, and
.Degree of airflow limitation.

7. According to American Thoracic Society
workshop consensus for definition of
severe/refractory asthma: (published in 2000(.
Definition requires that at least one
major criterion and two minor criteria
are met.provided that:
1.other disorders have been excluded,
2.exacerbating factors have been
treated, and
3.patient is generally compliant.

8. 1.Treatment with continuous or near
continuous (≥50% of
year( oral corticosteroids.
2.Need for treatment with high-dose
inhaled corticosteroids.

9. Drug Dose (puffs/d( Dose (μg/d(
a. Beclomethasone
dipropionate
<40puffs (42
μg/inhalation
<20puffs (84
μg/nhalation
<1,260
b. Budesonide <6puffs <1,200
c. Flunisolide <8puffs <2,000
d. Fluticasone
propionate
<8puffs (110 μg/(, . 4
puffs (220 μg/(
<880
e. Triamcinolone
acetonide
<20puffs <2,000

10. 1.Need for additional daily treatment with a controller
medication (e.g long-acting β agonist, theophylline, or
leukotriene antagonist(.
2.Asthma symptoms needing short-acting β2 agonist
use on a daily or near-daily basis.
3.Persistent airway obstruction (FEV1 <80%
predicted, diurnal peak expiratory flow variability
<20%(
4.One or more urgent care visits for asthma per year.

11. 5.Three or more oral steroid bursts per year.
6.Prompt deterioration with ≤25% reduction in
oral or intravenous corticosteroid dose
7.Near-fatal asthma event in the past

13. .Misdiagnosis may be as high as 10%
.exposure to factors that may contribute to a poor
response to conventional therapy (risk factors(.
.Nonadherence with oral steroid therapy has been
reported at30%, and
.in some cases there is a significant psychological factors to
patients’ symptoms and percetion of their asthma.

14. 1.Chronic Obstructive Pulmonary Disease
(COPD(
2.Bronchiectasis and cystic fibrosis
3.Primary bronchiolar disorders
4.Congestive heart failure
5.Upper airway obstruction
6.Aspiration or inhaled foreign body

16. Fatal or near fatal asthma
Severe asthma
Steroid-dependent and/or resistant asthma
Difficult to control asthma
Poorly controlled asthma
Brittle asthma (either Type 1 or Type 2, depending on the stability of the
patient's maximum speed of expiration, or peak expiratory flow rate
(PEFR). Type 1 is characterized by sustained, chronic variability of PEFR,
while type 2 is distinguished by sudden unpredictable drops in PEFR
where asthma symptoms are otherwise well controlled and the function of
the lungs is not substantially impaired)
Irreversible asthma

18. 1exacerbating factors
Gastro-oesophageal reflux (GERD) is commonly
associated with chronic asthma both in adults and
children.
Environmental exposures
1.Tobacco smoke
a.In utero
b. Environmental
2.Allergen sensitization
3.Viral infections
4.Occupational agents
5.Air pollutants
6.Stress

19. Systemic diseases
Carcinoid syndrome
Churg-Strauss syndrome and others vasculitides
Drugs
B-blockers
Nonsteroidal anti-inflammatory drugs
Chronic infections
Mycoplasma
Chlamydia
Fungi (especially Aspergillus species(
Bronchopulmonary allergic aspergillosis is very important,
if left untreated it can lead to bronchiectasis
Psycological factors

20. Comorbidity,The coexistence of:
Chronic rhinitis, nasal polyposis, and sinusitis contribute
to asthma severity.
Endocrine factors:
Severe asthma is two to three times more common in
women than in men
Due to a genetic polymorphism of the oestrogen receptor
which affecting disease severity
Thyrotoxicosis
Obesity

21. 4.The Pathology of Refractory Asthma
Pathological features of severe/ refractory asthma:
1.persistent inflammation:
Although chronic asthma is associated with airway
eosinophilia but when the disease adopts a severe
phenotype the inflammatory profile commonly
changes to the presence of neutrophils alone or in
combination with eosinophils.

22. the neutrophils also seem to be in an activated state
with their numbers correlating with indices of airway
damage and reduced corticosteroid responsiveness
with increased expression of TNFα and interferon-γ.
.In addition, neutrophils have been seen in increased numbers
in patients dying of status asthmaticus
.Studies of sputum samples from patients undergoing
emergency room
.visits for status asthmaticus, as well as studies of bronchial
washes from patients intubated for status asthmaticus, also
support the concept that the neutrophil may be an important
inflammatory cell in more severe forms of asthma

24. Figure 3: Possible cellular targets for TNFα in severe
corticosteroid refractory asthma
ICAM=interstitial cell adhesion molecule. VCAM=vascular cell
adhesion molecule. MAPK=mitogen-activated protein kinase. TNFα
is stored in granules and is released
in large amounts from mast cells and macrophages as a result of
immunological stimulation. In the airways, TNFα elicits a general
infl ammatory response mainly
through enhanced release of pro-infl ammatory and chemotactic
mediators and upregulation of adhesion molecules. These series
of events will ultimately lead to
chronic eosinophilic and neutrophilic infi ltration and irreversible
airway remodelling. TNFα also has a potent direct e ect on theff
airway smooth muscles leading to an increase in airway hyper-
responsiveness
. Adapted from Clin Sci 2005; 109: 135–42 with permission of
Portland Press.
www.thelancet.comVol 368 August 26, 2006

25. .The mass of airway smooth muscle appears to be
clearly increased in severe/refractory asthma as
opposed to mild to moderate asthma or COPD
.Thickness of the basement membrane, though of
unknown pathophysiological relevance, has been
shown to be increased in severe/refractory asthma
as compared to mild asthma and COPD

27. Figure 2: Infl ammatory and remodelling
responses in asthma with activation of the
epithelial mesenchymal trophic unit
Epithelial damage alters the set point for
communication between bronchial
epithelium and underlying mesenchymal
cells, leading to myofibroblast activation, an
increase in mesenchymal volume, and
induction of structural changes throughout
airway wall.
)Adapted from J Allergy Clin Immunol 2003; 111: 215–25, with
permission of Elsevier(.

28. In fatal asthma and sever asthma these
inflammatory and remodelling processes are
found not only in large but also small
airways.
Extensive small-airway involvement in severe disease has
important implications for inhaled drug delivery and
might explain the increased efficacy of the hydrofl-
uoroalkane formulations of corticosteroids and available
drugs.

29. Evidence-based Management of
Severe/Refractory Asthma:

30. it is important to:
)1(confirming the diagnosis of asthma,
)2(evaluate and treat confounding or
exacerbating
factors, and
)3(optimized the “standard” asthma
pharmacotherapy

31. -To prevent chronic and troublesome
symptoms,
-To normalize pulmonary function,
-To maintain normal activity levels,
-To prevent exacerbations
-To improve health-related quality of life and
-To provide optimal pharmacotherapy with
minimal or no adverse effects.

32. A personalized self-treatment written Asthma Action
plan guided by symptoms or peak flow meter should
be developed in collaboration with the educator and
the respirologist.
The action plan should include instructions:
regarding the maintenance medication schedule
doses of rescue therapy for increased symptoms,
and when and how to seek urgent or emergency care.

33. such as yearly influenza vaccines
and pneumococcal polysaccharide
vaccine

34. GERD
Obesity and OSA
5.smoking cessation
6.Adherence
especially to corticosteroid therapy
7.Psychological disturbances control

35. at home such as
dust mites,
cats, cockroaches and other domestic
pets should be
reviewed.
and ABPA treatment

36. Levels of Asthma Control
(Assess patient impairment(
Assessment of Future Risk (risk of exacerbations, instability, rapid decline in
lung function, side effects(

37. Shaded green - preferred controller options
TO STEP 3 TREATMENT,
SELECT ONE OR MORE:
TO STEP 4 TREATMENT,
ADD EITHER

38. Mainstay pharmacotherapy for
severe/refractory
asthma is combination of inhaled
corticosteroids
)ICS( and one or two controller agents such
as long
acting ß2-agonists (LABA), leukotriene
modifiers or
oral theophylline. Recently, tiotropium bromide
was demonstrated to be effective as an add-
on controllertherapy to ICS in uncontrolled
asthma

39. several alternative options have been evaluated in
treating severe/refractory asthma. Cochrane review of
randomized controlled trial determined that there was
insufficient evidence to support the use of
azathioprine,
chloroquin, cyclosporine, gold or methotrexate in
the
treatment of chronic asthma as a steroid sparing-
agent.
For most of these agents the side-effect profile is not
preferable

40. Macrolide antibiotics have shown
immunomodulatory effects in neutrophilic lung
diseases such as panbronchiolitis in East Asians
and cystic fibrosis.
More recently, clarithromycin was demonstrated
to modulate IL-8 and neutrophil accumulation in
refractory asthmatics in a randomized trial.

41. A randomized placebocontrolled trial by Denning and
colleagues on severe asthmatics with fungal
sensitization demonstrated by skin prick or specific
IgE testing showed treatment
with oral itraconazole (200 mg twice a day) over a 32
week period increased asthma related quality of life.

42. Immunoglobulin E (IgE) plays a pivotal role in
the molecular pathway responsible for the allergic response.
Omalizumab which is a humanized recombinant monoclonal anti-
IgE antibody was shown to reduce emergency room visits and
exacerbations, when added to high dose ICS and LABA
therapy.
Also several studies evaluating Omalizumab have demonstrated
a clinical effect on markers of airway inflammation,
asthma symptom severity, inhaled corticosteroid use,
and quality of life in patients with moderate to severe asthma

43. Bronchial thermoplasty
.Bronchial thermoplasty is a bronchoscopic procedure
where controlled radiofrequency energy is delivered to
the airways through the catheter, heating the smooth musclethrough the catheter, heating the smooth muscle
walls of the airway to approximately 149˚walls of the airway to approximately 149˚ F (F (65 degrees Celsius) in
order to reduce the airway smooth muscle mass
and attenuate bronchoconstriction.
.More than 5 years ago, dog experiments revealed
that:
Bronchial thermoplasty might have therapeutic benefits
for asthma subjects by reducing airway
hyperresponsiveness.

44. This has now been tested in asthmatic subjects
in randomized controlled trials(A well
powered, sham controlled, double-blind multi-center
Study(
The earlier trials performed on moderately severe
and severe asthmatic subjects were
disappointing due to the notable adverse
effects of the treatment and the lack of any
effect on airway hyperresponsiveness

45. Thus, bronchial thermoplasty can not be offered to
severe/refractory asthmatics as it has neither
proven to be effective nor safe.
While the National Institue for Health and Clinical Excellence (NICE) issued a
consultation document on bronchial thermoplasty for severe asthma,
which states that evidence on the safety of bronchial thermoplasty is
adequate in the short- and medium-term, although patients may
experience exacerbation of symptoms after the procedure.
(Campbell, 2011).
In summary, although available data are promising, more
research is needed to ascertain what role, if any, bronchial
thermoplasty should play in the treatment of patients with
asthma

46. Figure 4: Algorithm of possible strategies and
recommendations for managing patients with
difficult to control asthma despite maximum
combination treatment

48. 1.Titrate down oral steroids (administer the lowest amount
of oral steroid to control/stabilise symptoms)
2. Consider adding a steroid sparing drug (eg,
azathioprine, methotrexate)
3. Add treatment for steroid-induced adverse e ects (eg,ff
osteoporosis)
4. If uncontrolled, consider alternative therapeutic options
(eg, omalizumab, etanercept, high dose IVIG)
5. Frequent periodic re-evaluations.
Reference:Stephen T Holgate and Riccardo Polosa; The mechanisms, diagnosis, and
management of severe asthma in adults Lancet 2006; 368: 780–93+-

49. Other references:
1.Smita Pakhale, Sunita Mulpuru and Matthew Boyd; Optimal Management of
Severe/Refractory Asthma. Clinical Medicine Insights: Circulatory, Respiratory
and Pulmonary Medicine 2011:5 37–47
2.National Institute for Health and Clinical Excellence (NICE). Bronchial Thermoplasty for
severe asthma - consultation document. London, UK: NICE; July 2011. Available
at:http://guidance.nice.org.uk/IP/675/DraftGuidance
3.D.L. URSO, D. VINCENZO, F. PIGNATARO, P. ACRI*and G. CUCINOTTA*; Diagnosis
and treatment of refractory asthma European Review for Medical and
Pharmacological Sciences 2008; 12: 315-320
4.Stephen T Holgate and Riccardo Polosa; The mechanisms, diagnosis, and management of
severe asthma in adults Lancet 2006; 368: 780–93
5..Proceedings of the ATS Workshop on Refractory Asthma Current Understanding,
Recommendations, and Unanswered Questions AMERICAN JOURNAL OF
RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000