1. Management of Severe Asthma
An Update
M.Moin M.D
Professor of Allergy & Clinical Immunology
Immunology, Asthma & Allergy Research Institute
IAARI
Children's Medical Center
Tehran University of Medical Sciense
1392
2014

2. Severe Asthma : Many Clinical
phenotypes!
Subgroups :
 Severe Asthma / Refractory Asthma
 Difficult to control asthma
 Poorly controlled asthma
 Steroid-dependent & /or Steroid resistant asthma
 Brittle asthma
 Irreversible asthma
 Fatal or Near-fatal asthma
ATS & ERS joint workshop consensus
Am J Respir Care Med,162:2341-51,2000

3. Diagnostic Criteria for Severe Asthma
ATS – ERS Joint Workshop Consensus -2000
Diagnosis : One or both major criteria & Two minor criteria
Major criteria
In order to achieve control(mild-mod , persistent asthma) :
1. Rx with continuous or near continuous(≥50% of
the year)
1. Rx with high dose I.C.S(1000ug Fluticasone/BDP)
ATS & ERS joint workshop consensus
Am J Respir Care Med,162:2341-51,2000

4. Diagnostic Criteria for Severe Asthma
ATS – ERS Joint Workshop Consensus -2000
Minor criteria
1. Daily Rx with ICS + LABA , theophylline or LA
2. Daily SABA(Rescue medication)
3. Persistent daily FEV1<80% & diurnal PEF variab.
>20%
ATS & ERS joint workshop consensus
Am J Respir Care Med,162:2341-51,2000

5. Diagnostic Criteria for Severe Asthma
ATS – ERS Joint Workshop Consensus -2000
Minor criteria,Cot'd
4. ≥1 ED visist/year
5. ≥3 OCS/year
6. Prompt deterioration with ≤25% ↓ICS/OCS
7. Near-fatal asthma in the past.
ATS & ERS joint workshop consensus
Am J Respir Care Med,162:2341-51,2000

6. WHO Definition of Severe Asthma
1- Asthma for which control is not achieved
despite the highest level of recommended
treatment: refractory asthma and corticosteroidresistant asthma
2- Asthma for which control can be maintained
only with the highest level of recommended
treatment.
• Severe asthma includes 3groups:
- Untreated severe asthma
- Difficult-to-treat severe asthma
- Treatment-resistant severe asthma
–Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleek ER, et alUniform definition of asthma severity, control, and exacerbation:
document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010;126:926-38.
–Desai D, Brightling C, Cytokine and anti- Cytokine therapy in asthma: ready for the chinic? Clin Exp Immunol 2009;158:10-9

7. Severe Asthma Phynotypes in Childhood
Well controlled with
maximal therapy
Poorly controlled with
maximal therapy
Difficult-to-threat
asthma
Severe
therapyresponsive
asthma
Untreated severe
asthma
Severe, therapyresistant asthma
The WHO definition of severe asthma

8. Classification of Asthma Severity
Night Symp.
Daytime Symp.
< 2 times/mth.
< 1 time/wk
Intermittent
> 2 times/mth.
> 1 time/ wk
Mild Persistent
> 1 time/week
Continuous
Daily
Continuous
Moderate Persistent
Severe Persistent

9. Levels of Asthma Control
(Assess patient impairment)
Characteristic
Controlled
Partly controlled
(All of the following)
(Any present in any week)
Daytime symptoms
Twice or less
per week
More than
twice per week
Limitations of
activities
None
Any
Nocturnal symptoms
/ awakening
None
Any
Need for rescue /
“reliever” treatment
Twice or less
per week
More than
twice per week
Normal
Uncontrolled
< 80% predicted or
personal best (if
known) on any day
Lung function
(PEF or FEV1)
3 or more
features of
partly
controlled
asthma
present in
any week
Assessment of Future Risk (risk of exacerbations, instability, rapid
decline in lung function, side effects)

10. Stepwise Management of Asthma
by severity :
*At all levels patient should have a SABA prn
Step 5: Severe Persistent
High-dose ICS + LABA + Oral CS
Step 4 : Severe Persistent
Medium dose ICS + LABA
Step 3: Moderate Persistent
Low -dose ICS+ LABA
Step 2: Mild Persistent
Low -dose ICS , LTAs 2nd line
Step 1: Intermittent
No daily medicines , SABA p.r.n.
Pharmacological management. Thorax 2003; 58 (Suppl I): i1-i92

11. GINA 2006: Asthma education
Asthma treatment steps
Environmental control
as needed rapidacting β2-agonist
Oral
glucocorticosteroid
(lowest dose)
*in children <6yrs:
moderate-dose ICS
anti-IgE
antibodies

12. Diagnostic Assessment of
Severe Asthma
• Is the diagnosis correct or is there an alternative
diagnosis?
• Is the patient compliant with treatment and is the
technique correct?
• Are there trigger factors e.g. Allergens, Irritants,
ETS, Drugs?
• Are there co- morbidities? e.g. Rhinosinusitis, GERD
etc.

13. Diagnostic Assessment of
Severe Asthma
 Alternative diagnoses?
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

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Cystic fibrosis
Bronchiectasis
Recurrent aspiration
COPD
CHF
Obstructive bronchiolitis
Bronchial amyloidosis

14. Diagnostic Assessment of
Severe Asthma
 Alternative diagnosis?






ABPA
Eosinophilic syndromes
Laryngotracheal tumours
Inhalation of foreign body
Tracheomalacia
Tracheobronchial malformations

15. Education and removal of
triggering factors
Compliance & technique ?
 Educate about adherence and proper technique
 Systematic reviws showed that education about selfmanagement significantly improved health
outcomes
 Educational material used should be at appropriate
health literacy level

16. Education and removal of
triggering factors
Trigger factors ?
 Implement strict environmental control
 Advise about the negative effects of smoking and
obesity on asthma control
 Smoking reduces the effects of ICS

17. Diagnostic Assessment of
Severe Asthma
 Comorbid conditions ?
- Upper airway obstruction (VCD, Tracheal stenosis)
- Hyperventilation syndrome
- Gastro esophageal reflux (Does treatment improve
asthma?)
- Rhinosinusitis
- Hyperthyroidism
- Bronchiectasis
- Depression

18. Diagnostic Approach of
Severe Asthma
 Complete history and clinical examination critical
in making an accurate diagnosis
 Pre- and post- bronchodilator spirometry for
diagnosing reversible airway obstruction.
 Flow- volume loops helpful to R/O upper airway
obstruction.

19. Diagnostic Assessment of
Severe Asthma
 Methacholine challenge test to evaluate
bronchial hyperresponsiveness
 Skin prick test, RAST
 Laryngoscopy to evaluate upper airway
dysfunction
 CXR and HRCT of chest when indicated
 Investigate appropriately for other diseases PRN
(CBC & Diff, Sweat test & CF-genotype, Ig,s, Ig Subclasses,
…)

20. Treatment Approach
 Guidelines recommend stepwise Rx according to
severity for control of the disease at all times
 No clear internationally accepted regimens for
uncontrolled asthma despite treatment at the
highest point at each step
 This is due to paucity of studies and different
definition used in the available studies

21. Treatment Approach
• Aim of treatment should be to obtain the
best possible results when there is failure
of optimal control
• Also aim to have the fewest undesirable
effects
• Have a practical & good treatment plan

22. Intensive initial therapy to achieve
control of symptoms
 High does ICS + LABA BD and a short course of
OCS 40mg/day prednisolone for 15 days
 Introduce a strategy of reducing dosage
 If deterioration on withdrawal of OCS introduce
other drugs e.g. antileukotrienes, theophyllins etc
while giving low does OCS
 Trial and error done with monitoring of functional
parameters and inflammation

23. Deficient Response to OCS
possible causes :
 Incompete absorotion may be due to GIT disorder
 Failure to covert prednisone to prednisolone due to
enzymatic alterations
 Rapid elimination due to drug interaction eg
rifampicin, phenytoin etc.
 Corticosteroid resistance : Confirmed when FEV1 is <
70% of predicted after treatment with 40mg OCS for
2weeks but responds to a bronchodilator test

24. Deficient response to OCS (Cont.)
 If no response double dose for another 2 weeks
 Those responding to the higher doses have altered
response to OCS
 Some may respond to IM ateroids e.g.
triamcinolone 40mg every 10 days. (Level C)
 Always use prednisolone in case of conversion
failure

25. Treatment Approach Cont,d
 Omalizumab has shown a reduction of 50% of
steroids dose in atopic asthma with high IGE levels
 Safety profile require long term evaluation
 Administered every 2 or 4 weeks at a dose of 150375mg.

26. Follow-up and written action plan
Omalizumab
 Close monitoring essential
 2 to 3 visits per month in the first 2 months until
best results are achieved
 Then monitor 3 monthly
 Self treatment plan needed to avoid lifethreatening attacks

27. C.S. Sparing Agents
(Evidence- based)
 Chloroquine, methotrexate, cyclosporine, gold
salts have been widely used
 They have modulatory effects on inflammation
 They also have side effects that need monitoring

28. C.S. Sparing Agents
(Not Evidence- based)
 Insufficient data to justify use of the following
drugs as corticosteroid sparing agents: colchicine,
chlorquine, dapsone(level C evide for all 3)
 Intravenous immunoglobulins and azathioprine
(level B evidence)
 Oral or parenteral gold salts and cyclosporin not
recommended for routine use (level B evidence)

29. From Phenotype to Endotype!
Asthma: defining of the persistent adult phenotypes
Sally E Wenzel
The Lancet 2006, 368 : 804-13

30. From Phenotype to Endotype!
Phenotype:Observable characteristics
often with no direct relationship to
disease process.
Endotype:Biological mechanisms
that underlie a distinct disease entity
present within a phenotype.
Phenotyping the severe asthma
Personalized Strategy
in Treatment
Endotyping
The right Rx. to the right patient

31. From Phenotype to Endotype!
Inflammatory Phenotypes in Stable
Persistent Asthma, on ICS
Pauci –
granulocytic Eosinophilic
31%
Eosinophilic
Eosinophilic
41%
59%
Neutrophilic
28%
Simpson J et al, Respirology 2006;11:54-61
Neutrophilic
Non- eosinophilic
Paucigranulocytic

32. Treatment of Severe Asthma with
Eosinophilic Bronchitis
•
•
•
•
ICS/LABA :adherence !!
OCS: trial
LTRA: add on montelukast
Maintenance OCS:
dose adjustment by sputum eos, [adherence !!!]
• Itraconazole for ABPA
• Oral gold/ methotrexate
• Parenteral steroid
From Phenotype to Endotype! & Personalized Rx.

33. Treatment of Severe Asthma with
Noneosinophilic Bronchitis
• ICS/LABA
• Triggers:
– smoking
– infection
• Macrolide
• ? Theophylline
• ?TNFa
From Phenotype to Endotype! & Personalized Rx.

34. Treatment Plan in Children
Licensed therapeutic approches :
High- dose inhaled steroids
Symbiocort maintenance and reliever therapy
(SMART)
Anti- IgE Rx. (→ 50% ↓ CS dose)

35. Treatment Plan in Children
Unlicensed treatments:
Methotrexate
Azathioprine
Ciclosporin
Subcutaneous terbutaline
? Cytokine- specific monoclonal antibody
(Anti-IL5, Anti-IL13, …)
? Bronchial thermoplasty

36. Severe Asthma- Differential diagnosis
and management
Exclude an alternative diagnosis
Exclude comorbidities
“Not asthma at all”, e.g.vocal cord dysfunction.
Foreign body aspiration, CF
“Asthma plus”, e.g.GERD, allergic
rhinitis, chronic sinusitis, food allergy,
OSA, vitamin D deficiency
Severe Asthma
Differential diagnosis and management
If asthma treatment is not working, check
DAT: Diagnosis, Adherence, Technique
Therapeutic approaches
Difficult asthma
Improves when basic
management is corrected:
-Adherence
-Inhaler technique
25% of asthma exacerbations
are due to ICS nonadherence
Therapy- resistant asthma
Licensed treatments (FDA-approved)
-high-dose inhaled steroid (ICS) and
LABA
-Single-inhaler maintenance and reliever
therapy (SMART) (ICS/formoterol)
-Anti-IgE therapy, omalizumab (Xolair)
- Bronchial thermoplasty
Unlicensed treatments
Methotrexate,
azathioprine, cyclosporin,
terbutaline infusion SC
Still symptomatic even when
basic management issues
resolved
DDx. With Difficult asthma

37. References
1. Assembly on asthma of the Spanish Society of Pulmonology and
Thoracic Surgery.Guidelines for the Diagnosis and Management of
difficult-to-control Asthma.Arch Brononeumol 2005:41(9) :513-523
2. Fitzgerald JM,Shahidi N , Achieving asthma control in patients with
moderate disease .J Allergy Clin immunnol 2010;125:307-311.
3. Ayres JG et al.Brittle asthma .Paed Resp Reviews.2004;5:40-44
4. Wenzel S, Szefler SJ, Managing severe asthma , J Allrgy Clin Immunol
2006;117:505-511.
5.Moin M et al. Risk Factors Leading to Hospital Admission in Iranian
Asthmatic Children .Int Arch Allergy Immunol 2008;145:244-248
6.Moin et al Acta Medica; Risk Factors For Asthmatic Children Requiring
Hospitalization2001:39(1):14-16
6. Fanta CH , Steroid Dependent Asthma , Asthma Grand Rounds Bulletin
2005;1-7.
7.Moin M et al. A systemic review of recent asthma surveys in Iranian
children Chron Resp Dis.2009:6(2):109-14
6. Spahn JD , Bratton DL , Refractory Childhood Asthma : New insights into
the Pathogenesis ,Diagnosis , and Management in :Leung DYM ,
Sampson HA et.al . Pediatric Allergy : Principles and Practice
;2003,Mosby :444-464

38. THANKS