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Management of Severe Asthma An Update
M.Moin M.DProfessor of Allergy & Clinical ImmunologyImmunology, Asthma & Allergy Research Institute
IAARI
Children's Medical CenterTehran University of Medical Sciense
1392
2014
” خرد و جان خداوند نام “به
Severe Asthma : Many Clinical phenotypes!
Subgroups :Severe Asthma / Refractory AsthmaDifficult to control asthmaPoorly controlled asthmaSteroid-dependent & /or Steroid resistant
asthmaBrittle asthma Irreversible asthmaFatal or Near-fatal asthmaATS & ERS joint workshop consensusAm J Respir Care Med,162:2341-51,2000
Diagnostic Criteria for Severe AsthmaATS – 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)2. Rx with high dose I.C.S(1000ug Fluticasone/BDP)
ATS & ERS joint workshop consensusAm J Respir Care Med,162:2341-51,2000
Diagnostic Criteria for Severe AsthmaATS – 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 consensusAm J Respir Care Med,162:2341-51,2000
Diagnostic Criteria for Severe AsthmaATS – ERS Joint Workshop Consensus -2000
Minor criteria,Cot'd
4. ≥1 ED visist/year5. ≥3 OCS/year6. Prompt deterioration with ≤25%
↓ICS/OCS7. Near-fatal asthma in the past.
ATS & ERS joint workshop consensusAm J Respir Care Med,162:2341-51,2000
WHO Definition of Severe Asthma
• Severe asthma includes 3groups: - Untreated severe asthma- Difficult-to-treat severe asthma- Treatment-resistant severe asthma
1- Asthma for which control is not achieved despite the highest level of recommended treatment: refractory asthma and corticosteroid-resistant asthma2- Asthma for which control can be maintained only with the highest level of recommended treatment.
–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
Well controlled with maximal therapy
Poorly controlled with maximal therapy
Untreated severe asthma
Severe therapy-responsive asthma
Difficult-to-threat asthma
Severe, therapy- resistant asthma
Severe Asthma Phynotypes in Childhood
The WHO definition of severe asthma
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 Daily Moderate Persistent Continuous Continuous Severe Persistent
Levels of Asthma Control(Assess patient impairment)
Characteristic Controlled(All of the following)
Partly controlled(Any present in any week)
Uncontrolled
Daytime symptomsTwice or less
per weekMore than
twice per week
3 or more features of partly controlled asthma present in any 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
Lung function (PEF or FEV1)
Normal< 80% predicted or
personal best (if known) on any day
Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side effects)
Stepwise Management of Asthmaby severity :
*At all levels patient should have a SABA prn
Step 5: Severe Persistent
High-dose ICS + LABA + Oral CS
Step 4 : Severe PersistentMedium dose ICS + LABA
Step 3: Moderate PersistentLow -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
GINA 2006: Asthma treatment steps
*in children <6yrs:moderate-dose
ICS
Oral glucocorticosteroid
(lowest dose)
anti-IgE antibodies
as needed rapid-acting β2-agonist
Asthma educationEnvironmental control
• 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.
Diagnostic Assessment of Severe Asthma
Cystic fibrosis Bronchiectasis Recurrent aspiration COPD CHF Obstructive bronchiolitis Bronchial amyloidosis
Diagnostic Assessment of Severe Asthma
Alternative diagnoses?
Laryngotracheal tumours Inhalation of foreign body Tracheomalacia Tracheobronchial malformations
ABPA Eosinophilic syndromes
Alternative diagnosis?
Diagnostic Assessment of Severe Asthma
Education and removal of triggering factors
Educate about adherence and proper technique
Systematic reviws showed that education about self- management significantly improved health outcomes
Educational material used should be at appropriate health literacy level
Compliance & technique ?
Implement strict environmental control
Advise about the negative effects of smoking and obesity on asthma control
Smoking reduces the effects of ICS
Education and removal of triggering factors
Trigger factors ?
- Gastro esophageal reflux (Does treatment improve asthma?)
Diagnostic Assessment of Severe Asthma
Comorbid conditions ? - Upper airway obstruction (VCD, Tracheal
stenosis) - Hyperventilation syndrome
- Rhinosinusitis - Hyperthyroidism - Bronchiectasis - Depression
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.
Diagnostic Approach 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, …)
Diagnostic Assessment of Severe Asthma
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
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
Treatment Approach
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
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
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
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 150-375mg.
Treatment Approach Cont,d
Follow-up and written action plan
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 life- threatening attacks
Omalizumab
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
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)
Asthma: defining of the persistent adult phenotypesSally E Wenzel
The Lancet 2006, 368 : 804-13
From Phenotype to Endotype!
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 The right Rx. to the right patient
Endotyping
Inflammatory Phenotypes in Stable Persistent Asthma, on ICS
Eosinophilic
Neutrophilic
Paucigranulocytic
41%
28%
31%
Simpson J et al, Respirology 2006;11:54-61
59% Non- eosinophilicNeutrophilic
EosinophilicPauci – granulocytic
Eosinophilic
From Phenotype to Endotype!
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 steroidFrom Phenotype to Endotype! & Personalized Rx.
Treatment of Severe Asthma with Noneosinophilic Bronchitis
• ICS/LABA• Triggers:
– smoking– infection
• Macrolide• ? Theophylline• ?TNFa
From Phenotype to Endotype! & Personalized Rx.
Licensed therapeutic approches :
High- dose inhaled steroidsSymbiocort maintenance and
reliever therapy (SMART)
Anti- IgE Rx. (→ 50% ↓ CS dose)
Treatment Plan in Children
Unlicensed treatments:MethotrexateAzathioprineCiclosporinSubcutaneous terbutaline? Cytokine- specific monoclonal
antibody (Anti-IL5, Anti-IL13, …)? Bronchial thermoplasty
Treatment Plan in Children
Severe Asthma- Differential diagnosis and management
Exclude an alternative diagnosis“Not asthma at all”, e.g.vocal cord dysfunction.
Foreign body aspiration, CF
Exclude comorbidities“Asthma plus”, e.g.GERD, allergic
rhinitis, chronic sinusitis, food allergy, OSA, vitamin D deficiency
Severe AsthmaDifferential diagnosis and management
If asthma treatment is not working, check DAT: Diagnosis, Adherence, Technique
Therapeutic approaches
Difficult asthmaImproves when basic
management is corrected:- Adherence
- Inhaler technique25% of asthma exacerbations are due to ICS nonadherence
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 treatmentsMethotrexate,
azathioprine, cyclosporin, terbutaline infusion SC
Therapy- resistant asthmaStill symptomatic even when
basic management issues resolved
DDx. With Difficult asthma
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;5:40-444. 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):14-166. 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):109-146. 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
THANKS
متشكرم
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