management of severe asthma an update 2014

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


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%



Minor criteria,Cot'd

4. ≥1 ED visist/year5. ≥3 OCS/year6. Prompt deterioration with ≤25%

↓ICS/OCS7. Near-fatal asthma in the past.


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 comorbidities? e.g.

Rhinosinusitis, GERD etc.

Diagnostic Assessment of Severe Asthma

Cystic fibrosis Bronchiectasis Recurrent aspiration COPD CHF Obstructive bronchiolitis Bronchial amyloidosis


Alternative diagnoses?

Laryngotracheal tumours Inhalation of foreign body Tracheomalacia Tracheobronchial malformations

ABPA Eosinophilic syndromes

Alternative diagnosis?


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?)


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, …)


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!


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


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

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management of severe asthma an update 2014

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