Optimizing management of asthma and COPD

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Optimizing Management of Asthma and COPD

• Dr. Surinder K Jindal
• www.jindalchest.com

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Definition of COPD Asthma

• COPD is a preventable and treatable disease with
  some significant extrapulmonary effects that may
  contribute to the severity in individual
  patients.
• It is characterized by airflow limitation that is
  not fully reversible. The airflow limitation is
  usually progressive and associated with an
  abnormal inflammatory response of the lung to
  noxious particles or gases.
• Asthma - Chronic Inflammatory disorder of
  airways
• characterized by Episodic, Reversible
  bronchospasm
• resulting from an exaggerated
  bronchoconstrictor response
• to various stimuli.

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COPD IS NOT ASTHMA

• Different causes
• Different inflammatory cells
• Different mediators
• Different inflammatory consequences
• Different sites

• Different response to treatment

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Inflammation
Asthma COPD
Inflammatory cells Mast cell, Eosinophil Neutrophil
CD4 cells CD8 cells
Macrophages Macrophages
Inflammatory LTB4, histamine LTB4
mediators IL-4, IL-5, IL-13 TNF-a
Oxidative stress Oxidative stress
Inflammatory effect All airways Peripheral airways
AHR AHR
Epithelial shedding Epithelial metaplasia
Fibrosis Fibrosis
No parenchymal involvement Parenchymal destruction
Mucus secretion Mucus secretion
Response to steroid
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Pathogenesis of COPD
Cigarette smoke Biomass particles Particulates
Host factors Amplifying mechanisms
LUNG INFLAMMATION
Anti-oxidants
Anti-proteinases
Oxidative stress
Proteinases
Repair mechanisms
COPD PATHOLOGY
Source Peter J. Barnes, MD
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Asthma Pathogenesis
INFLAMMATION
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Investigations
Asthma COPD
Chest radiograph Normal Suggestive
Spirometry Obstructive defect Obstructive defect
Good reversibility Poor reversibility
AHR Very common May be present
DLCO Normal / Increased Decreased
Lung elastic recoil Normal Increased
Thoracic CT scan Airway wall thickening Airway wall thickening
Mucus plugs (ABPA) Emphysema
Air trapping Air trapping
In general, investigations are poor discriminators
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Basic Principles of Management of Asthma And COPD

• Removal/ Avoidance of risk-factor/s
• Pharmacotherapy
• Bronchodilators
• Anti-inflammatory drugs
• (Corticosteroids)
• Supportive therapy
• Non-pharmacological managements
• Management of Acute Exacerbations
• Management of Complications

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Bronchodilators

• Bronchodilator medications - central to symptom
  management
• Reduce breathlessness, improve lung function,
  improve HRQOL
• Inhaled therapy is preferred
• Choice between ß2-agonist (short acting and
  long-acting), anticholinergic agents,
  theophylline or a combination of these drugs

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Inhalers vs Oral drugs

• Inhalation route preferred
• MDI, DPI, or nebulized aerosol
• MDI with spacer - preferred device
• DPI easier to use, but costlier
• Patients should be instructed regarding proper
  use of the inhaler device and technique should be
  checked regularly

Cochrane Database Syst Rev 2002 1 CD002170
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Bronchodilators

• Therapy - availability and individual response in
  terms of symptom relief and side effects
• Prescribed - on as-needed or regular basis to
  prevent or reduce symptoms
• Long-acting drugs are more convenient
• Combination of ß2-agonist and anticholinergic
  agents - better than either drug given alone
  (lung function)

Eur Respir J 2005 25 1084-1106
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Anti-inflammatory Drugs

• Corticosteroids
• Inhaled (Beclomethasone, Budesonide,
• Fluticasone, Mometasone,
  Triamcinalone)
• Oral (Prednisone, Prednisolone,
• Dexamethasone,
  Methylprednisolone)
• Parenteral (Hydrocortisone,
• Methylprednisolone,
  Dexamethasone etc)
• Immunosuppressants
• Immunomodulators

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What are your objectives while treating a patient
with COPD?
No treatment has shown to reverse the
pre-existing changes that have occurred in COPD
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Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

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Objectives

• Prevent disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve health status
• Prevent and treat exacerbations
• Prevent and treat complications
• Reduce mortality
• Minimize side effects from treatment

Am J Respir Crit Care Med 2001 163 1256-1276
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Management of stable COPD

• None of the existing medications for COPD has
  been shown to modify the long-term decline in
  lung function that is the hallmark of this
  disease (Evidence A)
• Therefore, pharmacotherapy for COPD is used to
  decrease symptoms and/or complications

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Basic considerations

• Heterogeneous condition
• All patients should be viewed as individuals -
  presentation, history, symptoms, disability
  response to drugs
• Important factors - acceptability, adverse
  effects, efficacy
• Drug titration - airflow obstruction, symptoms,
  exercise tolerance, frequency of exacerbations

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Which bronchodilator???1. Theophylline2.
Ipratropium3. Tiotropium4. Beta-2 agonists
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Bronchodilator in COPD

• Predominant parasympathetic tone first choice
  anticholinergic
• Tiotropium or Ipratropium
• Tiotropium reduced the COPD exacerbation (OR
  0.74 95 CI 0.66 to 0.83) and hospitalizations
  (OR 0.64 95 CI 0.51 to 0.82) compared to
  placebo or ipratropium
• Combination of tiotropium and formoterol ideal

Cochrane Database Syst Rev 2005 2 CD002876
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Cochrane Database Syst Rev 2005 2 CD002876
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Commonly used bronchodilators

• Drugs MDI/DPI (µg/dose) Oral (mg)
• Beta agonists
• Salbutamol 100-200 2-4mg tid/qid
• Terbutaline 250-500 2.5-5 mg tid
• Salmeterol 25-50
• Formoterol 6-12
• Bambuterol 10-20mg/day
• Anticholinergics
• Ipratropium 40-160
• Tiotropium 18
• Methylxanthines
• Theophyllines 200-600 mg/day

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Is there a role for ICS in COPD?

• Is there a role for ICS in COPD?
• Yes
• No
• Limited
• Acute exacerbation

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Inhaled corticosteroids in COPD
Anti-inflammatory effects with ICS in COPD
include Attenuation of neutrophil activation
recruitment Reduction of neutrophil
chemotaxis Reduction in the CD8/CD4
ratio Reduction in IL-8 levels Reduction in
eosinophils RANTES, associated with
exacerbations of COPD.
Decreased symptoms Decreased number and severity
of exacerbations Improved health status Reduction
of cardiac events - IHD Decreased mortality (?)
Options beclomethasone, budesonide, fluticasone,
triamcinolone Oral glucocorticosteroids not
recommended for long-term use in COPD
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Cochrane review on efficacy of the use of ICS in
COPD
Forty-seven primary studies with 13,139
participants met the inclusion criteria. Long
term use of ICS (gt six months) did not
significantly reduce the rate of decline in FEV1
in COPD patients Long term use of ICS reduced
the mean rate of exacerbations There was an
increased risk of oropharyngeal candidiasis and
hoarseness. No major effect on fractures and
bone mineral density over 3 years.
Cochrane Database Syst Rev. 2007 Apr
18(2)CD002991.
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30 reduction in exacebations
Am J Med 2002 113 59-65
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Pooled analysis of randomized trials of ICS on
mortality in COPD
27 reduction
27 risk reduction
Thorax 2005 60 992-997
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What other therapies can be used in patients with
COPD?

1. Mucolytics
2. Immunomodulators
3. Antibiotics
4. Respiratory stimulants

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Other drugs

• Vaccines Influenza and Pneumococcus in all
  patients
• Oral mucolytics - reduce the viscosity of sputum,
  no effect on lung function
• Oral immunostimulatory agent OM-85 BV (extract
  of 8 bacteria) - recurrent exacerbations
• Antioxidants - N-acetylcysteine- no clear role

Am J Respir Crit Care Med 2001 163 1256-1276
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Other drugs

• Respiratory stimulants almitrine and doxapram
  no role
• Antibiotics no role in stable COPD
• Others - Nedocromil, leukotriene modifiers and
  alternate forms of medicine - no clear role

Am J Respir Crit Care Med 2001 163 1256-1276
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Therapy at Each Stage of COPD
IV Very Severe
III Severe
II Moderate
I Mild
FEV1/FVC lt 70 FEV1 lt 30 predicted or FEV1 lt 50 predicted plus chronic respiratory failure
FEV1/FVC lt 70 30 lt FEV1 lt 50 predicted
FEV1/FVC lt 70 50 lt FEV1 lt 80 predicted
FEV1/FVC lt 70 FEV1 gt 80 predicted
Add regular treatment with one or more
long-acting bronchodilators (when needed) Add
rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long term oxygen if chronic respiratory
failure. Consider surgical treatments
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Management of Stable COPD Non-Pharmacologic
Treatments

• Rehabilitation All COPD patients benefit from
  exercise training programs, improving with
  respect to both exercise tolerance and symptoms
  of dyspnea and fatigue (Evidence A).
• Oxygen Therapy The long-term administration of
  oxygen (gt 15 hours per day) to patients with
  chronic respiratory failure has been shown to
  increase survival (Evidence A).

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ExacerbationsWhat are they?

• An event which in the natural course of the
  disease characterized by a change in the
  patients baseline dyspnea, cough and/or sputum
  and beyond the normal day-to-day variations
• Acute in onset
• May warrant a change in regular medication

• Patients are living with daily breathlessness and
  cough
• Fear about worsening
• Unpredictable

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Exacerbations result in worsening of quality of
life Data from GLOBE study
Am J Med 2006119(10A)S38-S45
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Treatment of exacerbation

• Inhaled bronchodilators salbutamol/ ipratropium
• Oral prednisolone 30-40 mg for 7-10 days
• Antibiotics
• respiratory quinolones, macrolides, co-amoxyclav,
  2o or 3o cephalosporins
• FEV1lt 35 with recurrent courses of oral steroids
  etc FQ with antipseudomonal activity

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Acute exacerbations are defining moments in a
COPD patient particularly if hospitalization is
needed
Disease Accelerated progression Enhanced airway
inflammation Adverse effects of oral steroids
Patient Death Worsening quality of life Costs
It is no less serious than an acute myocardial
infarction
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Goals of Asthma Management

1. Minimal (ideally no) symptoms
2. Minimal (or no) symptoms on exercise
3. Minimal need for relievers
4. No exacerbations
5. No limitation of physical activity
6. Normal (or near normal) PFT
7. Minimal side effects of drugs
8. Prevention of irreversible obstruction
9. Prevent asthma related mortality

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Stage-wise Control

• Day time symptoms lt 1/week
  Relievers
• and night time lt 2/month
• Need for relievers lt 1/week
  Controllers
• Need for relievers lt 3/day
  Doctor visit
• Requirement for drugs (as per table)
• Maintenance of goals for
  Step down
• at least 3 months
  (25 reduction in dosages)

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Anti-asthma Drugs

• Controllers
• Glucocorticoids Inhaled/Systemic
• Inhaled long acting ?-2 agonists
• Oral theophyllines
• Leukotriene receptor antagonists
• Cromones
• Oral long acting ?-2 agonist
• Relievers
• Rapid acting ? 2 agonists
• Oral glucocorticoids
• Inhaled anticholinergics
• Oral short acting ?2 agonists

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GINA Guidelines for Asthma

• Mild intermittent
• Mild persistent
• Moderate persistent
• Severe Persistent

SOS bronchodilators
ICS/LTRA
ICS LABA/LTRA combination
ICS LABA LTRA AC OS
At each step SOS bronchodilator therapy is
required
GINA 2004
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Asthma Control vs. Severity

• Asthma Control
• Clinical status of disease (with ongoing therapy)
• Patient-centered approach

• Asthma Severity
• Underlying disease (asthma)
• (in absence of any treatment)
• Physician-centered approach

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Asthma Levels of Control
Controlled (All of the following) Partly Controlled (Any measure present) Un-controlled
Nocturnal symptoms or awakening None Any 3 features of partly controlled asthma
Daytime symptoms 2 per week gt 2 per week 3 features of partly controlled asthma
Limitation of activities None Any 3 features of partly controlled asthma
Need for reliever or rescue treatment 2 per week gt 2 per week 3 features of partly controlled asthma
FEV1 or PEF Normal lt80 predicted 3 features of partly controlled asthma
Adapted from GINA (Global Initiative for Asthma)
guidelines 2010
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Asthma Management

• Maintain well controlled state
• Add drugs, step-wise, determined by control
• ICS LABAs constitute the cornerstone of
  treatment
• Use of SABA, as needed
• SMART approach (Use of single inhaler for
  maintenance and SOS use)

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Difficult Asthma

• Asthma which is difficult to control with maximum
  treatment recommended as appropriate for that
  stage
• Persistence of symptoms, frequent exacerbations
  or airway obstruction despite high (or optimum)
  medication

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Considerations in Management of SR/SD Asthma

• Correct diagnostic work up
• SR asthmatics do respond to bronchodilator
  therapy and such medications should be instituted
  early as rescue therapy.
• Presence of persistent airway inflammation
  predisposes them to airway remodeling and long
  term irreversible airways diseases. Thus it is of
  paramount importance to treat their inflammation
  early and effectively.

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SUMMARY- Asthma

• Airway inflammation, a prominent feature in
  asthma, needs to be targeted with effective
  medication to achieve asthma control.
• Appropriate guidelines need to be followed for
  best results. ICS ina combination with LABAs
  remain the cornerstone of treatment.
• A major unmet need is to treat patients with
  severe asthma who are relatively
  corticosteroid-resistant more effectively.
• A number of pharmaceutical approaches currently
  in clinical development, show promise in
  targeting specific cytokines, inflammatory cells,
  or inflammatory mechanisms.

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Summary - COPD
Current therapy for COPD remains
sub-optimal Concomitant use of LABAs with ICS
influences both airflow obstruction airway
inflammation. The use of ICS LABA in
combination for severe COPD help in achieving
patient centered outcomes. The clinical benefits
are manifested by the reduction in the number and
severity of exacerbations, lung function
improvement improved health status of COPD
patients
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Conclusion

• Budesonide/formoterol was shown to be an
  effective treatment for the management of
  moderate-to-severe COPD in
• Reducing severe exacerbations
• Providing early and sustained improvements in
  lung function and symptoms, Improvements in
  health-related quality of life.
• Budesonide/formoterol demonstrated a similar
  safety profile to placebo.

Szafransky Eu Resp J 20032174-81
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Important Treatment Recommendations
GINA NIH BTS
1 Management steps 4 4 5
2 Inhaled CS Steps 2 to 4 Low doses Step 2 Steps 2 to 5
3 Add on Therapies
LABA Steps 3 and 4 Step 2 onwards Step 3 onwards
SR Theophylline Step 4 -do- -do-
LT modifiers -do- -do- -do-
Oral CS -do- -do- Step 5
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PDE-4 Inhibitors

• Roflumilast, orally active PDE-4 inhibitor,
  dose-related inhibition of late-phase
  bronchospasm following allergen challenge in mild
  asthma
• Improvements in lung function ( FEV1) , asthma
  symptoms, and reductions in rescue medication
  use, vs ICS
• Ciclamilast - mediates AHR through inhibition of
  PDE-4D mRNA expression and down-modulation of
  PDE-4 activity, reduced inflammation and mucus
  hypersecretion

Ann Allergy Asthma Immunol 2006 96679686 Eur J
Pharmacol 2006 547125135
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A new paradigm A systemic disease, needs a
systemic approach

• Asthma is a systemic disease
• Required
• New classes that are effective in severe poorly
  controlled asthma
• An oral treatment that is as effective as inhaled
  corticosteroids without any side effects
• Drugs that modify or even cure the disease

J Allergy Clin Immunol 2007
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Well Controlled asthma

• No or minimal symptoms
• Minimal use of rescue medication
• No significant limitation in activity
• (Near) normal lung function
• GINA-2006

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Algorithmic Management of Acute Severe
Asthma Unable to complete a sentence in one
breath, RR gt 30/minute, use of accessory muscles
of respiration, HR gt 120/minute, pulsus paradoxus
gt 25 mm Hg, extensive wheeze, PEFR lt 50, PaO2 lt
60 mm Hg, PaCO2 gt 45 mm Hg
Salbutamol 2.5 mg q 15 minutes Ipratropium 250
mcg q 15 minutes PO prednisolone 40-60 mg/day
Sustained improvement at 1hour- Discharge on oral
steroids and bronchodilators
No improvement- ADMISSION IN HOSPITAL OR ICU
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Management of SRA/SDA

• High dose inhaled corticosteroids are the first
  line option
• Omalizumab is effective in reducing oral
  corticosteroid requirements in allergic asthma
• Methotrexate, gold, and cyclosporine have
  corticosteroidsparing effects clinically that
  must be weighed against a serious adverse effect
  profile
• Nebulized diuretics and lidocaine, with a low
  adverse effect profile, offer promising results
  but require further study

Randhawa et al. 30 yrs review
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Acute asthma Algorithmic management
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Use of ACT

• Different populations and sub-populations
  (Literacy, language, socio-economic factors,
  urban/rural residence, age, sex etc.)
• Primary health-care settings
• Abandoning lung function measurements
• Under-assessment and under treatment

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GINA Classification of Control

• Controlled
• No or minimal symptoms
• Minimal use of rescue medication
• No significant limitation in activity
• (Near) normal lung function
• Partly controlled
• Poorly controlled
• 
  
  GINA-2006

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A new paradigm A systemic diseaseneeds a
systemic approach

• Asthma is a systemic disease
• New classes that are effective in severe poorly
  controlled asthma
• An oral treatment that is as effective as inhaled
  corticosteroids without any side effects
• Drugs that modify or even cure the disease

J Allergy Clin Immunol 20071201269-75
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Instruments for control measurements

• Asthma Control Test (ACT)
• Asthma Control Questionnaire (ACQ)
• Asthma Therapy Assessment Questionnaire (ATAQ)
• Asthma Control Scoring System (ACSS)
• Asthma-symptom diary

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Thank you