CHRONIC OBSTRUCIVE PULMONARY DISEASE and ASTHMA: Treatment Options

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CHRONIC OBSTRUCIVE PULMONARY DISEASE and ASTHMA
Treatment Options

• PETER KRUMPE MD
• PULMONARY and CRITICAL CARE MEDICINE
• VA Sierra Nevada Health Care System
• University of Nevada SOM, Reno, NV

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Peter Krumpe, MD

• Boehringer-Ingelheim Support
• Speakers bureau
• Research grants
• Other support
• Altana, Pfizer, Lilly, Chiron, Bayer, Cubist

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Objectives Discuss Major Symptoms of Lung
Disease

• Cough
• Sputum (volume, color, cohesiveness)
• Noisy breathing (wheezes, ronchi, crackles)
• Shortness of breath (rest, exercise, position)
  tachypnea
• Cyanosis

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Cough

• Productive versus dry
• Duration
• acute viral tracheitis, bronchitis, pneumonia
• chronic Post-nasal drip, GERD, asthma, irritant
  exposures (smoking), lung cancer, TB, CHF,
  foreign body
• Irwin, R , et al. Diagnosis and Management of
  Cough ACCP Evidence-Based Clinical Practice
  Guidelines. 2006. Chest 129 Supplement 1.

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Objectives- COPD Epidemiology

• Understand changing population at risk for COPD
• Know relation of smoking, airway inflammation to
  COPD progression
• Know the consequences of exacerbations of COPD

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Traditional Prognostic Factors for COPD

• Age
• FEV1
• Hypoxemia
• Hypercapnea

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Mortality in COPD

• FEV1 lt35 normal predicts of COPD mortality
• Oga, T et al. Am J Respir Crit Care Med 2003.
  16754

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Changing Ideas About COPD

• Women
• Age
• Pathophysiology
• Role of inflammation
• Causes other than smoking ???

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New COPD Prognostic Factors

• Fat-free body mass loss
• Symptoms score (SGQL)
• Hospitalizations for exacerbations
• Frequency, Severity

Dolan, S. Prognostic factors in chronic
obstructive pulmonary disease. Curr Opin Pulm
Med. 2005. 11149-52.
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Objectives- COPD Pathophysiology

• Know causes of airway obstruction
• Understand environmental and genetic causes of
  emphysema
• Understand the damaging cycle of dyspnea,
  deconditioning and disability

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Pathophysiology of COPD

• Smoking induces airway inflammation TNF alpha is
  central to smoke induced airway inflammation
• Macrophages and PMNs recruited to respiratory
  bronchioles amplify inflammation, burp elastase
• Elastolytic damage causes loss of lung recoil
  and supporting structures

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Dynamic Airway Collapse Inspiration vs.
Expiration
N Engl J Med 20043501036
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Airway epithelium in Emphysema
Scanning Electron Micrograph of the Lining of the
Bronchus of a Lung Affected by Emphysema
Franks T. N Engl J Med 20063541435-1436
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Causes of COPD in Non-smokers

• Alpha 1 AT Deficiency
• Primary Ciliary Dysknesia
• Beta receptor heterogeneity
• Dietary deficiency Retinoic acid, Beta-carotene
• Strong family history in absence of these other
  genetic factors?

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Why do only 20 of Smokers Develop COPD?

• Actually about 80 will, if followed with
  spirometry to age 75 and older
• They die of heart disease or cancer first?

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Markers of inflammation and oxidative stress in
exacerbated COPD

• H2O2 in breath condensate increased
• Serum IL-8, soluble ICAM in serum increased
• Both decreased with treatment decreased
  inflammation and oxygen free radical stress

Gerritsen, W, Respir Med. 2005 9984-90.
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Histone Deacetylase in COPD
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Why Does COPD Progress in Ex-smokers?

• Chronic or Latent Viral Infection Causing
  Enhanced Lung Inflammation?
• Adenovirus E1A DNA in airway cells of COPD
• Inflammation continues after the smoke stops!
• Enhanced transcription of IL-8 and ICAM-1

Retamales I, Amplification of inflammation in
emphysema and its association with latent
adenoviral infection. Am J Respir Crit Care Med.
2001164(3)469-73.
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Time Spend Inside the House

• Being house-bound increases after exacerbations
• Frequent exacerbations were most severely
  impacted
• On any day, number who never went outside
  increased from 34 to 44 after exacerbation

Donaldson, G Am J Respir Crit Care Med. 2005.
171(5)446-52
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Objectives- COPD Treatment

• Understand the evidence supporting treatments
  that changes in natural history of COPD
• Smoking cessation, Vaccines, Home Oxygen, Long
  acting bronchodilators (LABAs, Anticholinergics),
  Inhaled corticosteroids
• Symptomatic relief
• Short acting bronchodilators, antibiotics, rehab

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Pulmonary Vaccines

• Polyvalent pneumococcal vaccine every 6 years.
  23 strains.
• Influenza vaccine annually

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Oxygen Therapy Prevents Cor Pulmonalle

• Tune up patients
• PaO2 less than 55 mm Hg (RA)
• Sat less than 86 RA
• Concentrators are cost effective
• E-tanks/ cart or pulse dose delivery systems for
  mobility

Pulse Oximeters Replacing Blood Gases
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Frequent Flyers!

• Multiple exacerbations
• Major cost of careProgressive loss of function,
  disabilityleading to death

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Treatments Directed To Prevention of Exacerbations

• Ipratropium and Tiotropium Bromide
• Beta Agonists- long and short of it
• Xanthines, PDE4 inhibitors
• Inhaled and systemic steroids
• Oxygen
• Rehab, VRLS, transplantation

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SAMA, LAMAs
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Cholinergic Innervation of Proximal Airways

• Acetycholine mediates bronchial constriction
• Atropine, ipratropium bromide, tiotropium bromide
  block constriction
• Particle deposition easiest to achieve in central
  airways

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Tiotropium Reduces COPD Exacerbations VA Patients

• Six month placebo controlled trial
• 26 VA Medical Centers
• Exacerbations defined new respiratory sx, gt 3
  days, requiring rx with steroids, antibiotics or
  hospitalization

Niewoehner, D et al. Annals Int Med 2005 143,
317-326
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Tiotropium Reduced COPD Exacerbation in VA
Patients

• Tio reduced exacerbations vs. placebo
• (27 vs. 33)
• Tio reduced hospitalizations
• (7 vs. 9)
• Tio delayed time to first exacerbation and number
  of treatment days

Niewoehner, D et al. Annals Int Med 2005 143,
317-326
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Tiotropium in COPD- 4 Year Trial

• UPLIFT, a randomized double-blind trial
• Tiotropium vs. Placebo 5993 patients.
• Measured rate of decline FEV1 and FEV1/FVC
  post-bronchodilator Tio not different from
  placebo
• Tio improved rates of COPD exacerbation,
  hospitalization and quality of life scores

Tashkin, D. N Engl J Med 2008. 359 1543 1544.
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SABA, LABAs
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Beta 2 Agonists- Side Effects

• The twitchies
• Tachycardia
• Low K
• Tachyphylaxsis

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Levalbuterol (Xopenex)

• R-isomer less side effects than racemic
  albuterol
• Nebulized solution
• HFA-MDI

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LABAs

• Salmeterol, Formoterol
• Anti-inflammatory?
• Abrupt withdrawal may cause airway hyperactivity
  (FDA alert)
• Combination fluticasone-salmeterol
• Calverley P, Pauwels R, Vestbo J, Jones P, Pride
  N, Gulisvik A et al. Combined salmeterol and
  fluticasone in the treatment of chronic
  obstructive pulmonary disease a randomized
  controlled trial. Lancet 2003361449-56

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Corticosteroids

• Some COPD patients may have asthmatic
  component.
• About 10 of COPD patients have an increase in
  FEV1 after Prednisone trial.
• Exacerbations high dose IV steroids x 3 days,
  switch to PO prednisone in a two week tapering
  dose. (eventually re institute MDI steroids)

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Inhaled corticosteroid/LABA- Fluticasone/Salmeter
ol

• Combination inhaler(Seritide Advair) is at least
  equivalent to its components administered
  separately
• Combination therapy reduced exacerbation rates,
• Salmeterol has been shown to be an effective
  first-line bronchodilator in COPD and fluticasone
  has been shown to reduce the frequency and or
  severity of exacerbations in COPD patients in two
  key trials.

Chapman, K. Expert Opin Pharmacother. 2002
3341-50.
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ICS plus Salmeterol vs. Salmeterol alone
Survival in COPD

• Mortality 12.6 in combination vs. 15.2 for
  salmeterol alone (p 0.052)
• Combination decreased exacerbation rates but
  increased pneumonia rates (19.6 vs. 12.3 p
  0.001)
• Torch study
• Calverley, P, et al. N Engl J Med 2007 775-89.

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Theophylline non-selective PDF Inhibitor

• Sustained release
• Bed time
• Chicken dosing
• Avoid escalation of dose as patient becomes more
  symptomatic
• Roflumilast- selective PDE4 inhibitor

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Acute Exacerbations of COPD

• Over 50 are viral
• About 10 are Chalmydia Pneumoniae or Mycoplasma
• Legionella uncommon in NV
• Bacteria Strep, Haemophilus (non-typable),
  Moroxella, Pseudomonas, Staph often new strains

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Managing Acute Exacerbations

• Industrial strength bronchodilators
• Systemic corticosteroids
• Consider antibiotics (increased cough, yellow
  sputum, thick sputum)
• Controlled Oxygen
• CPAP/BIPAP
• Intubation for fatigue, somnolence

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Systemic Corticosteroids

• Treatment of an exacerbation of COPD with oral or
  parenteral corticosteroids significantly reduces
  treatment failure and the need for additional
  medical treatment . It increases the rate of
  improvement in lung function and dyspnoea over
  the first 72 hours, but at a significantly
  increased risk of an adverse drug reaction

Cochrane Database Syst Rev. 2005 Jan
25(1)CD001288.
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Bacterial vs. Non-bacterial

• Bacterial potential pathological microorganism
  isolated in 19 of 116 COPD exacerbations
• Non-bacterial negative result of a sputum Gram
  stain, absence of a decrease in lung function and
  occurrence of lt2 exacerbations in the previous
  year .100 predictive of a nonbacterial origin
  of the exacerbation.
• The presence of all 3 of these clinical
  characteristics yielded a positive predictive
  value of 67 for a bacterial exacerbation. Save
  ?

Van der Valk, P. Clin Infect Dis. 2004. 39980-6.
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AECB Antibiotics

• Co-Trimoxazole
• Doxycycline
• Azithromycin or Clarythromycin
• Levofloxacin, Gatifloxacin, Moxifloxacin
• Risk for pseudomonas? CIPROFLOXACIN 750 mg BID

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Objectives Rehabilitation for COPD
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Pulmonary Rehabilitation

• Deconditioning from dyspnea
• Range of Motion
• Upper body weight training
• Endorphins reduce depression
• Socialization
• Panic Training pursed lips resp.
• End of life decision making.

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Volume Reduction Lung Surgery the NETT Trial

• Selection moderately severe COPD with apical
  bullae, low exercise capacity
• Improves diaphragm mechanics by decreasing
  hyperinflation
• Timed walk increases from about 900 to 1200 feet.
  FEV1 increases about 20
• Some come off Oxygen therapy
• Costs about 50K

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Resect Apical Bullae
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Lung Transplantation for Emphysema

• Ex-smokers x 1 year, age lt65, CO2 lt55, diffuse
  air trapping, STRONG support network, no
  transfusion hx.
• Exclusions CAD, CRF, HIV, colon CA or other
  malignancies, Hep C, RPR or PPD, Psych dx,
  substance abuse.
• Donor availability (ironically, CMV increases
  donor availability)

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Lung Volume Reduction by Bronchoscopic
Obstruction of Apical Airways

• Occlusive balloons left in situ
• Airway to bullus stints (like a TIPS)
• Major Problems
• collateral ventilation prevents apical collapse,
  so thwarts the intended advantage of improved
  diaphragm mechanics
• Retained secretions, pneumonitis?

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Asthma

• Its hard to define but I know it when I see it
• Stuart Potter, Supreme Court Justice

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Objectives- COPD or Asthma?

• Contrast COPD with asthma symptoms, lab tests,
  responses to inhaled challenges
• Recognize asthma syndromes
• Understand asthma prevention
• Understand unique therapeutic opportunities to
  treat asthma

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Contrasts

• COPD
• sputum at awakening
• normal IgE
• smoking hx
• less atopy
• less reversible
• PMNs IL8

• Asthma
• 4AM wheezing
• increased IgE
• less smoking
• triggers, atopic hx
• more reversible
• Eosinophiles
• IL5, IL10, IL13
• Seasonal Fall, winter

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Asthma Triggers

• Pollens
• Dust mites
• Cockroaches
• Cat saliva
• Molds, fungi, helmenths
• Chemicals (SO2, TDI)
• Chitin exoskeletons

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Genetics and Environment in Asthma
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Airway Smooth Muscle Constriction
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Airways without and with Asthma
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Treatment for Asthma

• Allergen avoidance
• Inhaled corticosteriods
• Leukotriene receptor antagonists
• Rescue plan (prednisone rescue)
• Desensitization (induce blocking antibodies. IgG)

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Omalizumab prevents IgE from binding to
cell-surface receptors
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Dry Powder Inhalers

• Salmeterol in combination with Fluticasone
  (Diskus)
• Rapid inhalation from RV, breath hold

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Inhaled Corticosteroids

• Not of benefit in COPD morality
• Decreased hospitalization
• Assists on titration of patients off of systemic
  corticosteroids.
• Mainstay of Asthma therapy!!!
• Must use a spacer with MDI, slow inhale
• Swish and spit

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Steroid Resistant Asthma

• Methotrexate
• Anti- IgE MAB (Xolair)
• Anti-TNFa (Etanercept)

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Omalizumab prevents IgE from binding to
cell-surface receptors
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TNFa Contributions to Asthma
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Anti TNFa in Steroid Resistant Asthma
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Additional Ideas

• Diet, vitamins A,C, E
• Alpha 1 AT replacement
• Secretion management
• Check for immunoglobulin deficiency
• Look for causes non-asthmatic wheezing

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Summary Prevent COPD Exacerbations!

• Smoking cessation
• Viral and bacterial vaccines
• LABAs corticosteroids tiotropium
• Theophylline at bedtime
• Antibiotics for potential bacterial AECB
• Oxygen prevents cor pulmonalle
• Corticosteroid trial?
• Rehabilitation VRLS for selected patients

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