Transcript Bronchiectasis

Bronchiectasis
Questions
Dean E. Schraufnagel, MD
ATS President-Elect
University of Illinois at Chicago
May 6, 2010
Nothing to disclose
ATS
Founder
American Thoracic Society: An
International Society
• ATS International Conference (May 14-19, 2010 New
Orleans) features over 5,500 original research
presentations with 16,000 attendees
– About half of participants from outside the US
• American Journal of Respiratory and Critical Care
Medicine has the highest impact factor in respiratory or
critical care medicine
• Over half of articles submitted to ATS journals come
from outside the US
We know about Bronchiectasis
… or do we?
Definition?
Definitions
• “Permanently” dilated bronchi
Reid. Thorax 1950;5:233-47
• 1.5 x larger than accompanying artery
Desai et al., Br J Radiol 1994;67:257-62
• Larger than accompanying artery
Li et al., Eur Resp J 2005;26:8-14
• What about
– Bronchial wall thickness?
– Tree in bud?
– Reversible?
Is
bronchiectasis
in different
locations
different
Diseases?
Commonly held
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Upper lobe – TB
Middle lobe – environmental mycobacteria
Lower lobe – post-infectious
Central – allergic aspergillosis
Focal – obstruction
Diffuse – agammaglobulinemia
Upper lobe → tuberculosis
• Old or active tuberculosis
• Unsuspected until hemoptysis
• Other upper lobe
– Cystic fibrosis
– Sarcoidosis
• “Dry bronchiectasis”
– Post-TB, Sjögren's, unable to expectorate
» Yazisiz et al., Rheumatol Int. 2009
Post TB
Mother had TB.
Skin test positive
Adult presentation cystic fibrosis
Middle lobe
• Middle to older-aged, nonsmoking ♀
• Mitral valve prolapse & chest deformity
• Why environmental mycobacteria?
• Why middle lobes?
– Clearance?
Postnatal respiratory distress + sicca
Allergic bronchopulmonary
aspergillosis
• Eosinophilia, transient alveolar opacities,
↑IgE (specific), precipitins, immediate skin
test
• Paradox
– Intense inflammation - Rx steroids
– But oral steroids ∝ poor outcome
• Itraconazole
Lower-lobe
How often
is it not
associated
with an
etiological
Infection?
Focal – Obstruction?
• Bronchoscopy?
• Other focal areas often present
– Important if considering surgery
» Gursoy et al., Surgery Today 2010;40:26-30
Diffuse - Immune deficiency?
• Immune deficiency
– Common variable, HIV
• Global airway disease
– Mounier Kuhn, papillomatosis, relapsing
polychondritis
• Advanced bronchiectasis of any type
Why hemoptysis?
♀ - cc: cough and breathlessness
(on questioning-hemoptysis)
→ Interstitial lung disease
→ Biopsy
Pathogenesis
Pathogenesis
• Secretions not cleared
• Organisms grow in secretions
• Immune response → ongoing inflammation
– Hyperemia, vascular hyperplasia
– Bronchospasm
– Peribronchial tissue destruction
• Upper lobe→ less secretions, less destruction?
Pathogenesis
• Organisms remain external to body
–
–
–
–
Reason for mild symptoms?
Difficulty in treating and diagnosis
Immune cells - less impact
Antibiotics - less penetrance
• Little abscesses?
– Organisms protected by secretions?
– Reason for inadequate treatment?
Excess matrix metalloproteinases
• Breakdown tissue
• 1607GG allele of promoter MMP1
• ↑ 37 bronchiectasis pts cf 102 nl
–Heterozygote O.R. = 5.3
–Homozygotes O.R. = 8.7
– Stankovic et al., J Investig Med 2009;57:500-3
Lung PMN dysfunctional?
• Bronchiectatic sputum: ↑ Human neutrophil
peptides
– ∝ Defective phagocytosis
– Multiple PMN ∆’s controlled by i.c. Ca2+
– Also found in α1-antitrypsin animal model
– Voglis et al., Am J Respir Crit Care Med 2009;180:159-66
• Low neutrophil oxidative burst
– IFNγ restores
– King et al., APMIS 2009;117:133-39
What about
biofilms?
Biofilms
• Complicated slime layers
– Glycoprotein matrix from bacteria
– E.g. dental plaque
• Acinetobacter & pseudomonas – more stable
than ancestral colonies
– Hansen et al., Nature 2007;445:533-6
• M. mucogenicum & B. cepacia →↑biofilm
– Simões et al., Appl Environ Microbiol 2007;73:6193-6200
Complex communities
• Antagonistic, competitive, commensal, or
symbiotic
• Benefits
– Plasmid sharing
– Metabolism sharing
– Defense sharing
• Disadvantage – nutrient competition
– Biofilm mass ↯∝ metabolic activity
Simões et al., Appl Environ Microbiol 2007;73:6193-6200
Biofilms
Protect
inhabitants
Biofilms protect inhabitants
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•
•
•
•
Macrophage engulfment ↓
Antibiotic penetration ↓
↑antibiotic resistance
↓ stimulation to mucosa
Bacteria switch to latent form
– pH, nutrient Δ
• Exacerbation - bacteria emerge from
biofilm?
Quorum sensing
Quorum sensing
• Bacteria ↦ molecules ∝ population density
– E.g. Gram neg: Acylated homoserine lactones
• Sensing → Δ gene expression
– ↦ virulence factors, biofilm, antibiotic
production, swarming, conjugation, sporulation,
bioluminescence
• Autoinducer
Treatment potential?
• Quorum sensing inhibitors
– ↛ gene regulation, production, reception
– Enzymes inactivate QS molecules
• ↛ biofilm
• Fewer toxic effects?
– Not required for bacterial growth
• Animals and plants →↑survival
– Rasmussen & Givskov. Microbiol 2006;152:895-904
Organisms?
Which organisms important?
• Most common in established bronchiectasis
– H. influenza (47%), P. aeruginosa (12%)
– King et al., Resp Med 2007;101:1633-8
• Multiple species
• Role of mouth flora?
• Role of mycobacteria?
• Role of in vitro antibiotic testing?
Low virulent organisms?
• Low virulence
– Little damage, invasiveness
– Living in biofilm different than culture?
– UIC BAL - stomatococcus ~15%
• Often “normal respiratory flora”
– How do deal with it?
• No growth - adequate sputum?
– Mycobacteria, fungi, handling problem
Direction?
Basic premises
• Rx -- underlying disease
– E.g. Immune deficiency
• Clear secretions
• Rx symptom based problems
– Bronchospasm
– Dyspnea, cough, respiratory failure
• Bacterial monitoring and eradication
Chest physiotherapy?
• Small improvement
– Leicester Cough Questionnaire
– 24-h sputum volume
– Exercise capacity
– SGRQ total score
• No difference
– Sputum bacteriology
– Pulmonary function tests
– Murray et al., Eur Respir J 2009;34:1086-92
Do antibiotics work?
• →↑ lung function (FEV1, FVC, VC, FRC, TLC)
– Small but significant
– Hill et al., Thorax 1986;41:798-800
• →↑ QOL in absence of PFT improvement
– Hill et al., Thorax 1986;41:559-65
• 4 months
– cleared sputum for 0.5 to 10 months (μ 2.5)
– ↓ sputum elastase
– ↓ indices of inflammation
– Hill et al., Q J Med 1986;66:163-7
Macrolides
• Useful in CF
• Erythromycin, azithromycin and clarithromycin
→↓exacerbations
– Alter resident bacteria, but may not kill main pathogen
• Tsang et al., Eur Respir J 1999;13:361-4
• Cymbala et al., Treat Respir Med 2005;4:117-122
• Yalcin et el., J Clin Pharm Ther 2006;31:49-55
• Anwar et al., Respir Med. 2008;102:1494-96
Inhaled antibiotics
• Tobramycin improved health status
– 62% vs. 38%
– Associated transient dyspnea, wheezing,
chest tightness
– Couch. Chest 2001;120:114S-117S
• Fosfomycin/tobramycin
– MacLeod et al., J Antimicrob Chemother 2009;64:829-36
• Aztreonam lysine
– McCoy et al., Am J Respir Crit Care Med 2008;178:921-8
Inhaled steroids?
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Withdrawal for 12 weeks
→↑ bronchial hyperreactivity
→↓ neutrophil apoptosis
No change in sputum inflammatory
markers
– Guran et al., J Clin Pharm Ther 2008;33:603-11
Tiotropium?
• →↑ Cough, sputum, breathlessness
– Visual analog scale
• → ↑ FEV1
• Radiology unchanged
• Saito et al., Intern Med 2008;47:585-91
Ambient Humidification?
• Chronic humidifier use ∝
bronchiectasis
• Pts inhaled saturated air for 3
hours day for 7days
• ↑Lung mucociliary clearance
– Hasani et al., Chron Respir Dis 2008;5:81-86
Management questions
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•
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Cost-effectiveness of workup?
Exacerbation - treat or not?
Sterilize or not?
How long to treat?
Treat infection based on drug sensitivity?
– Surveillance cultures?
• How much effort for secretion clearance?
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