Bronchiectasis Questions
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Transcript of Bronchiectasis Questions
BronchiectasisBronchiectasisQuestionsQuestions
Dean E. Schraufnagel, MDDean E. Schraufnagel, MDATS President-ElectATS President-ElectUniversity of Illinois at University of Illinois at ChicagoChicagoMay 6, 2010May 6, 2010Nothing to discloseNothing to disclose
ATSATS FounderFounder
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 We know about BronchiectasisBronchiectasis… … or do we?or do we?
Definition?Definition?
Definitions
• “Permanently” dilated bronchiReid. Thorax 1950;5:233-47
• 1.5 x larger than accompanying arteryDesai et al., Br J Radiol 1994;67:257-62
• Larger than accompanying arteryLi et al., Eur Resp J 2005;26:8-14
• What about– Bronchial wall thickness?– Tree in bud?– Reversible?
IsIsbronchiectasis bronchiectasis
in differentin different locations locations differentdifferentDiseases?Diseases?
Commonly held
• 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-lobeLower-lobe
How oftenHow oftenis it notis it not
associatedassociatedwith an with an
etiologicaletiologicalInfection?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?Why hemoptysis?
♀ ♀ - cc: cough and breathlessness- cc: cough and breathlessness(on questioning-hemoptysis)(on questioning-hemoptysis)
→ → Interstitial lung diseaseInterstitial lung disease → → BiopsyBiopsy
PathogenesisPathogenesis
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 aboutWhat about biofilms?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
BiofilmsBiofilmsProtect Protect
inhabitaninhabitantsts
Biofilms protect inhabitants
• Macrophage engulfment ↓• Antibiotic penetration ↓ • ↑antibiotic resistance• ↓ stimulation to mucosa• Bacteria switch to latent form
– pH, nutrient Δ
• Exacerbation - bacteria emerge from biofilm?
Quorum sensingQuorum 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?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
DirectioDirection?n?
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?
• 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
• 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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