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?

Teşekkürederim

∝