The role of infection in COPD

Antonio Anzueto, M.D.

Professor of Medicine

University of Texas Health Science Center

San Antonio, Texas

Disclosures

Non-commercial, non-governmental interests relevant to my presentation :Member of the ATS/ERS Task force on COPD and COPD Exacerbations, CurrentMember of Scientific Committee of GOLD, Current

Personal financial interests in commercial entities that are relevant to my presentation: Boehringer Ingelheim: consultant: advisory board, CurrentGlaxoSmithKline: consultant, advisory board, Research Grant to the University, CurrentChiesi: consultant, advisory board, PastBayer-Schering Pharma: consultant, advisory board, CurrentDey Pharma: consultant, advisory board, CurrentForest laboratories: consultant, advisory board, Current

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Pathogenesis of Airway Infection

• Lungs are sterile

• Suitable large inoculum of pathogenic sp. enters the lower respiratory tract

• Overwhelms host defenses

• Unrestrained growth of a bacteria species

Pasteur L. C R Acad Sci 1881; 92:159-65

This

theory

is NOT

True

Alternative Concepts for Lung Infections

- Effect of environmental gradients on lung microbiota

- An adapted island model of lung biogeography

-LRTI are the results of unexplored positive feedback loops

Alternative Concepts for Lung Infections

Effect of environmental gradients on lung microbiota

- An adapted island model of lung biogeography

LRTI are the results of unexplored positiveFeedback loops

Pooled studies of bronchoscopy in stable COPD and patient during AECB

0

10

20

30

40

50

60

Healthy Stable COPD AECB

Per

cent

of

patie

nts

with

> 1

02 D

FU

/ml

0

5

10

15

20

25

30

Healthy Stable COPD AECB

H. flu

S. pneumo

M. cat

P. aer

Per

cent

of

patie

nts

with

par

ticul

ar o

rgan

ism

Rosell et al. Arch Int Med 2005; 165: 891-7Rosell et al. Arch Int Med 2005; 165: 891-7

Colour of sputum as marker of bronchial colonization

Miravitlles M.Respir Res 2010; 11: 58

Recurrence

Clinicalthreshold

Ba

cte

ria

l lo

ad

(C

FU

/ml)

Time (days)

PPM3PPM1

PPM2

Recurrentcolonization

40%

Persistence

10%

“fall & rise” of bacteria in COPDB

acte

rial

load

(C

FU

/ml)

Time (days)

Clinicalthreshold

AE AB Cure

Time to relapseModified from

Miravitlles. Eur Respir J 2002: 20: 9s-19s

New strain / Individual factors / External modifying factors

~5 % of microorganisms currently culturable, depending on environment, sample and effort.

“The Great Plate Count Anomaly”

Staley and Konopka1985 Annual Review of Microbiology 39 pp 321-346

16S RibosomalSubunit

Carl WoesePhylogenetic structure of the prokaryotic domain: the primary kingdomsWoese and Fox, 1977 PNAS 74(11) pp 5088-5090

Norman Pace:Rapid determination of 16S ribosomal RNA sequences for phylogenetic analysesLane et al, 1985 PNAS 82(20) pp 6955-6959

PCR PROVIDES A BETTER STANDARD THAN CULTURE FOR DETECTION OF AIRWAY BACTERIA

*p<0.05

Garcha D S et al. Thorax -2012

Immigration and extinction rates for an island as a function of number of species present

MacArthur and Wilson Evolution 1963; 17:373

Microbiota within the respiratory tract

Dickson et al Lancet Respir Med 2014; 2:238

Airway Phylogenetic Tree

Hilty M, et al. PLoS ONE 2010; 5: e8578.

Does the lung have an indigenous bacterial microbiota?

Erb-Downward et al. PLoS One. 2011;6(2):e16384.

YES

Microbiota in asthma and COPD

Hilty M, et al. PLoS ONE 2010; 5: e8578.

Microbiota Diversity in COPD compared with controls: Equivalent

Sze et al AJRCCM 2012; 185:1073–1080

Positive immigration factors:Favors Increase Bacterial Burden

Proximity to oropharynxIncreased oropharyngeal microbial burdenLaryngeal dysfunctionGross aspiration, impaired consciousnessGastro-oesophageal refluxSupine positioningMedications (eg, proton-pump inhibitors)

Effect of Body position

PharyngealPharyngeal BronchialBronchial

Orozco-Levi M. AJRCC Med 1995;152:1387

• Supinoo Semi-incorporado

Rates of Hospital-Acquired Pneumonia According to Acid-Suppressive

Medication Status

Herzig et al JAMA. 2009;301:2120-2128

Negative extinction factors:Allows bacteria growth

Impaired cough reflex

Endobronchial obstruction

Impaired ciliary function

Presence of endotracheal tube

Impaired innate, adaptive immune response

Medications (eg, inhaled corticosteroids,

pentobarbital)

Endotracheal Tube

Subglottic Secretions

Endotracheal Tube Cuff

Pooled Secretions in Airway

Biofilm on ETT

Dispersal of Biofilm With Ventilation

Ruge CA, et al. Lancet Respir Med 2013

What happens to a drug after deposition in the lungs?

(1) = first contact with airway surface liquid, (2) = absorption of active ingredients across pulmonary epithelium, this process is controlled mainly by physiochemical

properties (dissolution rate and lipophilicity) (3) = Clearance of non-dissolved particles by mucocilliary clearance or phagocytosis

Bacterial load: Asthma C-Steroid resistant or sensitive

Goleva et al AJRCCM 2013 188:1193–1203

Bacterial load increased by

rhinovirus infection

2/10 (20%) controls

5/9 (55.6%) COPD group developed a positive bacterial culture (p=0.17)

Johnston S AJRCCM 2013

Distribution of bacterial phyla at each time pointafter rhinovirus (RV) inoculation

Control COPD

Molyneaux et a l AJRCCM 2013:188, 1224–1231

Alternative Concepts for Lung Infections

Effect of environmental gradients on lung microbiota

An adapted island model of lung biogeography

LRTI are the results of unexplored positiveFeedback loops

Regional differences in gas exchange in the upright lungs

West JB Chest 1978; 74:426

Does the indigenous bacterial microbiota is different in the lungs?

Erb-Downward et al. PLoS One. 2011;6(2):e16384.

Mean wall and air temperature in the tracheobronchial tree of human beings after

hyperventilating cold air

Ignito et al J Appl Physiol 1987:63:2075

Alternative Concepts for Lung Infections

Effect of environmental gradients on lung microbiota

An adapted island model of lung biogeography

LRTI are the results of unexplored positiveFeedback loops

Mechanism of Exacerbation

Susceptible Patient

Non-Susceptible Patient

Sufficient Trigger

EXACERBATION

SUSCEPTIBLE PATIENT + SUFFICIENT STIMULUS = EXACERBATIONPsusc + Ssuff = E

Potential positive feedback explaining the emergence of infection from pre-existing homoeostasis

Dickson et al Lancet Respir Med 2014; 2:238

BACTERIAL LOAD AND AIRWAY INFLAMMATION

Patel et al Thorax 2002

rho = 0.459

p = 0.02

Species-specific bronchial inflammatory response

Marin. Eur Respir J 2010;35:295

Statistically significant Inflammatory response associated with H influenzae

Species-specific bronchial inflammatory response

Marin. Eur Respir J 2010;35:295

H. influenzae P. aeruginosa/enterobacteria H.parainfluenzae

Lung Infection: positive feedbacks increases bacteria growth

• Catecholamines promote the in-vitro growth of many

pneumonia-associated bacterial species, including

Streptococcus pneumoniae69 and many Gram-negative rods

• Host production of catecholamines in response to bacteria-

induced inflammation could in turn accelerate bacterial growth.

• Quorum sensing has been used to explain the change in

virulence in acute exacerbations of cystic fibrosis, and could be

present in other respiratory infectious processes

Belay et al Life Sci 2002; 71: 447–56. Fresstone et al Chest 2012;142: 1200–10.

Plan

DoLargeinoculum

Sterile

Old Model

Sterile- Large inoculum-infection- bacteria growth

Plan

infection

Large inoculum

sterile

Bacteria

growth

infection

Large

inoculum

Sterile

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

Facto

rs th

at a

lter b

acter

ia

bala

nce

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

A P

S D

A PS D

A P

S D

D SP A

New ModelComplex Adaptive Systems

©2001 Institute for Healthcare Improvement

GERDBody positionImpaired cough

Medications:PPI, ICS

Lacto-bacillus supplement: time to microbiologically confirmed VAP

Morrow et al AJRCCM 2010;182:1058–1064

Lacto-bacillus

No- Lacto-bacillus

SURVEILLANCE CULTURE DATA

Morrow et al AJRCCM 2010;182:1058–1064

Conclusions

The airways are not sterile

There is every day more data that airway microbial communities are disturbed in asthma and COPD

Different factors affects microbiome including the environment and different areas of the lung

Balance between positive and negative loops result in infection

It is possible to manipulate the airway community?

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