The role of infection in
COPD
Antonio Anzueto, M.D.
Professor of Medicine
University of Texas Health Science
Center
San Antonio, Texas
Disclosures
Personal financial interests in commercial entities that are relevant to
my presentation:
Boehringer Ingelheim: consultant: advisory board, Current
GlaxoSmithKline: consultant, advisory board, Research Grant to the
University, Current
Chiesi: consultant, advisory board, Past
Bayer-Schering Pharma: consultant, advisory board, Current
Dey Pharma: consultant, advisory board, Current
Forest laboratories: consultant, advisory board, Current
Non-commercial, non-governmental interests relevant to my presentation :
Member of the ATS/ERS Task force on COPD and COPD Exacerbations, Current
Member of Scientific Committee of GOLD, Current
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Velasquez
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Picasso
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
Alternative Concepts for Lung
Infections
- An adapted island model of lung
biogeography
- Effect of environmental gradients
on lung microbiota
-LRTI are the results of unexplored
positive feedback loops
Alternative Concepts for Lung
Infections
- An adapted island model of lung
biogeography
Effect of environmental gradients
on lung microbiota
LRTI are the results of unexplored positive
Feedback loops
Pooled studies of bronchoscopy in
stable COPD and patient during AECB
30
10
0
5
Percent of patients
with > 102 DFU/ml
Percent of patients
with particular organism
60
50
40
30
20
25
20
H. flu
S. pneumo
15
M. cat
P. aer
10
0
Healthy
Healthy
Rosell et al. Arch Int Med 2005; 165: 891-7
Stable COPD
Stable COPD
AECB
AECB
Colour of sputum as marker of
bronchial colonization
Miravitlles M.
Respir Res 2010; 11: 58
Recurrence
Bacterial load (CFU/ml)
40%
Clinical
threshold
Recurrent
colonization
PPM1
PPM
2
Time (days)
PPM3
Persistence
10%
“fall & rise” of bacteria in COPD
Bacterial load (CFU/ml)
New strain / Individual factors / External
modifying factors
Clinical
threshold
Time (days)
AE
AB
Modified from
Miravitlles. Eur Respir J 2002: 20: 9s-19s
Cure
Time to relapse
~5 % of microorganisms currently culturable, depending on
environment, sample and effort.
“The Great Plate Count Anomaly”
Staley and Konopka
1985 Annual Review of Microbiology 39 pp 321-346
16S
Ribosomal
Subunit
Carl Woese
Phylogenetic structure of the prokaryotic domain: the primary kingdoms
Woese and Fox, 1977 PNAS 74(11) pp 5088-5090
Norman Pace:
Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses
Lane et al, 1985 PNAS 82(20) pp 6955-6959
PCR PROVIDES A BETTER STANDARD THAN CULTURE
FOR DETECTION OF AIRWAY BACTERIA
Prevalence of bacteria (%)
70
60
*p<0.05
*
culture
50
qPCR
40
*
30
*
20
*
10
0
Overall
HI
SP
MC
Typical bacteria species
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?
YES
Erb-Downward et al. PLoS One. 2011;6(2):e16384.
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 oropharynx
Increased oropharyngeal microbial burden
Laryngeal dysfunction
Gross aspiration, impaired consciousness
Gastro-oesophageal reflux
Supine positioning
Medications (eg, proton-pump inhibitors)
Effect of Body position
Pharyngeal
Bronchial
• Supino
o Semi-incorporado
Orozco-Levi M. AJRCC Med 1995;152:1387
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
Biofilm on ETT
Pooled Secretions in
Airway
Dispersal of Biofilm
With Ventilation
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
Ruge CA, et al. Lancet Respir Med 2013
Bacterial load: Asthma C-Steroid resistant
or sensitive
Goleva et al AJRCCM 2013 188:1193–1203
8
Bacterial load
increased by
rhinovirus
infection
Bacterial load (log10 CFU)
* p<0.05
*
*
D12
D15
6
4
2
0
D0
D5
D9
3/52 4/52 5/52 6/52
Study days
FIGURE 6.08
Johnston S AJRCCM 2013
Sputum virus load (log10 RV RNA/ml)
group developed a
positive bacterial
culture (p=0.17)
6
Virus
Bacteria
5
5
4
4
3
3
2
2
1
1
0
D0
0
D5
D9
D12
D15
3/52
Study days
4/52
5/52
6/52
Bacterial load (log10 CFU)
 2/10 (20%) controls
 5/9 (55.6%) COPD
6
Distribution of bacterial phyla at each time point
after rhinovirus (RV) inoculation
Control
COPD
Molyneaux et a l AJRCCM 2013:188, 1224–1231
Alternative Concepts for Lung
Infections
An adapted island model of lung
biogeography
Effect of environmental gradients
on lung microbiota
LRTI are the results of unexplored positive
Feedback 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
An adapted island model of lung
biogeography
Effect of environmental gradients
on lung microbiota
LRTI are the results of unexplored positive
Feedback loops
Mechanism of Exacerbation
Susceptible
Patient
Non-Susceptible
Patient
Sufficient Trigger
EXACERBATION
SUSCEPTIBLE PATIENT + SUFFICIENT STIMULUS = EXACERBATION
Psusc + 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
Statistically significant Inflammatory response associated with H influenzae
Marin. Eur Respir J 2010;35:295
Species-specific bronchial inflammatory
response
H. influenzae
Marin. Eur Respir J 2010;35:295
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 bacteriainduced 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.
Old Model
Sterile
Plan
Large
inoculum
Do
Sterile-  Large inoculum
-infection- bacteria growth
New Model
Complex Adaptive Systems
Impaired cough
Body position
GERD
Medications:
PPI, ICS
©2001 Institute for Healthcare Improvement
Lacto-bacillus supplement: time to
microbiologically confirmed VAP
Lacto-bacillus
No- Lacto-bacillus
Morrow et al AJRCCM 2010;182:1058–1064
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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