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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