Transcript An adapted island model of lung biogeography
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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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 60 50 40 30 20 10 0 30 25 20 15 10 5 0 Healthy Healthy Stable COPD Stable COPD AECB AECB H. flu S. pneumo M. cat P. aer Rosell et al. Arch Int Med 2005; 165: 891-7
Colour of sputum as marker of bronchial colonization
Miravitlles M.
Respir Res 2010; 11: 58
PPM1
Recurrence
Recurrent colonization
PPM 2 PPM3
40%
Clinical threshold Time (days)
Persistence
10%
“fall & rise” of bacteria in COPD
New strain / Individual factors / External modifying factors Clinical threshold Time (days) AE AB Cure Modified from Miravitlles. Eur Respir J 2002: 20: 9s-19s 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
70 60 50 40 30 20 10 0 * Overall * * * *p<0.05
culture qPCR HI SP
Typical bacteria species
MC
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 Pooled Secretions in Airway Biofilm on ETT 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
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 4 2 8 6 Figure 6.08
* p<0.05
* * 6 5 0 D0 D5 D9 D12 D15 3/52 Study days FIGURE 6.08
4/52 5/52 6/52 6 Virus Bacteria 5 4 3 2 1 1 0 D0 D5 D9 D12 D15 3/52 Study days 4/52 5/52 6/52 0 4 3 2
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
Sufficient Trigger
Non-Susceptible Patient EXACERBATION SUSCEPTIBLE PATIENT + SUFFICIENT STIMULUS = EXACERBATION P susc + S suff = 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 P. aeruginosa
/enterobacteria
H.parainfluenzae
Marin. Eur Respir J 2010;35:295
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.
Old Model
Sterile Plan Large inoculum Do Sterile-
-infection-
Large inoculum 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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