new concepts in microbiology of exacerbations of copd

New Concepts in New Concepts in Microbiology of Microbiology of

Exacerbations of COPD Exacerbations of COPD Sanjay Sethi MDSanjay Sethi MD

ProfessorProfessorPulmonary, Critical Care and Sleep MedicinePulmonary, Critical Care and Sleep Medicine

University at Buffalo, SUNYUniversity at Buffalo, SUNYssethi@buffalo.edussethi@buffalo.edu

AECOPD: Perception vs RealityAECOPD: Perception vs Reality

PerceptionPerception A nuisance A nuisance

problem with no problem with no serious serious consequencesconsequences

RealityReality Contributes to:Contributes to:

Cost of health Cost of health care care (35-45%)(35-45%)

Poor quality of lifePoor quality of life Mortality Mortality Progression of Progression of

lung diseaselung diseaseMannino et al. MMWR 2002;51(SS-6):1-16Andersson et al. Resp Med 2002;96:700-8

Etiology of AECOPDEtiology of AECOPD

S. pneumoniae

H. influenzae

M. catarrhalisVirus

Chlamydia

Pseudomonas

Gram -

H para

Non-infectious

Obaji & Sethi. Drugs and Aging; 2001;18:1-11

Etiology of AECOPDEtiology of AECOPD

Bacteria

Bacteria and Virus

Virus

Non-infectious

Papi et al AJRCCM 2006;173:1114-21

AECOPD: Bacterial etiologyAECOPD: Bacterial etiologySputum culture studiesSputum culture studies

Gump et al. ARRD 1976;113:465-473

25 patients

Outpatient clinic every 2 weeks for 4 years

Sputum culture

1886 clinic visits

116 exacerbations

1870 stable

StableExacerbation

00

1010

2020

3030

4040

5050

6060

SP NTHI

%%

33.1

59.957.0

37.2

Bacterial load model of Bacterial load model of pathogenesis of AECBpathogenesis of AECB

S E S E S E S

1,E+08

1,E+07

1,E+06

1,E+05

1,E+04

1,E+03

1,E+02

NTHI titer

Bacterial Load ModelBacterial Load Model

0

1

2

3

4

5

6

7

8

9

10

HI HH MC SP HP

Pathogen

stable

exacerbation

Log Titer

*

*

Sethi et al AJRCCM 2007

Bacterial Bacterial Infection in Infection in

COPDCOPD

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulenceHost lung defense

Change in airway inflammation

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulenceHost lung defense

Change in airway inflammation

Bacterial Bacterial Infection in Infection in

COPDCOPD

COPD Study ClinicCOPD Study Clinic

AimsAims Dynamics of Dynamics of

bacterial infection in bacterial infection in COPDCOPD

HypothesisHypothesis Acquisition of new Acquisition of new

strains of bacterial strains of bacterial pathogens is pathogens is associated with an associated with an increased risk of increased risk of exacerbationexacerbation

Clinic visits:Clinic visits: MonthlyMonthly Suspected Suspected

exacerbationexacerbation

At each visit:At each visit: Clinical evaluation Clinical evaluation Serum sampleSerum sample Sputum sample for Sputum sample for

quantitative quantitative bacteriologybacteriology

Sethi et al. NEJM 2002, 347:465-471

ex ex ex

Patient 6: Time line

HI HI HI HI HI

108 106 106 108 107

1 month

1 2 3 4 5 6 7 8 9 10 11 12 13

Typing the NontypeableTyping the Nontypeable

Nontypeable Nontypeable H. H. influenzae influenzae sputum sputum isolatesisolates Whole bacterial Whole bacterial

lysates lysates Analyzed on a SDS- Analyzed on a SDS-

PAGE gelPAGE gel

Sethi et al. NEJM 2002, 347:465-471

Patient 6: Time line

1 2 3 4 5 6 7 8 9 10 11 12 13

ex ex ex1 month

HI HI HI HI HI

108 106 106 108 107

A A B C C

33

15.4

26.2

17.1

48.8

16.6

32

18

13.6

18.2

0

10

20

30

40

50

Any NTHI MC SP PA

COPD Study Clinic: New strain isolation COPD Study Clinic: New strain isolation and exacerbationand exacerbation

*

*

*

*

Relative risk (95% CI) of exacerbation:

Any 2.15 (1.83–2.63)

NTHI 1.69 (1.37–2.09)

MC 2.96 (2.39–3.67)

SP 1.77 (1.14–2.75)

PA 0.61 (0.21–1.82)

Sethi et al. NEJM 2002;347:465-71

New strain +New strain –

*p<0.05

Exacerbation frequency

Pathogen

AECB: Bacterial etiologyAECB: Bacterial etiologySputum culture studiesSputum culture studies

Gump et al. ARRD 1976;113:465-473

25 patients

Outpatient clinic every 2 weeks for 4 years

Sputum culture

1886 clinic visits

116 exacerbations

1870 stable

StableExacerbation

00

1010

2020

3030

4040

5050

6060

SP NTHI

%%

33.1

59.957.0

37.2

Bacterial Bacterial Infection in Infection in

COPDCOPD

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulenceHost lung defense

Change in airway inflammation

NTHI Colonization vs Exacerbation NTHI Colonization vs Exacerbation strainsstrains

•10 exacerbation strains

•7 colonization strains

•In vivo mouse model

•In vitro respiratory epithelial cell line

Chin et al AJRCCM 2005

Bacterial Infection Bacterial Infection in COPDin COPD

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulence

Host lung defense

Change in airway inflammation

Moraxella catarrhalisMoraxella catarrhalisFrequency of Immune Response Frequency of Immune Response

0

10

20

30

40

50

60

% p

osi

tive

Sputum IgA Serum IgG

Exacerbation

Colonization

p = 0.009p = 0.009 p = 0.11p = 0.11

Murphy et al, AJRCCM 2005

Lymphocyte Proliferative Response to Lymphocyte Proliferative Response to OMP P6 of NTHIOMP P6 of NTHI

PBMC stimulated with PBMC stimulated with purified OMP P6purified OMP P6

GroupsGroups H: healthy controlsH: healthy controls C: COPD without C: COPD without

NTHI exacerbation NTHI exacerbation in previous 12 in previous 12 monthsmonths

N: COPD with NTHI N: COPD with NTHI exacerbation in exacerbation in previous 12 monthsprevious 12 months

Abe et al AJRCCM, 165:967-71, 2002

Bacterial Infection Bacterial Infection in COPDin COPD

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulenceHost lung defense

Change in airway inflammation

Patient 6:Time line

1 2 3 4 5 6 7 8 9 10 11 12 13

ex ex ex1 month

HI HI HI HI HI

108 106 106 108 107

A A B C C

SP0 0 0 0 0 0

Changes in Airway Inflammation with Onset of Exacerbations

-2

-1

0

1

2

3

4

5

No new strain New strain

IL-8

ch

ang

e n

g/m

l

p = 0.40

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

No new strain New strain

TN

Fα

ch

ang

e n

g/m

l

p < 0.001

-100

0

100

200

300

400

500

600

No new strain New strain

NE

ch

ang

e n

M

p = 0.01

• Airway inflammation increases with exacerbations

• Bacterial exacerbations are associated with greater neutrophilic inflammation

Sethi et al ATS, 2005

Changes in Airway Inflammation with Resolution of Exacerbations

-3

-2

-1

0

1

2

3

Non-resolution Resolution

IL-8

ch

ang

e n

g/m

l

p = 0.35 p = 0.05

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Non-resolution Resolution

TN

Fα

ch

ang

e n

g/m

l

p = 0.79 p = 0.007

-200

-100

0

100

200

300

400

500

Non-resolution Resolution

NE

ch

ang

e n

M

p = 0.18 p = 0.02

Sethi et al ATS, 2005

• Airway inflammation decreases with resolution of exacerbation

• Correlation between clinical resolution and resolution of inflammation

Bacterial Persistence and Bacterial Persistence and Airway Inflammation following Airway Inflammation following

AECOPDAECOPD

White et al. Thorax 2003;58:680-685

LT

B4

(nM

)

100

10

1

0.1

0.01

1 10 1 10

Bacteria eradicated by day 10

Bacteria persisting at day 10

p<0.001p<0.001

Day

MP

O (

un

its/

ml)

10

1

0.1

0.01

1 10 1 10

Bacteria eradicated by day 10

Bacteria persisting at day 10

p<0.05p<0.001

Day

Bacterial Infection Bacterial Infection in COPDin COPD

Acquisition of new bacterial strain

Level of symptoms

Exacerbation

Strain-specific immune response

+/- antibiotics

Elimination of infecting strain

Colonization

Persistent infection

Tissue invasionAntigenic alteration

Pathogen virulenceHost lung defense

Change in airway inflammation

H. influenzaeH. influenzae: : Bactericidal Bactericidal assaysassays

%

Kil

l

-20

0

20

40

60

80

100

120

Pre-exacerbationserum

Post-exacerbationserum

• New bactericidal antibody developed to 18 of 26 (69.2%) new strains following exacerbation

Sethi et al AJRCCM 169;448-453, 2004

Strain-specificity of bactericidal Strain-specificity of bactericidal antibodies to NTHIantibodies to NTHI

Bactericidal antibodies Bactericidal antibodies from 10 patients were from 10 patients were tested against 9 tested against 9 heterologous strains heterologous strains each. each.

79 of 90 (88%) of 79 of 90 (88%) of heterologous strains heterologous strains were were notnot killed. killed.

8 of the 10 sera killed 8 of the 10 sera killed only the homologous only the homologous strain or 1 strain or 1 heterologous strain.heterologous strain.

0

12

34

5

67

89

n

11 13 14 18 32 37 45 55 6 70

patient #

Sethi et al AJRCCM 169;448-453, 2004

Viral AECB:Culture and Viral AECB:Culture and Serology StudiesSerology Studies

Percentage of total viral isolates

n %Viral

Rhino Infl Parainfl

RSV Corona Adeno

Total 1081

Mean 135 36 38 26 15 11 10 3

Range 42-522 20–61 0-78 0-45 0-39 0-40 6-18 0-10

Comments 8studies

7studies

4studies

Carilli 1964, Eadie 1966, McNamara 1969, Lamy 1974,

Gump 1976, Buscho 1978, Smith 1980, McHardy 1980

Viral RTI: Cohort StudyViral RTI: Cohort Study

171722223939RTVI/RI %RTVI/RI %0.520.520.380.380.540.54RTVI/yrRTVI/yr3.03.01.81.81.41.4RI/yrRI/yr323230305555nn

FEVFEV11<50%<50%FEVFEV11 >50% >50%ControlsControls

Greenberg et al AJRCCM, 2000;162:167-173

Viral RTI: Clinical Viral RTI: Clinical Manifestations and Lung Manifestations and Lung

FunctionFunction

0

10

20

30

40

50

60

70

80

90

% o

f R

TVI

Controls FEV1>50% FEV1<50%

URI

URI + LRI

LRI

Greenberg et al AJRCCM, 2000;162:167-173

Greenberg SB, et al. Am J Respir Crit Care Med. 2000;162:167-173.

Viral RTI: PathogensViral RTI: Pathogens

0

5

10

15

20

25

30

35

Picorna-viruses

Para-influenzaviruses

Corona-viruses

Influenzaviruses

RSV Adeno-viruses

Control

FEV1 50%

FEV1 <50%

% o

f T

ota

l Id

enti

fied

RSV Infection in Elderly RSV Infection in Elderly High-Risk AdultsHigh-Risk Adults

Falsey AR, et al. New Engl J Med. 2005;1749-1759.

VariableVariable RSV RSV infectioninfection

Influenza AInfluenza A

Duration of illnessDuration of illness 15 15 ± 13 days± 13 days 17 17 ± 10 days± 10 daysHospitalizationHospitalization 16%16% 20%20%HouseboundHousebound 41%41% 55%55%Confined to bedConfined to bed 25%25% 25%25%Unable to Unable to perform ADLperform ADL

45%45% 60%60%

DeathsDeaths 4%4% 0%0%

Airway Inflammation and Airway Inflammation and EtiologyEtiology

Papi et al AJRCCM 2006;173:1114-21

New DirectionsNew Directions

Bacterial-viral-environmental Bacterial-viral-environmental

interactioninteraction

Molecular detection and Molecular detection and

quantification of infectious quantification of infectious

pathogenspathogens

Host susceptibility to infectionHost susceptibility to infection

Effect of Pathogen Combinations Effect of Pathogen Combinations on % Decrease in FEVon % Decrease in FEV11 at at

ExacerbationExacerbation

Wilkinson, T. M. A. et al. Chest 2006;129:317-324

PCR detection of bacterial PCR detection of bacterial pathogens in COPDpathogens in COPD

S. pneumoniae

0

5

10

15

20

25

30

Num

ber

posi

tive

Visit

CulturePCR

+

-

lytA

psaA

p<0.05

El-Dika et al ATS 2007

ConclusionsConclusions

Exacerbations are importantExacerbations are important Bacteria cause a significant Bacteria cause a significant

proportion of exacerbationsproportion of exacerbations Understanding Host-Pathogen Understanding Host-Pathogen

interaction is keyinteraction is key Therapeutic interventionTherapeutic intervention