julio a. ramirez, md, facp professor of medicine chief, infectious diseases university of louisville...

Julio A. Ramirez, MD, FACPProfessor of Medicine

Chief, Infectious Diseases University of Louisville

Chief, Infectious Diseases Veterans Affairs Medical Center

Louisville, Kentucky, USA

Clinical Outcomes in Patients with

Community-Acquired Pneumonia

1. CAP Pathogenesis

2. CAP Early Clinical Outcomes

3. CAP Late Clinical Outcomes

CAP Clinical Outcomes

Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003

Pneumonia Pathogenesis

AlveolarMacrophage

Capillary

Pneumonia

White Blood Cell

Lymphatic


AlveolarMacrophage

Capillary

Pneumonia

White Blood Cell

Lymphatic


AlveolarMacrophage

Capillary


Cytokines

PneumoniaGeneration of Cytokines

White Blood Cell

Lymphatic


AlveolarMacrophage

Capillary


Cytokines

Pneumonia

Cytokines

Generation of Cytokines

White Blood Cell

Lymphatic

Cytokines

White Blood Cell

Lymphatic

Proinflammatory Cytokines

Anti-inflammatory Cytokines

Chemotactic Cytokines (Chemokines)

CCL2 CCL3 CCL4 CCL5 CXCL1 (KC) CXCL10 (IP-10)

IL-1 IL-1β IL-6 TNF-α G-CSF IFN-γ

Interleukin-10 (IL-10)IL-1 receptor antagonist (IL-1ra)


AlveolarMacrophage

Capillary


PneumoniaActivation of Neutrophils

White Blood Cell

Lymphatic


Local Inflammatory Response

AlveolarMacrophage

Capillary


PneumoniaConsolidation Phase

Cytokines

White Blood Cell

Neutrophils

Monocytes

B / T cells

Dendritic cells

Lymphatic

Fluid/Proteins


AlveolarMacrophage

Capillary


PneumoniaConsolidation Phase

Cytokines

White Blood Cell

Neutrophils

Monocytes

B / T cells

Dendritic cells

Lymphatic

Fluid/Proteins


Local Inflammatory Response Systemic

Inflammatory Response

Days0 1 2 3 4 5 6 7

A

ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001

Diagnosis


Systemic Inflammatory ResponseSev

erit

y of

Dis

ease


Days0 1 2 3 4 5 6 7

A


v

Diagnosis

FeverLeukocytosisCRPESRProcalcitonin

CoughSputumTachypneaHypoxemiaInfiltrate


Systemic Inflammatory ResponseSev

erit

y of

Dis

ease


1. CAP Pathogenesis




Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

A

CAP: Clinical Outcomes

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

AClinical

Response to Therapy



Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

BA



Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Late Clinical

Deterioration3 4

BA



Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA



Days

Clinical Response

Severity of Disease

CAP: clinical, radiographic, immunologic, & microbiologic responses


Point of Clinical Stability

Clinical Response

X-rayResolution

Severity of Disease

Pulmonary Infiltrate

Days



Clinical Response

X-rayResolution

Severity of Disease


Inflammatory Markers

ImmuneResponse

Days



MicroResponse

Clinical Response

X-rayResolution

Severity of Disease


Bacterial

Colony Counts


ImmuneResponse

Days



MicroResponse

Clinical Response

X-rayResolution

Severity of Disease


Bacterial

Colony Counts


ImmuneResponse

Days

Time to Switch Therapy



Time to Clinical Stability

Point of Clinical Stability

Point of Switch Therapy

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA


Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

CAP

SevereCAP

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Aliberti S et al. Chest. 2008;134:955-962

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Aliberti S et al. Chest. 2008;134:955-962

Etiology of Failure

1. Severe Sepsis(33%)

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Etiology of Failure

1. Severe Sepsis(33%)

1Late

ClinicalImprovement

2

Days

Late Clinical

Deterioration

3

5

4

B

LIR

Local Infection

Clinical Outcomes

LIR SIRS

Local Infection

CAP

Clinical Outcomes

LIR SIRS Organ Dysfunction/Failure MODS

Local Infection

CAPSevereCAP

Clinical Outcomes


Cardiovascular↑HR, BP<90/60, Refractory Shock

Renal↓Urinary output, ↑BUN, ↑Creatinine

CNSMental status changes, Abnormal EEG

Metabolism ↑Glucose, ↓Temperature, ↓Ph, ↑Lactate,

Local Infection

SepsisSevereSepsis

HematologyNeutropenia, ↓Hb, Platelets<100K, DIC

RespiratoryRR>30, PO2<60, PA/FI<250, ARDS, MV

Mortality rates increase in patients >65yo (↓immunologic response to infection)

Clinical Outcomes









Local Infection

CAPSevereCAP

Clinical Outcomes







CURB-65



Local Infection

CAPSevereCAP

PSI

Clinical Outcomes









Local Infection

CAPSevereCAP

CURB-65

PSI

Clinical Outcomes

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical OutcomesClinical Failure:Severe Sepsis30%

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Clinical Failure:

AMI 20%

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Ramirez J et al. Clin Infec Dises. 2008;47:182-7

Clinical Failure:

AMI 20%

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Ramirez J et al. Clin Infec Dises. 2008;47:182-7

Clinical Failure:

AMI 20%

40 60 80 100 120 140 160 180

0%

5%

10%

15%

20%

25%

Pneumonia Severity Index Score

Ris

k o

f A

cute

Myo

card

ial

Infa

rcti

on Propensity-adjusted association P: 0.048

Risk of AMI

95 % CI

95 % CI

Early Clinical

Improvement1

Late Clinical

Improvement

2

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Clinical Failure:

AMI 20%

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical OutcomesClinical Failure:Males

vsFemales

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

CAP due to Mycobacterium tuberculosis

CAP complicated with empyema

CAP associated with deterioration of preexisting medical conditions (COPD, CHF)

Early Clinical

Improvement1

Late Clinical

Improvement

2

Days0 1 2 3 4 5 6 7

Sev

erit

y of

Dis

ease

Early Clinical

Deterioration

Nonresponding

Pneumonia

Late Clinical

Deterioration3

5

4

BA

Clinical Outcomes

100%

15%

45% 25%

5%

10%

1. CAP Pathogenesis




1 2 3 4 5 6 7 Weeks Days

ClinicalDeterioration

ClinicalImprovement

ACAP

2 3 4


1 2 3 4 5 6 7 Weeks Days


ClinicalImprovement

B


ClinicalImprovement

ACAP


2 3 4

1 2 3 4 5 6 7 Weeks Days


ClinicalImprovement

B


ClinicalImprovement

ACAPRe-hospitalization


Death

2 3 4

1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAPRe-hospitalization


Death

Weeks 2 3 4

ClinicalImprovement

BAMI (+): 31%

AMI (-): 10%

1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAP

Clinical Cure: Resolution of S&S with resolution of pulmonary infiltrate


1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAP

CAP (+) 624

CAP (-) 6,347

Long Term Survival:5 years


1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAP


1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAPCAP (-) 6,347

CAP (+) 624


1 2 3 4 5 6 7 Weeks Days

2 3 4


ClinicalImprovement

B


ClinicalImprovement

ACAP


1 2 3 4 5 6 7 Weeks

1 2 3 4 5 Years Days


ClinicalImprovement

C


ClinicalImprovement

B


ClinicalImprovement

ACAP

2 3 4

CAP Mortality:Days after diagnosis

CAP Mortality:Weeks after diagnosis

CAP Mortality:Years after diagnosis

1 2 3 4 5 6 7 Weeks


2 3 4

Acute Systemic Inflammatory Disease


1 2 3 4 5 6 7 Weeks



ClinicalImprovement

C


ClinicalImprovement

B


ClinicalImprovement

ACAP

2 3 4

CAP Mortality:Days after diagnosis

CAP Mortality:Weeks after diagnosis

CAP Mortality:Years after diagnosis

1 2 3 4 5 6 7 Weeks


2 3 4

Acute Systemic Inflammatory Disease

Chronic Systemic Inflammatory Disease?


Pneumonia: Clinical Outcomes

1. CAP Pathogenesis




julio a. ramirez, md, facp professor of medicine chief, infectious diseases university of louisville...

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