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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
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
AlveolarMacrophage
Capillary
Pneumonia
White Blood Cell
Lymphatic
Pneumonia Pathogenesis
AlveolarMacrophage
Capillary
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
Cytokines
PneumoniaGeneration of Cytokines
White Blood Cell
Lymphatic
Pneumonia Pathogenesis
AlveolarMacrophage
Capillary
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
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)
Pneumonia Pathogenesis
AlveolarMacrophage
Capillary
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
PneumoniaActivation of Neutrophils
White Blood Cell
Lymphatic
Pneumonia Pathogenesis
Local Inflammatory Response
AlveolarMacrophage
Capillary
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
PneumoniaConsolidation Phase
Cytokines
White Blood Cell
Neutrophils
Monocytes
B / T cells
Dendritic cells
Lymphatic
Fluid/Proteins
Pneumonia Pathogenesis
AlveolarMacrophage
Capillary
Ramirez J. Community-Acquired Pneumonia. Lippincott Williams & Wilkins, 2003
PneumoniaConsolidation Phase
Cytokines
White Blood Cell
Neutrophils
Monocytes
B / T cells
Dendritic cells
Lymphatic
Fluid/Proteins
Pneumonia Pathogenesis
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
Local Inflammatory Response
Systemic Inflammatory ResponseSev
erit
y of
Dis
ease
Pneumonia Pathogenesis
Days0 1 2 3 4 5 6 7
A
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
v
Diagnosis
FeverLeukocytosisCRPESRProcalcitonin
CoughSputumTachypneaHypoxemiaInfiltrate
Local Inflammatory Response
Systemic Inflammatory ResponseSev
erit
y of
Dis
ease
Pneumonia Pathogenesis
Days0 1 2 3 4 5 6 7
A
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
v
Diagnosis
FeverLeukocytosisCRPESRProcalcitonin
CoughSputumTachypneaHypoxemiaInfiltrate
Local Inflammatory Response
Systemic Inflammatory ResponseSev
erit
y of
Dis
ease
Pneumonia Pathogenesis
1. CAP Pathogenesis
2. CAP Early Clinical Outcomes
3. CAP Late Clinical Outcomes
CAP Clinical Outcomes
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
CAP: Clinical Outcomes
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
Early Clinical
Improvement1
Late Clinical
Improvement
2
Days0 1 2 3 4 5 6 7
Sev
erit
y of
Dis
ease
BA
CAP: Clinical Outcomes
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
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
CAP: Clinical Outcomes
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
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
CAP: Clinical Outcomes
ATS Guidelines for CAP. Am J Respir Crit Care Med 163:1730, 2001
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
CAP: Clinical Outcomes
Days
Clinical Response
Severity of Disease
CAP: clinical, radiographic, immunologic, & microbiologic responses
CAP: Clinical Outcomes
Point of Clinical Stability
Clinical Response
X-rayResolution
Severity of Disease
Pulmonary Infiltrate
Days
CAP: clinical, radiographic, immunologic, & microbiologic responses
CAP: Clinical Outcomes
Clinical Response
X-rayResolution
Severity of Disease
Pulmonary Infiltrate
Inflammatory Markers
ImmuneResponse
Days
CAP: clinical, radiographic, immunologic, & microbiologic responses
CAP: Clinical Outcomes
MicroResponse
Clinical Response
X-rayResolution
Severity of Disease
Pulmonary Infiltrate
Bacterial
Colony Counts
Inflammatory Markers
ImmuneResponse
Days
CAP: clinical, radiographic, immunologic, & microbiologic responses
CAP: Clinical Outcomes
MicroResponse
Clinical Response
X-rayResolution
Severity of Disease
Pulmonary Infiltrate
Bacterial
Colony Counts
Inflammatory Markers
ImmuneResponse
Days
Time to Switch Therapy
CAP: clinical, radiographic, immunologic, & microbiologic responses
CAP: Clinical Outcomes
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
CAP: 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
CAP: 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
CAP: 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
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
LIR SIRS Organ Dysfunction/Failure MODS
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
LIR SIRS Organ Dysfunction/Failure MODS
Cardiovascular↑HR, BP<90/60, Refractory Shock
Renal↓Urinary output, ↑BUN, ↑Creatinine
CNSMental status changes, Abnormal EEG
Metabolism ↑Glucose, ↓Temperature, ↓Ph, ↑Lactate,
HematologyNeutropenia, ↓Hb, Platelets<100K, DIC
RespiratoryRR>30, PO2<60, PA/FI<250, ARDS, MV
Mortality rates increase in patients >65yo (↓immunologic response to infection)
Local Infection
CAPSevereCAP
Clinical Outcomes
Cardiovascular↑HR, BP<90/60, Refractory Shock
Renal↓Urinary output, ↑BUN, ↑Creatinine
CNSMental status changes, Abnormal EEG
LIR SIRS Organ Dysfunction/Failure MODS
Mortality rates increase in patients >65yo (↓immunologic response to infection)
Metabolism ↑Glucose, ↓Temperature, ↓Ph, ↑Lactate,
CURB-65
HematologyNeutropenia, ↓Hb, Platelets<100K, DIC
RespiratoryRR>30, PO2<60, PA/FI<250, ARDS, MV
Local Infection
CAPSevereCAP
PSI
Clinical Outcomes
RespiratoryRR>30, PO2<60, PA/FI<250, ARDS, MV
Cardiovascular↑HR, BP<90/60, Refractory Shock
Renal↓Urinary output, ↑BUN, ↑Creatinine
CNSMental status changes, Abnormal EEG
LIR SIRS Organ Dysfunction/Failure MODS
Mortality rates increase in patients >65yo (↓immunologic response to infection)
Metabolism ↑Glucose, ↓Temperature, ↓Ph, ↑Lactate,
HematologyNeutropenia, ↓Hb, Platelets<100K, DIC
Local Infection
CAPSevereCAP
CURB-65
PSI
Clinical Outcomes
RespiratoryRR>30, PO2<60, PA/FI<250, ARDS, MV
Cardiovascular↑HR, BP<90/60, Refractory Shock
Renal↓Urinary output, ↑BUN, ↑Creatinine
CNSMental status changes, Abnormal EEG
LIR SIRS Organ Dysfunction/Failure MODS
Mortality rates increase in patients >65yo (↓immunologic response to infection)
HematologyNeutropenia, ↓Hb, Platelets<100K, DIC
Metabolism ↑Glucose, ↓Temperature, ↓Ph, ↑Lactate,
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 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
2. CAP Early Clinical Outcomes
3. CAP Late Clinical Outcomes
CAP Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
ClinicalDeterioration
ClinicalImprovement
ACAP
2 3 4
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAP
CAP: Clinical Outcomes
2 3 4
1 2 3 4 5 6 7 Weeks Days
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAPRe-hospitalization
CAP: Clinical Outcomes
Death
2 3 4
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAPRe-hospitalization
CAP: Clinical Outcomes
Death
Weeks 2 3 4
ClinicalImprovement
BAMI (+): 31%
AMI (-): 10%
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAP
Clinical Cure: Resolution of S&S with resolution of pulmonary infiltrate
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAP
CAP (+) 624
CAP (-) 6,347
Long Term Survival:5 years
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAP
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAPCAP (-) 6,347
CAP (+) 624
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks Days
2 3 4
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
ClinicalImprovement
ACAP
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks
1 2 3 4 5 Years Days
ClinicalDeterioration
ClinicalImprovement
C
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
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
1 2 3 4 5 Years Days
2 3 4
Acute Systemic Inflammatory Disease
CAP: Clinical Outcomes
1 2 3 4 5 6 7 Weeks
1 2 3 4 5 Years Days
ClinicalDeterioration
ClinicalImprovement
C
ClinicalDeterioration
ClinicalImprovement
B
ClinicalDeterioration
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
1 2 3 4 5 Years Days
2 3 4
Acute Systemic Inflammatory Disease
Chronic Systemic Inflammatory Disease?
CAP: Clinical Outcomes
Pneumonia: Clinical Outcomes
Pneumonia: Clinical Outcomes
Pneumonia: Clinical Outcomes
1. CAP Pathogenesis
2. CAP Early Clinical Outcomes
3. CAP Late Clinical Outcomes
CAP Clinical Outcomes