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Community Acquired Pneumonia:
Diagnosis and outcome
Antonio Anzueto,
University of Texas Health Science
Center
San Antonio, USA
Disclaimer
Professional Relationships:
Member of the ATS/ERS Task force on COPD and COPD Exacerbations
Member of the ATS/IDSA 2001, 2003 and 2007 CAP guidelines Committee
Member of the Executive and Scientific Committee of GOLD
Advisory board, Consultant, Speaker:
Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Merck, Chiesi,
Bayer-Schering Pharma, Dey Pharma, Forest laboratories.
Grants:
NHLBI – COPD gene, LOOT
GSK – Eclipse, Horizon, Sumit
Lilly - Severe Sepsis Trial
Pfizer- Linezolid vs Vancomycin VAP study
Pneuma – Surfactant in ARDS
Stocks:
None
Update management CAP…..
•Biomarkers
•Epidemiology and disease severity
•Adjunctive Therapies
Update management CAP…..
•Biomarkers
•Epidemiology and disease severity
•Adjunctive Therapies
Kinetics After Bacterial Challenge
Relatively to measure in serum and plasma - stable in vivo and in vitro
IL-6
PCT
Time (Hours)
Pla
sm
a C
on
ce
ntr
ation
1 2 6 12 24 Day 2
Time (Days)
Day 3
IL-10
CRP
TNF-a
Kinetics After Bacterial Challenge
Brunkhorst F.M., et. Al., Intensive Care Medicine, 1998, 24 855-892
What is Procalcitonin?
• Prohormone (116 AA) pre-form of calcitonin
• Levels increase with bacterial infection
• Produced by numerous organs at cell levels after pro-inflammatory stimulation
Procalcitonin Differentiates between
Bacterial and Viral Infections
bacterial infections (proinflammatory cytokines - IL-1, IL-6 and
TNF-a - and endotoxin)
in viral infections (interferon gama)
inflammation-mediated expression of the CALC I gene
PCT and Diagnosis
Nyamande Int J TB Lung Dz 2006; 10: 510
P=0.0004
Procalcitonin in Different Infections
PCT (ng/ml) Assay
LU
MIt
es
t® P
CT
PC
T-Q
0.1
1
10
0.01
100
Kry
pto
r® P
CT
Septic shock
Sepsis
Healthy Persons
Pneumonia 0.25
AECOPD Asthma & Bronchitis
Pro
Ca-S
® / N
-Pro
CT
KL
B
What are the clinical scenarios
where PCT levels can be useful?
Recognizing response to and shortening duration
of antibiotic therapy
Determining the need for antibiotics in patients
with LRTI (i.e. AECOPD)
Determining severity of infection (e.g. localized
versus systemic)
Differentiating between septic and other forms of
shock
Distinguishing viral from bacterial infection in
febrile patients
PCT Algorithm PCT Level Recommendation for initiation or
continuation of antibiotics
< 0.1 Strongly Discouraged
0.1-0.25 Discouraged
0.25 to 0.5 Encouraged
> 0.5 Strongly Encouraged
10
Discontinuation of antibiotics was
encouraged if PCT decreased to < 20% of the
initial value.
PCT levels were reassessed after 4, 6, and 8 days
Procalcitonin Guidance for Antibiotic
Treatment of Pneumonia
0
10
20
30
40
50
60
70
80
90
100
AB
started
> 4d > 6d > 8d > 10d > 14d > 21d
Standard group Procalcitonin group
An
tib
ioti
c P
rescri
pti
on
(%
)
Antibiotic duration ( days )
0
10
20
30
40
50
60
70
80
90
100
AB
started
> 4d > 6d > 8d > 10d > 14d > 21d
Standard group Procalcitonin group
An
tib
ioti
c P
rescri
pti
on
(%
)
Antibiotic duration ( days )
Percentage of values in range by clinical
likelihood of infection
Category Undetectable
(%)
< 0.25 <0.5 0.5-1 > 1
Unlikely (35) 17 (49%) 28 (80%) 32 (91%) 0 3 (9%)
Possible (22) 2 (9%) 9 (41%) 12 (55%) 4 (18%) 6 (27%)
Probable (24) 2 (8%) 6 (25%) 8 (33%) 2 (8%) 14 (58%)
Definite (18) 2 (11%) 5 (28%) 5 (28%) 1 (6%) 12 (67%)
Definite = bacteremia or septic shock with a definite focus of infection
Probable = Sepsis (SIRS + clinical diagnosis pneumonia, UTI, intra-abdominal
infection or SSTI)
Possible = + culture being treated but with 0 or 1 sirs criteria
Unlikely = negative cultures on patients with other alternative diagnosis
Mean, median and SD PCT levels by
category
Category Mean Median Range SD Outliers
Unlikely (35) 0.47 0.05 0-10.7 1.8 3*
Possible (22) 0.92 0.47 0-4.8 1.3 N/A
Probable (24) 3.8 1.4 0-21 5.6 N/A
Definite (18) 22.5 4.4 0-196 46.5 5**
Definite = bacteremia or septic shock with a definite focus of infection
Probable = Sepsis (SIRS + clinical diagnosis pneumonia, UTI, intra-abdominal
infection or SSTI)
Possible = + culture being treated but with 0 or 1 sirs criteria
Unlikely = negative cultures on patients with other alternative diagnosis
Procalcitonin Kinetics in Legionella
Pneumonia
Clin Microb Infect 2009; 15: 1020
ICU patients
Wards patients
C-Reactive Protein in LRTI Van der Meer et al BMJ 2005
•Testing for CRP is neither sufficiently
sensitive to rule out pneumonia nor specific to
rule in an infiltrate
•C- reactive protein guidance is not supported
•165 Medline / 340 Embase
•483 excluded on basis of title/abstract !
•Included 17 studies, at the end only 13 !
•Area under the curve for infiltrate 0.80
•Only 5 studies included
Copeptin – precursor of
anti-diuretic hormone
Lower Respiratory Tract
Infections
Bacterial
or
viral?
Bioluminescence S. pneumo –
Pneumococcal infection model
Inf and Immunity 2001; 69:3350
S. Pneumonia Diagnosis: New Techniques
• Rapid screening method – Binax NOW:
–Presence of pneumococcal C-polysaccharide
–Low sensitivity and specificity
–Can not identified strains
•Urine Antigen Diagnosis assay
–Luminescense technique
–Identified 13 serotypes – capsular polysaccharide
–Currently been validated
Murdoch et al J Clin Micro 2001; 39:3495
Diagnosis: use of Molecular Biology
Techniques
Sepsis assay: PCR and microaray based
on amplification of gene particles 50 bacterial
species.
Tissari et al Lancet 2010; 375:224
Biomarkers in CAP
Biomarker
Outcomes
•Procalcitonin
•C-reactive
protein
•Pro-ADMD and
B-NP
•Reduced use antibiotics
•Inadequate sensitivity and specificity
to differentiate viral vrs. bacterial.
•Correlates well with PSI and CURB65
•Higher with bacterial infections and
in-patients
•Improves predicting ability PSI and
CURB65
•Associated with severity
Update management CAP…..
•Biomarkers
•Epidemiology and disease severity
•Adjunctive Therapies
Pneumonia Mortality
0
20
40
60
80
100
120
140
160
180
200
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990
Year
Dea
ths
/10
0,0
00
Gilbert K, Fine MJ: Sem Respir Inf 1994; 9:140-52
Antibiotics
CAP: Hospitalization based age/gender
Ewin et al Thorax 2009:64:1062
CAP: Proportion co-morbid conditions
Fry et al JAMA 2005; 294:2712
Mortensen et al CID 2003; 37:1617
CAP: long term mortality
CV events after admission for CAP
Patients with no prior CV history
Perry et al Am J Med 2011:124:244
Yende et al AJRCCM 2008; 177: 1242
CAP: Circulating cytokines
and risk of mortality
CAP: cytokine profile
Endeman et al ERJ 2011:35:1431
Guertler et al.
ERJ 011;37:1439
CAP: risk factors for mortality
Guertler et al. ERJ 2011; 37:1439
Guertler et al. ERJ 2011; 37:1439
CAP: risk factors for mortality
Update management CAP…..
•Biomarkers
•Epidemiology and disease severity
•Adjunctive Therapies
Adjuvant Therapies for CAP
• Corticosteroids
• Prostaglandin inhibitors
• Anticoagulants/Anti-inflammatory Agents
• Drotrecogin alfa
• Tifacogin (rTFPI)
• Macrolides
• Surfactant
• Statins
• Immunoglobulin
• Interferon gamma
Retrospective Analysis of
Corticosteroids for Severe CAP
Variable Odds Ratio
(95% CI)
Systemic Steroids 0.287
(0.113-0.732)
Severity of CAP 2.923
(1.262-6.770)
COPD 3.087
(0.906-7.031)
Severe CAP - PSI class IV or V
October 2001 – December
2003
Barcelona, Spain
Steroids
n = 70
No Steroids
n = 238
Bronchospasm, n = 61
Chronic asthma, n = 2
Pulmonary fibrosis, n = 2
Unknown, n = 5
Risk Factors for mortality
in multivariate analysis
Garcia-Vidal, et al. Eur Respir J. 2007.
PaO2/FiO2
100
150
200
250
300
350
400
2 4 6 8
* Mechanical ventilation
*n = 19 *n = 15
*n = 15
*n = 6
placebo
hydrocortisone
Confalonieri M, et al. Am J Respir Crit Care Med. 2005.
LOS
Defervescence
Snijders D, et al. AJRCCM 2010;181:975-982
Effect on Inflammatory mediators
Meijvis, et al. Lancet 2011;377: 2023
CAP: effect of corticosteroids
Endeman et al ERJ 2011;35:1431
Variables
In-Hospital Mortality 30-Day Mortality
OR (95%
CI) p Value
OR (95%
CI) p Value
OR (95%
CI)
Initial
atypical
antibiotic
treatment
0.81
(0.61–
1.08) 0.154
0.76 (0.59–
0.98) 0.034
0.67 (0.51–
0.89) 0.024
Macrolide
0.59
(0.40–
0.88) 0.010
0.61 (0.43–
0.87) 0.007
0.59 (0.42–
0.85) 0.004
Quinolone
0.94
(0.69–
1.28) 0.693
0.82 (0.62–
1.07) 0.148
0.82 (0.61–
1.09) 0.165
Tetracycline
0.95
(0.25–
3.58) 0.939
1.28 (0.42–
3.92) 0.670
0.98 (0.32–
3.01) 0.968
Macrolides and Outcome in CAP
Metersky ML, et al. Chest 2007;131:466-73.
Giamarellos-Bourboulis EJ, et al. Clin Infect Dis 2008; 46:1157-1164.
Clarithromycin in Sepsis/VAP
Macrolides
n=104
No-Macrolides
n=133
Survival curves for Severe Sepsis
patients treated with Macrolides
HR=0.32; 95%CI 0.1-0.6; p=0.001
Restrepo et al ERJ 2009; 33:153
Statins and CAP
•Cohort 29,900 patients (median age 73) with
hospital discharge of CAP.
•4.6 % were current statin user (prescription filled
longer than 125 days).
•Strongest association of reduced mortality was
found patients older 80 yrs, and bacteremia
•Drug effect: Simvastatin (30 d. mortality - RR 0.60),
atorvastatin (0.81), pravastatin (0.96)
Thomsen Arch Inter Med 2008; 168: 2081
Proportion hospitalized CAP based in prior
use of statins after adjusted for the
propensity score
Mortensen, EM. Respir Res 2005. 6:82
Conclusions
• CAP continue to be an important cause of
morbidity and mortality (short and long
term).
• Procalcitonin will help in guide duration of
therapy.
• Corticosteroids are not indicated for routine
use in CAP.
Gracias!!!