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!!!