The lung and infection

1
The lung and infection

• John Simpson
• MRC Centre for Inflammation Research
• University of Edinburgh

2
Lets get the stereotypes out of the way
Consultant physician doing ward round in
3
Ventilator-associated pneumonia
4
VAP
Affects up to 30 of mechanically ventilated
patients Mortality rate of 24-50 P. aeruginosa
is the commonest organism isolated in historical
studies Prior use of antibiotics is a
significant risk factor for the development of
VAP New treatments are urgently required
5
Pathogenesis of HAP
6
VAP how good is clinical diagnosis?
7
Rough outline of our groups interests
SIRS
time
8
Elafin/trappin-2 is antimicrobial and inhibits
neutrophil proteases
9
Trappin-2 enhances ingestion of P. aeruginosa
by alveolar macrophages
10
In vivo, trappin-2-coated P. aeruginosa are
cleared more efficiently, through a
CD14-dependent mechanism
11
In the same mice, trappin-2-coated P. aeruginosa
drives early up-regulation of pulmonary CXCL1
(mKC)
12
Suspected VAP Mechanical ventilation for at
least 48 hours New infiltrates on chest x-ray
and at least one of the following temperature gt
38ºC purulent tracheal secretions white cell
count in circulating blood gt 11x109 per litre
Confirmed VAP gt104 CFU/ml of BAL fluid
13
Non-invasive markers of infection?
Gibot et al, NEJM 2004
14
Neutrophils from patients show defective
phagocytosis
15
Phagocytosis correlates with markers of C5a
exposure
CD88 - C5a receptor
16
Ex-vivo application of C5a to healthy neutrophils
recapitulates the defects seen in patients
17
GM-CSF can rescue phagocytosis
Healthy neutrophils exposed to C5a
Patients
18
Summary
Remarkably little known about HAP/VAP Better
understanding of very early host-pathogen
interactions is emerging Better understanding of
the innate immunoparesis in sick patients is
emerging We are appalling at making the
diagnosis of HAP/VAP but infection-specific tests
are emerging
19
Very considerable thanks to
CIR Chris Haslett Donald Davidson Nik
Hirani Adriano Rossi ICU, Royal Infirmary of
Edinburgh Tim Walsh Simon Mackenzie Penicuik
Health Centre Hamish Reid Centre for Infectious
Diseases/Microbiology John Govan Ian Poxton Ian
Laurenson Institut Pasteur Jean-Michel Sallenave
Andy Conway Morris Kev Dhaliwal Olga Lucia
Moncayo Nieto Tom Wilkinson Kallirroi
Kefala Kirsty Tyrrell
Funding bodies Sir Jules Thorn Charitable
Trust MRC Chief Scientists Office Wellcome
Trust CF Trust Medical Research Scotland Norman
Salvesen Trust
20
Recent guidelines
ATS/IDSA Guidelines on nosocomial pneumonia Am
J Respir Crit Care Med 2005, 171,
388-416 BSAC guidelines on hospital-acquired
pneumonia J Antimicrobial Chemother 2008, 62,
5-34
21
Not all guideline advice is good