Transcript Update on ATS Education Committee

Bacterial infections secondary to
rhinovirus infection in COPD
exacerbations
Dr Patrick Mallia MD PhD
NIHR Clinical Lecturer
Imperial College London
Background

COPD is predicted to be the 4th leading cause of death worldwide
by 2030

Morbidity, mortality and health-care costs of COPD largely
determined by acute exacerbations

Most exacerbations are associated with respiratory infections and
both bacteria and viruses are commonly detected in exacerbations

Few studies have examined the role of dual viral/bacterial
infections in COPD exacerbations
Viral/bacterial infections in COPD
Country
Viruses
Bacteria
Co-infection
Reference
Australia
43%
23%
6.5%
Cameron et al.
Int. Care Med. 2006
Australia
29%
25%
8%
Pant et al.
Respirology 2009
Switzerland
51%
64%
11.5%
Kherad et al
Chest 2010
Australia
21%
30%
12%
Hutchinson et al.
Resp Med. 2007
Canada
31%
49%
13%
De Serres et al.
J Clin Virol 2009
UK
24%
76%
17%
Hurst JR et al.
AJRCCM 2006
Italy
48%
55%
25%
Papi et al.
AJRCCM 2006
13.2%
Viral/bacterial infections in COPD

Secondary bacterial infections may follow viral infections –
established for flu but not for other respiratory viruses such as
rhinoviruses

Symptomatic colds frequently precede exacerbations

Rhinovirus infection in vitro increases bacterial adherence to
epithelial cells. H.influenzae increases rhinovirus binding and
replication in vitro

Therefore studies using a single sampling time point cannot
determine the true prevalence of co-infection or the sequence of
infection
Experimental rhinovirus infection
as a model of COPD exacerbations

We have developed a model of COPD exacerbation using
experimental rhinovirus (RV) infection in carefully selected
volunteers

RV infection induced the features of a COPD exacerbation – lower
respiratory symptoms, airflow obstruction and airways
inflammation
Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease
Exacerbation. Am J Respir Crit Care Med, Mar 2011; 183: 734 - 742

This model provides a tool to examine interactions between RV and
bacterial infections
Study Protocol
Induced
sputum
Study days
-14
5
9
12
15
21
RV INOCULATION
DAY 0
DAILY SYMPTOM DIARY CARDS
3 groups:
1) COPD (GOLD stage II, FEV1 50 – 80% predicted) – N=30
2) Smokers (SMK) with normal lung function – N=28
3) Non-smokers (NS) – N=18
Rhinovirus infection successful in 20 COPD, 21 SMK and 11 NS
42
Results
Bacteria
(PPM)
COPD
SMK
NS
60%
9.5%
10%
P<0.001
Incidence of bacterial infection following experimental RV infection
Rhinovirus
infected
Not infected
COPD
SMK
NS
60%
9.5%
10%
20%
P=0.038
16.7%
P=NS
12.5%
P=NS
Bacterial infection in subjects not infected with rhinovirus
Time course of bacterial infection
*P<0.05 vs. baseline, #P<0.05 vs. SMK, †P<0.05 vs. NS
Comparison of time course of
bacterial and viral infections
7
***
Virus load
Bacterial load
***
4
6
Sputum virus load
(Log10 copies/mL)
3
5
4
2
3
*
2
1
Sputum bacteria load
(Log10 cfu/mL)
***
1
0
Baseline
0
5
9
12
15
21
42
Study time points
(days from inoculation)
Significant correlation between virus and
bacterial loads R=0.47, P=0.039
Antimicrobial peptides

Antimicrobial peptides (AMPs) play a key role in innate lung
defence against infections

Two AMPs with both antmicrobial and anti-protease activity –
secretory leukocyte protease inhibitor (SLPI) and elafin

Inverse relationship between bacterial infection and SLPI in
COPD but the direction of relationship undetermined
SLPI and elafin – relationship
to bacterial infection in COPD
*P<0.05 vs. baseline, †P<0.05 vs. bacteria +ve COPD subjects
SLPI levels on day 12 and elafin levels on day 9 correlated
inversely with bacterial load (r=-0.51, P=0.023 and r=-0.71,
P=0004 respectively)
Neutrophil elastase degrades SLPI and elafin
High neutrophil numbers and neutrophil elastase levels
occur in bacteria +ve COPD subjects only
Conclusions

Bacterial infection is common following RV infection in COPD

There is a gap of 6-10 days between the peak of virus infection and
secondary bacterial peak

Reduced levels of SLPI and elafin in sputum are associated with
secondary bacterial infection in COPD and may be related to high
sputum levels of neutrophil elastase

Antiviral drugs may not only be effective against virus-induced
exacerbations but also reduce secondary bacterial infections
Acknowledgements

J Footitt, R Sotero, M-B Trujillo-Toralbo, T Kebadze, J
Aniscenko, G Oleszkiewicz, S Elkin, OM Kon, I Adcock, P
Barnes, Professor SL Johnston

Microbiology Laboratory Imperial College Healthcare NHS
Trust – Dr A Jepson, S Philip

Academy of Medical Sciences/Wellcome

NIHR