1. Bacterial infections secondary to rhinovirus infection in COPD exacerbations
Dr Patrick Mallia MD PhD
NIHR Clinical Lecturer
Imperial College London

2. 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

3. Viral/bacterial infections in COPD
Country
Viruses
Bacteria
Co-infection
Reference
Australia
43%
23%
6.5%
Cameron et al.
Int. Care Med. 2006
29%
25% 8%
Pant et al.
Respirology 2009
Switzerland
51%
64%
11.5%
Kherad et al
Chest 2010
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%
Papi et al.
13.2%

4. 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

5. 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:
This model provides a tool to examine interactions between RV and bacterial infections

6. DAILY SYMPTOM DIARY CARDS
Study Protocol
Induced
sputum
Study days
-14
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

7. Bacterial infection in subjects not infected with rhinovirus
Results
COPD
SMK NS
Bacteria (PPM)
60%
9.5%
10%
P<0.001
Incidence of bacterial infection following experimental RV infection
COPD
SMK NS
Rhinovirus infected
60%
9.5%
10%
Not infected
20%
16.7%
12.5%
P=0.038
P=NS
Bacterial infection in subjects not infected with rhinovirus

8. Time course of bacterial infection
*P<0.05 vs. baseline, #P<0.05 vs. SMK, †P<0.05 vs. NS

9. Comparison of time course of bacterial and viral infections
Significant correlation between virus and bacterial loads R=0.47, P=0.039

10. 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

11. 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)

12. Neutrophil elastase degrades SLPI and elafin
High neutrophil numbers and neutrophil elastase levels
occur in bacteria +ve COPD subjects only

13. 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

14. 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