Bacterial infections secondary to rhinovirus infection in COPD exacerbations

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

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 RespirCrit Care Med, Mar 2011; 183: 734 - 742 • This model provides a tool to examine interactions between RV and bacterial infections

6. Study Protocol Induced sputum Study days -14 5 9 12 15 21 42 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. Results Incidence of bacterial infection following experimental RV infection 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