Hypothesis: Possible epidemiological interactions between pandemic viruses and rhinoviruses in France during the 2009 pandemicArchived

Casalegno, J. S., M. Ottmann, M. Bouscambert et al. Rhinoviruses delayed the circulation of the pandemic influenza A (H1N1) 2009 virus in France. Clin Microbiol Infect 2010 16:326-9

The onset of the autumn/winter 2009 pandemic wave was somewhat slower in France during the first part of autumn 2009 than in some other European countries. As seen through the EISN system the upturn in influenza like illness was 4 weeks later than Spain, 2 weeks later than Italy and Germany but only one week behind the UK. The objective of this study was to test the hypothesis that an observed intense circulation of rhinoviruses might have reduced the probability of infection by the 2009 pandemic influenza A(H1N1) virus at the beginning of autumn 2009.(1) Systematic analysis for the detection of 2009 pandemic influenza A(H1N1) virus and human rhinovirus (HRV) was performed by RT-PCR from week 36 to week 48 on respiratory samples sent to the diagnostic laboratory by one children’s hospital.

During this period, both HRV and 2009 pandemic A(H1N1) viruses were detected but in different time frames. HRV dispersed widely during early September, peaking at the end of the month, whereas the 2009 A(H1N1) pandemic virus transmission really began during mid-October in France and was still active at the end of this survey.

The results suggest that the ILI activity reported in France during early autumn 2009 was initially caused by HRV and then from mid-October by H1N1. Moreover, in any single respiratory sample analysed, detection of HRV resulted in reduced likelihood of detection of the H1N1 virus. Thus, the results showed a significant inverse relationship between HRV and H1N1 virus irrespective of the time period and age group analysed, therefore, this data support a previous suggestion that the presence of HRV reduces the risk of infection by the H1N1 virus and thus, indirectly, the spread of the virus.

ECDC comment (8 April 2010)

This article noted that influenza like illnesses (ILI) activity in France during early autumn 2009 were initially caused predominately by HRV and from mid-October by 2009 pandemic influenza A(H1N1) virus (1). The results of this study in one hospital show a significant inverse relationship between HRV and 2009 pandemic influenza A(H1N1) virus irrespective of the time period and age group. However, the mean age amongst the patients positive for HRV was 2.4 years and for 2009 pandemic influenza A(H1N1) virus 5.6 years, respectively. In this pediatric cohort, co-infections of HRV and 2009 pandemic influenza A(H1N1) virus were observed in 0.7% of the cases. The epidemic due to HRV observed through this hospital began at week 37, peaked at week 40 and diminished gradually thereafter. In contrast, the epidemic due to 2009 pandemic influenza A(H1N1) virus  began later at week 43. The two viruses seemed to co-circulate from week 43 to week 47 in this population. The follow-up period of the study ended at week 48 although in France the acute respiratory infection (ARI) peaked in pediatric population during weeks 46-51 in 2009 (ECDC surveillance data). There was even a third, smaller, peak in ARI in week 5/2010, probably due to respiratory syncytial virus. In Swedish study similar results were obtained suggesting that a rhinovirus epidemic after the end of the summer holidays may have interfered with the spread of the 2009 pandemic A(H1N1) virus  during the early autumn 2009(2). Additionally, an Australian study found that HRV detection is associated with a reduced probability of detecting a variety of respiratory viruses, including influenza A virus (3). However, in the Australian study, HRVs were involved in the highest number of co-detections, being found with another virus in 23.6 % of HRV detections (3).

HRV replication, as well as influenza virus replication, produces double-stranded RNA intermediates. These molecules trigger interferon-stimulated genes to induce an antiviral state in the infected cells (4), which can shield the neighbouring cells from viral infection. However, this is a short-term shield and lasts only for hours (4). Influenza viruses can evade the immune response by antagonizing the interferon response by their NS1 protein (5). Therefore the biological data today does not immediately support the epidemiological data for viral interference. Based on the current literature, there are no defined mechanisms yet how HRVs antagonize the IFN cascade. The hypothesis that HRV can protect its host from infection by other viruses has still to be proven in vitro and in vivo.

A limitation of the French study is that the data are only representative for the paediatric population accessed through one hospital in one country. And though paediatric infections in children were especially numerous important the 2009 pandemic influenza A(H1N1) virus  pandemic occurred in older age groups as well. HRV infections occur also widely in the adult population and are the main cause for common colds. We do not have the HRV detection data from other countries close to France, however, the HRV epidemics usually occur after the school start in all countries as the spread of the virus is not affected by the climate (6). The 2009 pandemic influenza A(H1N1) virus  pandemic started somewhat later in France than in other European Union countries close by, however the  difference was only 2-4 weeks. Seasonal influenza usually progresses from West to East in Europe (7) as did the 2009 pandemic in the EU. However the pattern is never that simple as far as can be judged by surveillance data. It would be interesting to see if the findings here were replicated in other centres in France and in the other countries at about the same longitude in Europe (such as Denmark) where the autumn/winter wave also started later than in most. Hence while these findings are supportive of the hypothesis they are by no means conclusive and on the basis of the current literature, there is not yet virological explanation for the effect seen in the epidemiological studies that rhinoviruses would delay the circulation of influenza viruses.

References 

1. Casalegno, J. S., M. Ottmann, M. Bouscambert Duchamp, V. Escuret, G. Billaud, E. Frobert, F. Morfin, and B. Lina. 2010. Rhinoviruses delayed the circulation of the pandemic influenza A (H1N1) 2009 virus in France. Clin Microbiol Infect 16:326-9. http://www3.interscience.wiley.com/cgi-bin/fulltext/123266593/PDFSTARTCRETRY=1&SRETRY=0
2. Linde, A., M. Rotzen-Ostlund, B. Zweygberg-Wirgart, S. Rubinova, and M. Brytting. Does viral interference affect spread of influenza Euro Surveill 2009 14. http://www.eurosurveillance.org/ViewArticle.aspxArticleId=19354
3. Greer, R. M., P. McErlean, K. E. Arden, C. E. Faux, A. Nitsche, S. B. Lambert, M. D. Nissen, T. P. Sloots, and I. M. Mackay. Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections J Clin Virol 2009 45:10-5. http://www.journalofclinicalvirology.com/article/S1386-6532(09)00122-X/abstract
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5. Bergmann, M., A. Garcia-Sastre, E. Carnero, H. Pehamberger, K. Wolff, P. Palese, and T. Muster. Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J Virol 2000 74:6203-6.
6. Monto, A. S. 2002. The seasonality of rhinovirus infections and its implications for clinical recognition. Clin Ther 2002 24:1987-97.7. Paget J, Marquet R, Meijer A, van d V. Influenza activity in Europe during eight seasons (1999-2007): an evaluation of the indicators used to measure activity and an assessment of the timing, length and course of peak activity (aspreada) across Europe. BMC Infect Dis. 2007;7(1):141. http://www.biomedcentral.com/1471-2334/7/141