title: Mutations associated with severity of the pandemic influenza A(H1N1)pdm09 in humans: a systematic review and meta-analysis of epidemiological evidence.
abstract: Mutations in the haemagglutinin (HA), non-structural protein 1 (NS1) and polymerase basic protein 2 (PB2) of influenza viruses have been associated with virulence. This study investigated the association between mutations in these genes in influenza A(H1N1)pdm09 virus and the risk of severe or fatal disease. Searches were conducted on the MEDLINE, EMBASE and Web of Science electronic databases and the reference lists of published studies. The PRISMA and STROBE guidelines were followed in assessing the quality of studies and writing-up. Eighteen (18) studies, from all continents, were included in the systematic review (recruiting patients 0 - 77 years old). The mutation D222G was associated with a significant increase in severe disease (pooled RD: 11 %, 95 % CI: 3.0 % - 18.0 %, p = 0.004) and the risk of fatality (RD: 23 %, 95 % CI: 14.0 %-31.0 %, p = < 0.0001). No association was observed between the mutations HA-D222N, D222E, PB2-E627K and NS1-T123V and severe/fatal disease. The results suggest that no virus quasispecies bearing virulence-conferring mutations in the HA, PB2 and NS1 predominated. However issues of sampling bias, and bias due to uncontrolled confounders such as comorbidities, and viral and bacterial coinfection, should be born in mind. Influenza A viruses should continue to be monitored for the occurrence of virulence-conferring mutations in HA, PB2 and NS1. There are suggestions that respiratory virus coinfections also affect virus virulence. Studies investigating the role of genetic mutations on disease outcome should make efforts to also investigate the role of respiratory virus coinfections.
authors: Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, 1st Floor Stopford building, Oxford Road, Manchester, M13 9PL, UK, edward.goka@postgrad.manchester.ac.uk.
authors: E A
authors: EA
authors: Goka
authors: P J
authors: PJ
authors: Vallely
authors: K J
authors: KJ
authors: Mutton
authors: P E
authors: PE
authors: Klapper
mesh_terms: D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D007251:Influenza, Human / Q000401:mortality / Q000473:pathology* / Q000821:virology*; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D016019:Survival Analysis; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence
chemical_list: C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C085820:INS1 protein, influenza virus; D050505:Mutant Proteins; C057027:PB2 protein, Influenzavirus A; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase