Age distribution of cases caused by different influenza viruses
Authors: Guus F Rimmelzwaan, Ron AM Fouchier, Albert DME Osterhaus
Journal: The Lancet Infectious Diseases (2013)

As of May 30, 2013, an outbreak1Gao R Cao B Hu Y et al.Human infection with a novel avian-origin influenza A (H7N9) virus.N Engl J Med. 2013; 368: 1888-1897Crossref PubMed Scopus (2029) Google Scholar of avian influenza A H7N9 virus had caused 132 human cases of influenza in China, most of which resulted in severe disease and 37 of which were fatal.2WHONumber of confirmed human cases of avian influenza A(H7N9) reported to WHO.http://www.who.int/influenza/human_animal_interface/influenza_h7n9/08_ReportWebH7N9Number.pdfGoogle Scholar These H7N9 viruses are avian influenza viruses with low pathogenicity. Gene segments are derived from H9N2 viruses of poultry origin and the haemagglutinin and neuraminidase gene segments come from wild-bird origin H7 and N9 viruses, respectively.1Gao R Cao B Hu Y et al.Human infection with a novel avian-origin influenza A (H7N9) virus.N Engl J Med. 2013; 368: 1888-1897Crossref PubMed Scopus (2029) Google Scholar 71% of 131 reported cases have been in individuals older than 50 years,3MCEIRShttp://www.cidrap.umn.edu/sites/default/files/public/downloads/topics/mceirs_h7n9_graphs.pdfGoogle Scholar and thus such patients seem more at risk of severe disease and death than are younger individuals.4Arima Y Zu R Murhekar M Vong S Shimada T Human infections with avian influenza A(H7N9) virus in China: preliminary assessments of the age and sex distribution.WPSAR. 2013; 4: 1-3Crossref Google Scholar The reasons for this disproportionate age distribution are largely unknown. It has been speculated that older individuals might have higher exposure to infected poultry, which could also be the reason why more men than women are affected.5Li Q Zhou L Zhou M et al.Preliminary report: epidemiology of the avian influenza A(H7N9) outbreak in China.N Engl J Med. 2013; (published online April 24.)https://doi.org/10.1056/NEJMoa1304617Crossref Scopus (592) Google Scholar However, many patients did not report contact with poultry, the incidence of H7N9 influenza virus infections in poultry seems very low, and the incidence of avian influenza A H5N1 virus infections was higher in younger than in older individuals within the same population, all of which argue against this possible explanation. Alternatively, elderly people could be more prone to develop severe disease upon infection with avian influenza A H7N9 viruses. Ageing is an important risk factor in viral respiratory tract infections (eg, caused by influenza or severe acute respiratory syndrome coronavirus) and is associated with changes in immune function.6Meyer KC The role of immunity in susceptibility to respiratory infection in the aging lung.Respir Physiol. 2001; 128: 23-31Crossref PubMed Scopus (111) Google Scholar In elderly people, these infections can cause severe pneumonia triggered by exacerbated innate host responses, which was confirmed experimentally in aged non-human primates.7Smits SL de Lang A van den Brand JM et al.Exacerbated innate host response to SARS-CoV in aged non-human primates.PLoS Pathog. 2010; 6: e1000756Crossref PubMed Scopus (286) Google Scholar However, the disease caused by H7N9 viruses resembles that caused by H5N1 viruses, and therefore changes in innate immunity are unlikely to be the only cause of the disproportionate age distribution. The age distribution of patients infected with H7N9 contrasts with that of the 2009 pandemic influenza A H1N1 virus. This virus was of swine origin and its haemagglutinin gene resembled that of human influenza A H1N1 viruses that circulated before 1950.8Garten RJ Davis CT Russell CA et al.Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans.Science. 2009; 325: 197-201Crossref PubMed Scopus (2095) Google Scholar Therefore, individuals born before 1957 could have been exposed to these viruses earlier in life and developed antibodies or memory B cells, or both, that cross-reacted with the pandemic A H1N1 viruses.9Hancock K Veguilla V Lu X et al.Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1119) Google Scholar, 10Itoh Y Shinya K Kiso M et al.In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.Nature. 2009; 460: 1021-1025PubMed Google Scholar The older age group were afforded some protection against the pandemic strain via the presence of these cross-reactive antibodies, 11Skountzou I Koutsonanos DG Kim JH et al.Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus.J Immunol. 2010; 185: 1642-1649Crossref PubMed Scopus (95) Google Scholar and were therefore spared compared with younger people during the 2009 pandemic and subsequent influenza seasons in which the virus continued to circulate. We postulate that interference of pre-existing antibodies with infection of elderly people by pandemic A H1N1 virus might have had negative effects. It might have prevented the induction of recall cross-reactive virus-specific T-cell response, which could contribute to heterosubtypic immunity. Rapid and strong CD4 and CD8 T-cell responses were recorded in individuals infected with the pandemic A H1N1 virus,12Hillaire ML van Trierum SE Bodewes R et al.Characterization of the human CD8(+) T cell response following infection with 2009 pandemic influenza H1N1 virus.J Virol. 2011; 85: 12057-12061Crossref PubMed Scopus (44) Google Scholar which might have been absent in older patients as a result of protective pre-existing antibodies to pandemic A H1N1 virus, resulting in higher susceptibility to infection with H7N9 virus (figure). Similarly, yearly vaccination of high-risk patients against seasonal influenza prevented the induction of virus-specific CD8 T-cell responses, which would usually be induced by natural infection with seasonal influenza viruses13Bodewes R Fraaij PL Geelhoed-Mieras MM et al.Annual vaccination against influenza virus hampers development of virus-specific CD8(+) T cell immunity in children.J Virol. 2011; 85: 11995-12000Crossref PubMed Scopus (77) Google Scholar and was noted in animal models.14Bodewes R Fraaij PL Kreijtz JH et al.Annual influenza vaccination affects the development of heterosubtypic immunity.Vaccine. 2012; 30: 7407-7410Crossref PubMed Scopus (33) Google Scholar A possible explanation is that the presence of cross-reactive antibodies predisposed for more severe disease, a finding that, although not previously noted in influenza, has been reported for some viral diseases.15Huisman W Martina BE Rimmelzwaan GF Gruters RA Osterhaus AD Vaccine-induced enhancement of viral infections.Vaccine. 2009; 27: 505-512Crossref PubMed Scopus (144) Google Scholar During the influenza pandemic of 1957, which was caused by the H2N2 subtype, individuals who had previously been infected with the H1N1 virus were less likely to be infected with H2N2 influenza than were those who had not.16Epstein SL Prior H1N1 influenza infection and susceptibility of Cleveland family study participants during the H2N2 pandemic of 1957: an experiment of nature.J Infect Dis. 2006; 193: 49-53Crossref PubMed Scopus (261) Google Scholar The low incidence of severe H5N1 infections in elderly compared with younger people might be related to the presence of cross-protective antibodies to neuraminidase that are induced by seasonal influenza A H1N1 viruses.17Sandbulte MR Jimenez GS Boon AC Smith LR Treanor JJ Webby RJ Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans.PLoS Med. 2007; 4: e59Crossref PubMed Scopus (245) Google Scholar Overall, we postulate that antibodies to pre-1957 influenza A H1N1 viruses protected elderly people against pandemic A H1N1 virus infection, but consequently affected the development of heterosubtypic immunity and the disease outcome of H7N9 virus infections. The rate and timing of pandemic A H1N1 virus infections might have revealed the differences in H7N9 disease outcome, by contrast with historical infections with seasonal influenza A H3N2 viruses. This counterproductive imprinting of immunity might increase susceptibility to H7N9 virus infection. For that reason, older individuals should be given priority for vaccination if sustained person-to-person transmission of H7N9 viruses emerges. To obtain a better understanding of the role of imprinting of the adaptive immune system in H7N9 disease severity, prospective cohort studies in which cross-reactive T-cell immunity and virus-specific serum antibodies are tested for are imperative before possible wider spread of the virus. We declare that we have no conflicts of interest. Age and different influenza virusesWe read with interest the Comment by Guus Rimmelzwaan and colleagues1 explaining the different age distribution of cases caused by avian influenza A viruses of the H5N1 and H7N9 subtypes. They proposed that the low incidence of severe H5N1 infections in elderly people compared with that in younger people might be related to the presence of cross-protective antibodies to neuraminidase that had been induced by seasonal influenza A H1N1 viruses. There is another type of cross-reactive antibody that might contribute to protection against the H5N1 subtype. Full-Text PDF