Case fatality ratio of pandemic influenza
Authors: Hiroshi Nishiura
Journal: The Lancet Infectious Diseases (2010)

As pandemic influenza H1N1 spread around the world in 2009, disease severity was one of the main areas of interest. The case fatality ratio (CFR) is a representative measurement of severity of a disease that directly captures virulence (ie, the conditional risk of death for patients with a disease or infection), whereas mortality (ie, the risk of death in a population) depends not only on the disease severity but also the risk of infection in a population. Because there have been several conflicting estimates of the CFR for pandemic H1N1,1Fraser C Donnelly CA Cauchemez S et al.Pandemic potential of a strain of influenza A (H1N1): early findings.Science. 2009; 324: 1557-1561Crossref PubMed Scopus (1586) Google Scholar, 2Garske T Legrand J Donnelly CA et al.Assessing the severity of the novel influenza A/H1N1 pandemic.BMJ. 2009; 339: b2840Crossref PubMed Scopus (207) Google Scholar, 3Nishiura H Klinkenberg D Roberts M Heesterbeek JA Early epidemiological assessment of the virulence of emerging infectious diseases: a case study of an influenza pandemic.PLoS ONE. 2009; 4: e6852Crossref PubMed Scopus (91) Google Scholar, 4Wilson N Baker MG The emerging influenza pandemic: estimating the case fatality ratio.Euro Surveill. 2009; 14 (pii=19255.)Google Scholar, 5Presanis AM Lipsitch M De Angelis D et al.The severity of pandemic H1N1 influenza in the United States, April–July 2009.PLoS Med. 2009; 6: e1000207Crossref PubMed Scopus (254) Google Scholar, 6Nishiura H The relationship between the cumulative numbers of cases and deaths reveals the confirmed case fatality ratio of a novel influenza A (H1N1) virus.Jpn J Infect Dis. 2010; 63: 154-156PubMed Google Scholar I offer an interpretation of these reports and identify key areas that need to be clarified. In the early stages of the 2009 influenza pandemic, two approaches were taken when calculating the CFR. One approach focused on estimation of CFR during the course of the pandemic.1Fraser C Donnelly CA Cauchemez S et al.Pandemic potential of a strain of influenza A (H1N1): early findings.Science. 2009; 324: 1557-1561Crossref PubMed Scopus (1586) Google Scholar, 2Garske T Legrand J Donnelly CA et al.Assessing the severity of the novel influenza A/H1N1 pandemic.BMJ. 2009; 339: b2840Crossref PubMed Scopus (207) Google Scholar, 3Nishiura H Klinkenberg D Roberts M Heesterbeek JA Early epidemiological assessment of the virulence of emerging infectious diseases: a case study of an influenza pandemic.PLoS ONE. 2009; 4: e6852Crossref PubMed Scopus (91) Google Scholar During outbreaks of severe acute respiratory syndrome from 2002 to 2003, use of a crude ratio of the cumulative number of deaths to the number of cases at a given point in time underestimated the CFR.7Ghani AC Donnelly CA Cox DR et al.Methods for estimating the case fatality ratio for a novel, emerging infectious disease.Am J Epidemiol. 2005; 162: 479-486Crossref PubMed Scopus (183) Google Scholar To avoid similar underestimations, accounting for the time delay from onset of disease to death, the confirmed CFR of pandemic H1N1, which took confirmed cases as the denominator, was estimated to be about 0·5%.1Fraser C Donnelly CA Cauchemez S et al.Pandemic potential of a strain of influenza A (H1N1): early findings.Science. 2009; 324: 1557-1561Crossref PubMed Scopus (1586) Google Scholar, 2Garske T Legrand J Donnelly CA et al.Assessing the severity of the novel influenza A/H1N1 pandemic.BMJ. 2009; 339: b2840Crossref PubMed Scopus (207) Google Scholar, 3Nishiura H Klinkenberg D Roberts M Heesterbeek JA Early epidemiological assessment of the virulence of emerging infectious diseases: a case study of an influenza pandemic.PLoS ONE. 2009; 4: e6852Crossref PubMed Scopus (91) Google Scholar, 6Nishiura H The relationship between the cumulative numbers of cases and deaths reveals the confirmed case fatality ratio of a novel influenza A (H1N1) virus.Jpn J Infect Dis. 2010; 63: 154-156PubMed Google Scholar However, because the estimate depends on the proportion of symptomatic patients who have confirmatory diagnosis, it is not useful for prediction of the overall mortality.6Nishiura H The relationship between the cumulative numbers of cases and deaths reveals the confirmed case fatality ratio of a novel influenza A (H1N1) virus.Jpn J Infect Dis. 2010; 63: 154-156PubMed Google Scholar In other words, the difficulty in case ascertainment remains a limitation of confirmed CFR. Motivated by this limitation, the second approach calculated the CFR by taking symptomatic cases as the denominator, although in this study the denominator was not clearly defined.4Wilson N Baker MG The emerging influenza pandemic: estimating the case fatality ratio.Euro Surveill. 2009; 14 (pii=19255.)Google Scholar Despite several technical problems, this approach emphasised the importance of accounting for unconfirmed cases to yield an appropriate order of the CFR estimate (figure 1).4Wilson N Baker MG The emerging influenza pandemic: estimating the case fatality ratio.Euro Surveill. 2009; 14 (pii=19255.)Google Scholar Subsequent to these earlier efforts, Presanis and colleagues5Presanis AM Lipsitch M De Angelis D et al.The severity of pandemic H1N1 influenza in the United States, April–July 2009.PLoS Med. 2009; 6: e1000207Crossref PubMed Scopus (254) Google Scholar have offered a way to predict the mortality in a population, by explicitly taking symptomatic cases as the denominator and thus calculating the symptomatic CFR. The symptomatic CFR among all medically attended cases was estimated to be 0·048%, one-tenth of the CFR estimate from confirmed cases. In other words, only one of ten symptomatic cases seems to have been confirmed. By use of self-reported influenza-like illness as the denominator, the estimate was even smaller. Presanis and colleagues5Presanis AM Lipsitch M De Angelis D et al.The severity of pandemic H1N1 influenza in the United States, April–July 2009.PLoS Med. 2009; 6: e1000207Crossref PubMed Scopus (254) Google Scholar and a later study in the UK8Donaldson LJ Rutter PD Ellis BM et al.Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study.BMJ. 2009; 339: b5213Crossref PubMed Scopus (16) Google Scholar have adeptly shown that 2009 pandemic H1N1 influenza can be subjectively perceived as mild. Caution is needed when interpreting age-specific estimates (figure 2). The confirmed CFR in Mexico9Secretaría de Salud, MéxicoSituación actual de la epidemia. Mexico City, Mexico: Secretaría de Salud (as of May 10, 2010).http://portal.salud.gob.mx/contenidos/noticias/influenza/estadisticas.htmlGoogle Scholar and the USA10Fiore A Novel influenza A (H1N1)epidemiology update—advisory committee on immunization practices meeting.http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-jul09-flu/02-Flu-Fiore.pdfDate: 29 July, 2009Google Scholar increases with age, most probably because underlying medical conditions that can increase the risk of influenza death are most common in elderly people.10Fiore A Novel influenza A (H1N1)epidemiology update—advisory committee on immunization practices meeting.http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-jul09-flu/02-Flu-Fiore.pdfDate: 29 July, 2009Google Scholar, 11Wada K Nishiura H Kawana A An epidemiological analysis of severe cases of the influenza A (H1N1) 2009 virus infection in Japan.Influenza Other Resp Viruses. 2010; (in press.)Google Scholar The similar age-specific pattern is also seen in symptomatic CFR.8Donaldson LJ Rutter PD Ellis BM et al.Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study.BMJ. 2009; 339: b5213Crossref PubMed Scopus (16) Google Scholar The differing CFR estimates between age-groups hamper precise estimation for entire populations during the early stages of the pandemic.12Lipsitch M Riley S Cauchemez S Ghani AC Ferguson NM Managing and reducing uncertainty in an emerging influenza pandemic.N Engl J Med. 2009; 361: 112-115Crossref PubMed Scopus (169) Google Scholar Furthermore, although there might be two countries with very different CFR estimates, comparisons will be futile unless the composition of the cases (ie, age-groups and risk-groups of fatal and non-fatal cases) is known. The best way to describe the severity of pandemic influenza to non-experts is to compare its virulence with that of other influenza epidemics. However, because different methods have been used to predict the mortality impact associated with pandemic H1N1 and non-pandemic influenza, the strict comparison of virulence has been difficult. Estimations of mortality for non-pandemic influenza have been made mainly with Serfling cyclical regression,13Thompson WW Weintraub E Dhankhar P et al.Estimates of US influenza-associated deaths made using four different methods.Influenza Other Resp Viruses. 2009; 3: 37-49Crossref Scopus (282) Google Scholar which accounts for deaths that are both directly and indirectly associated with influenza. A recent study in the USA suggested that there were up to 44 100 excess deaths in May to December, 2009,14Viboud C Miller M Olson D Osterholm M Simonsen L Preliminary estimates of mortality and years of life lost associated with the 2009 A/H1N1 pandemic in the US and comparison with past influenza seasons.PLoS Curr Influenza. 2010; : RRN1153PubMed Google Scholar implying that the mortality effect of the influenza pandemic surpassed that of non-pandemic influenza seasons. However, because this estimate of excess mortality reflects both transmission potential and virulence, a comparative assessment of virulence alone has yet to be established. In addition to the above-mentioned issues surrounding the estimation of CFR, pharmaceutical interventions such as antiretroviral treatment or immunisation programmes also bias the estimated risk of death. Thus, to provide an unbiased CFR for the 2009 influenza pandemic that can accurately represent the overall virulence and permit comparisons within and between populations, we are faced with a challenge to adjust for such potential treatment effects that may require substantial epidemiological and statistical efforts. I declare that I have no conflicts of interest. HN has received support from the JST PRESTO programme.