Pandemic potential of a strain of influenza A (H1N1): early findings

Abstract

A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; >/=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.

Fig. 1

(A). The number of passengers flying out of Mexico by actual destination and the number of confirmed cases as reported on 30 April 2009. (B) The number of cases exported to country j as reported on 30 April 2009 as a function of the estimated average number of foreign travelers in Mexico from country j on any given day in March or April. Black circles: minimal number based on one exposure per epidemiological cluster; filled red circles, total number of confirmed cases. (C) Mean assumed generation time distribution (red) and 100 illustrative draws from the prior distribution, and (D) corresponding posterior distribution of R₀ estimates for a stochastic model of an epidemic within Mexico with travelers infected at a rate proportional to the estimated density of travelers per local resident. The two bar charts correspond to a 7-day delay between infection and confirmation (blue) and no delay (orange) in cases among travelers. (E) Number of acute respiratory infection cases per 100,000 inhabitants by state as reported on 5 May 2009 (1), demonstrating spatial distribution of disease within Mexico.

Fig. 2

(A) Starting from publicly available HA viral sequences, a posterior distribution of the estimated TMRCA was derived using a Bayesian coalescent model, which assumes exponential population growth (coded in BEAST 1.4), with the date of the first known human case highlighted. Details of the BEAST analysis and parameter estimates are presented in (8). Posterior distribution of the doubling time of the epidemic (B) and of R₀ (C). The bar charts show the results obtained from the first 11 sequences available on 2 May 2009 (orange) and from an updated analysis with 23 epidemiologically unlinked sequences available on 7 May 2009 (blue). The differences in estimates arise due to some sequences in the smaller sample being from epidemiological clusters, highlighting the importance of careful sampling.

Fig. 3

Results of a detailed investigation into an outbreak in the village of La Gloria. (A) The time series of cases based on repeat rounds of investigation into the outbreak, and the best fit of an age-stratified transmission model (see Table 2 for estimates). The graph also shows the best fit of a model where the generation time is constrained to be consistent with earlier estimates for influenza (2.6 days), which does not fit significantly worse than the unconstrained best fit (see Table 2 legend). (B) Observed (bars) and fitted (using best fit, circles) age-specific attack rates; (C) best fit and constrained estimate of the generation time distribution.

Fig. 4

(A) Time course of the Mexican epidemic with (B) the posterior estimates (median and 95% CrI) of the reproduction number over time obtained under Poisson and negative binomial models from the analysis of confirmed cases. The estimate ofthe negativebinomial dispersion parameter k is for a low-to-moderate overdispersion, but this is enough to greatly increase the uncertainty in R(t).