Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility

Abstract

Background: The novel Middle East respiratory syndrome coronavirus (MERS-CoV) had, as of Aug 8, 2013, caused 111 virologically confirmed or probable human cases of infection worldwide. We analysed epidemiological and genetic data to assess the extent of human infection, the performance of case detection, and the transmission potential of MERS-CoV with and without control measures.

Methods: We assembled a comprehensive database of all confirmed and probable cases from public sources and estimated the incubation period and generation time from case cluster data. Using data of numbers of visitors to the Middle East and their duration of stay, we estimated the number of symptomatic cases in the Middle East. We did independent analyses, looking at the growth in incident clusters, the growth in viral population, the reproduction number of cluster index cases, and cluster sizes to characterise the dynamical properties of the epidemic and the transmission scenario.

Findings: The estimated number of symptomatic cases up to Aug 8, 2013, is 940 (95% CI 290-2200), indicating that at least 62% of human symptomatic cases have not been detected. We find that the case-fatality ratio of primary cases detected via routine surveillance (74%; 95% CI 49-91) is biased upwards because of detection bias; the case-fatality ratio of secondary cases was 20% (7-42). Detection of milder cases (or clinical management) seemed to have improved in recent months. Analysis of human clusters indicated that chains of transmission were not self-sustaining when infection control was implemented, but that R in the absence of controls was in the range 0·8-1·3. Three independent data sources provide evidence that R cannot be much above 1, with an upper bound of 1·2-1·5.

Interpretation: By showing that a slowly growing epidemic is underway either in human beings or in an animal reservoir, quantification of uncertainty in transmissibility estimates, and provision of the first estimates of the scale of the epidemic and extent of case detection biases, we provide valuable information for more informed risk assessment.

Funding: Medical Research Council, Bill & Melinda Gates Foundation, EU FP7, and National Institute of General Medical Sciences.

Figure 1

Epidemiological and genetic data (A) Probability density and cumulative probability of the incubation period from data of exposure for a subset of seven cases. (B) Probability density and cumulative probability of the delay between onset of first and second cases in six case clusters with more than one case. The delay between onset of first and second cases is a lower bound of the generation time. (C) Cumulative number of confirmed cases and clusters detected of MERS-CoV. (D) Maximum likelihood phylogeny of viral sequences of MERS-CoV, obtained using PhyML with the TN93 model. More recent samples were found to cluster together (highlighted in red), suggesting these viruses are part of an emerging epidemic. Only Al-Hasa_1 was included in analysis, to avoid over-representation of this outbreak.

Figure 2

Alternative scenarios for animal-to-human and human-to-human transmission (A–C) Illustrative epidemic trajectories (incidence of human infections occurring in each transmission generation of length T_G=12 days) consistent with the timing of clusters and data on returning non-resident traveller cases for R₀=0·3 (A), R₀=0·7 (B), and R₀=1·06 (C). (D) Proportion of human cases due to human-to-human transmission in the epidemic so far as a function of the reproduction number, for T_G=12 days. (E) Probability that current chains of transmission will be sustained for a finite period (1 year) as a function of the reproduction number, for T_G=12 days. See appendix for details.

Figure 3

Outcome as a function of month of symptom onset for years 2012–13 When onset information was missing, the date of symptom onset was estimated by subtracting 10 days (the median delay from onset to reporting in 2013, once the Al Hasa cluster had been excluded) to the date of reporting.