Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk

Introduction

Since September, 2012, WHO has been notified of 64 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection.¹ This new disease has many features reminiscent of severe acute respiratory syndrome (SARS)—eg, predominance of respiratory symptoms, airborne transmission, high case-fatality ratio, and caused by a virus of the Betacoronavirus genus that is closely related to bat coronaviruses.2, 3, 4, 5 The SARS-CoV pandemic had been preceded by outbreaks in southeast China between November, 2002, and January, 2003.6, 7 During this period, the virus is thought to have been repeatedly introduced into human populations from its intermediate hosts (eg, the masked palm civet) before adapting to interhuman transmission.8, 9 The molecular events leading to the mutation that enabled the SARS-CoV spike protein to bind with the human ACE2 receptor have been particularly well described.¹⁰ The same sequence of events might be occurring with MERS-CoV, which has been repeatedly introduced into the human population for more than a year (from an unknown animal host) and might have human pandemic potential. One useful indicator of virus transmissibility is the basic reproduction number (R₀), which represents the number of secondary cases per index case in a fully susceptible population. When R₀ is above 1, epidemic potential has been reached. We aimed to adapt a recently published method of estimating R₀ ¹¹ to the MERS-CoV outbreaks and compare the results with similar findings obtained for prepandemic SARS.

Methods

Results

Overall, patients with confirmed MERS-CoV were aged between 2 and 94 years (median 56 years, IQR 41–68·5) and most were men (44 [74%] of 61 patients with sex reported). The case-fatality ratio was 59·4% (95% CI 46–71; 38 of 64 patients). Advanced age was a significant risk factor for death (case-fatality ratio 76% [55–91; 19 of 25] for age ≥60 years vs 38% [22–56, 13 of 34] for age <60 years; p=0·008).

We obtained an R₀ of 0·60 (95% CI 0·42–0·80) for scenario 1 and 0·69 (0·50–0·92) for scenario 2. The number of transmission trees for each scenario provided the number of MERS-CoV introductions into the human population during the period of data acquisition. Hence, we obtained yearly introduction rates of 22·3 (95% CI 13·0–31·5) and 17·1 (9·0–25·3) for scenario 1 and 2, respectively. We also obtained an R₀ of 0·80 (0·54–1·13) for prepandemic SARS. Repeating the analyses assuming the size of the Jordanian cluster to be between two and 13 or excluding the outstanding event of six secondary cases caused by patient C of the Al-Hasa cluster in the dialysis ward¹⁵ showed the robustness of our results (appendix). As shown in figure 2A , the average tree size is very sensitive to the value of R₀, particularly when R₀ is close to 1.

We further studied the expected yearly incidence of MERS-CoV infections, calculated by multiplying the introduction rate into the human population by the average tree size, 1 / (1 – R₀).¹¹ Figure 2B shows a contour map of the yearly incidence versus the introduction rate and R₀. Non-linear dependence qualifies R₀ as the key parameter, particularly for values close to 1. On the same figure 2B, we plotted the parameters corresponding to our scenarios 1 and 2 and showed the region in the parameter space most likely to include the true parameters of MERS-CoV. This plot suggests that the possibility of MERS-CoV having an R₀ above 1 or less than 0·4, or a yearly introduction rate above 35, is very small. To assess the potential effect of future MERS-CoV outbreaks on our R₀ estimation, we analysed the change in the probability that R₀ exceeds 1 versus the tree size that would be observed next (figure 2C). In scenario 2, a tree larger than 98 cases would imply that the probability of having a pandemic MERS-CoV strain exceeds 5%. In scenario 1, reaching the 5% threshold would need the next observed tree to consist of 200 cases.

When active contact tracing is operational, public health authorities might immediately stop viral transmission after the index patient has been diagnosed, and thus the available data would be just the number of secondary cases of the index patient before their isolation. This situation is addressed in figure 2D in which, in scenario 2, the 5% probability threshold is reached if the next index patient caused eight secondary cases. In scenario 1, the 5% threshold is reached if the next index patient caused 14 secondary cases.

Discussion

Our analysis suggests that MERS-CoV has not reached epidemic potential—ie, R₀ was less than 1. Although R₀ estimates of prepandemic SARS-CoV and MERS-CoV under our second scenario are close, we cannot conclude that MERS-CoV will follow a similar path toward pandemic spread. Despite phylogenetic similarities, the two viruses have distinct biology, such as the use of different human receptors.10, 17 SARS-CoV adaptation to human beings took just several months, whereas MERS-CoV has already been circulating for more than a year in human populations without mutating into a pandemic form. However, the speed of adaptation depends on several variables, some of which might widely differ between China and the Middle East (eg, animal and human density, baseline preventive measures, and, most importantly, the prepandemic R₀).¹⁸ Because of the very small number of MERS-CoV sequences available, non-synonymous mutations suggesting viral adaptation could not be yet established. Hence, comparison between SARS-CoV and MERS-CoV should remain cautious.

Figure 2B displays the yearly number of cases as a function of two variables, the yearly introduction rate and R₀. Control of this new zoonosis could therefore be exercised by addressing these two components.

First, control could target a reduction in the rate of MERS-CoV introductions into the human population. However, the animal host responsible for MERS-CoV introductions is not yet known. This search should take high priority, focus on Middle Eastern countries where most cases occurred, and address the broad variety of species known to host coronaviruses, including bats, birds, mice, dogs, pigs, and cattle.¹⁹ Reports have already pointed to sick goats and camels in the vicinity of patients as a potential source of MERS-CoV.20, 21

Second, control could focus on a reduction in the infectious period of infected individuals through improved surveillance, rapid diagnosis, and isolation. When done effectively, active contact tracing could reduce the number of cases to the number of MERS-CoV introductions (ie, index patients) and the secondary cases they might cause before isolation.²² We note that R₀ might also increase with the population density and is affected by the community age and contact structure. Large gathering events or travel of patients from the Middle East to densely populated areas might result in outbreaks with increased R₀.

Our analysis depends on the quality of the surveillance systems.²³ In view of the tendency for identification of large clusters at the beginning of an epidemic, and insufficient data for partitioning clusters into smaller transmission trees, our tree-size data analysis might overestimate R₀. Hence, this bias would not affect our conclusion that MERS-CoV does not have pandemic potential and is likely to be minimised now that public health surveillance systems are on alert. Also, timely control measures after diagnosis of a new patient will trim the natural pattern of transmission. Still, the virus will always have a short window of opportunity for transmission before the isolation of each new index patient. For this reason, we considered the situation in which the next available datapoint would be the count of cases secondary to the index patient, and provided a method that might be useful in places with effective surveillance.

Another important issue is the possibility of asymptomatic and mild infections. A confirmed case with mild symptoms, for which admission to hospital was not needed, occurred in the UK.⁴ If asymptomatic and mild infections constituted an important fraction of the total, R₀ might be higher than our estimate. In the future, serological analysis of contacts will allow a fair estimation of asymptomatic infections. Serological tests for MERS-CoV are under development, but have not yet been deployed. Retrospective analysis of sera of contacts of SARS-CoV patients showed a very small (0·2%) proportion of asymptomatic infections.²⁴ Of note, serum samples of 2400 control patients at the Dr Soliman Fakeeh Hospital in Jeddah, Saudi Arabia, where the first patient was diagnosed, did not detect MERS-CoV in an immunofluorescence assay that was strongly positive with the serum of the patient, suggesting that MERS-CoV was not circulating undetected in the general population during the previous 2 years.³

The main issue for now is how to interpret the data on the size of future outbreaks that surveillance systems will detect. Most certainly, future data will add to our knowledge about viral transmissibility and narrow the CIs around the R₀ estimate. Our analysis suggests that if effective contact tracing detected eight or more secondary cases caused by the next index patient, then, under scenario 2, this would suggest, together with all knowledge gathered so far, that there is a more than 5% chance that the MERS-CoV R₀ is larger than 1—ie, that MERS-CoV might have pandemic potential. This finding seems unlikely because the largest count of secondary cases attributed to a patient is seven (six in a dialysis ward and one outside) and is an outlier.

In conclusion, our analysis confirms the importance of enhanced surveillance of MERS-CoV infection and an active search for its animal host, particularly in the Middle East where MERS-CoV infection is most prevalent (panel ). Close monitoring of cases and contact tracing are of high priority to limit transmission, gather high-quality data to update the R₀ estimates, and decrease opportunities for viral adaptation to interhuman transmission. One of the main lessons of the SARS pandemic has been that early control of the virus (while it was still confined to southeast China) might have prevented its global spread.

Supplementary Material