Avian Flu Diary: The Elusive R0 of MERS

# 8601

Yesterday, the International Journal of Infectious Diseases published an `article in press’ peer-reviewed manuscript that attempts to quantify the risks from the MERS coronavirus, entitled:

Middle East Respiratory Syndrome Corona virus, MERS-CoV. Conclusions from the 2nd Scientific Advisory Board Meeting of the WHO Collaborating Center for Mass Gathering Medicine, Riyadh.

Ziad A Memish^a^,, Jaffar Al-Tawfiq^b, Christian Drosten^c, Abdullah Assiri^a, Rafaat Alhakeem^a, Ali Albarrak^a^,^d, Saber Yezli^a, Malak Almasri^a, Alimuddin Zumla^a^,^e, Eskild Petersen^f

After reviewing what is known about the outbreak, animal reservoirs, human transmission and the management of hospital patients with MERS, the authors enumerate 13 conclusions.

Conclusions

Sequencing of MERS-CoV isolates from Jeddah patients who’s the virus seems stable, showing no signs so far of mutations which indicate an adaption to humans with increased risk of human to human infections.

The primary animal reservoir is camels and dromedars. Transmission is thought to be due to close physical contact or due to consumption of camel products.

The epidemiology since the virus was first found in 2012 is compatible with multiple introductions into humans from the animal reservoir, with no long-term sustained human-to-human transmission.

There is no human reservoir of cases with few or no symptoms.

The basic reproductive rate of the virus (R0) is definitely below 1 and probably below 0.5 clearly showing that the virus has no pandemic or even local epidemic potential.

The incubation period was between 2 to 16 days? Period of infectivity was?

Nosocomial infection is an important risk factor for human to human transmission. Thus infection prevention and control measures are crucial to prevent the possible spread of MERSCoV within health care facilities. Hospital infection control procedures needs to be emphazised and enforced. The Jeddah outbreak showed that it is not always possible to identify patients with MERS-CoV early because some have mild or unusual symptoms.It is important that health-care workers apply standard precautions consistently with all patients irrespective of the diagnosis. Droplet precautions should be undertaken when providing care to patients with symptoms of respiratory tract infection. Contact precautions including eye protection should be added when caring for suspected or confirmed cases of MERS-CoV infection. Airborne precautions should be taken when performing aerosol generating procedures

In patients suspected of MERS-CoV, if initial tests using nasopharyngeal swab is negative, repeat testing should be performed, and other specimens from the lower respiratory tract should be obtained if possible.

Awareness of MERS-CoV is important in countries where camels and dromedars are a common livestock.

The importance of educational campaigns for educating health care workers, the general public, family contacts and travelers to the Middle East was emphasized. General hygiene measures such as regular hand washing, antiseptic before and after handling animals Owners of camels and dromedars should use gloves and mask when handling ill animals.

There is no evidence that camel's milk tested positive for MERS, however, milk has the potential of transmitting other infections. Camel milk should be boiled before consumption. Unpasteurised milk should not be consumed

There was no grounds for preventing children attending schools and closing schools

For the forthcoming Hajj, camel sacrifice or contact with camels should be avoided.

While all significant points of interest, from an epidemic standpoint, #5 in the list above would seem to have the most importance:

The basic reproductive rate of the virus (R0) is definitely below 1 and probably below 0.5 clearly showing that the virus has no pandemic or even local epidemic potential.

A definitive, and highly reassuring statement. And hopefully correct. But as with all reviews, at best reports like this can only tell us where this virus has been, not where it is going.

The R0 (pronounced R-naught) is epidemiological yardstick by which human transmission of an infectious disease is measured. Essentially, the number of new cases in a susceptible population likely to arise from a single infection.

With an R0 below 1.0, a virus (as an outbreak) begins to sputter and dies out.

Above 1.0, and an outbreak can have `legs’.

Calculating the R0 is notoriously difficult, even years after an epidemic has passed. Much hinges upon the existence and subtle differences between viral strains, the accuracy of surveillance and reporting, `seasonality’, and individual host responses to the virus (i.e. number of `super spreaders’).

Like the CFR (Case Fatality Ratio), the R0 can vary considerably over time or geography, often ends up being described as a `range’, and usually isn’t well established (or at least, generally agreed upon) until long after an outbreak has ended.

Last July in The Lancet: Transmissibility Of MERS-CoV we saw the first attempts to quantify the basic reproductive number of this virus – at a time when the total number of MERS cases was still under 70 worldwide. Based on an extremely limited data-set, and hobbled by limited surveillance and reporting out of Saudi Arabia, the authors produced an early estimate of the virus’ apparent R0 (which they fixed at between .60 and .69).

Too low (at that time) to spark a pandemic.

But as Helen Branswell noted in her report - MERS doesn't have pandemic potential – yet - experts, including Drs. Allison McGeer, Marc Lipsitch, and Chris Bauch (who co-authored a commentary on this study) - warned that past performance is no guarantee how this virus will behave in the future.

The following November, we looked at a study published in The Lancet Infectious Diseases, that looks at the likely extent of transmission of the MERS virus in the Middle East.

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

Simon Cauchemez PhD a †, Prof Christophe Fraser PhD a †, Maria D Van Kerkhove PhD a, Prof Christl A Donnelly ScD a, Steven Riley PhD a, Prof Andrew Rambaut PhD b, Vincent Enouf PhD c, Prof Sylvie van der Werf PhD c, Prof Neil M Ferguson DPh

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.

The results – that for every case identified, there are likely 5 to 10 that go undetected – suggest that this virus may be transmitting more efficiently than previously estimated. The authors believed the R0 of the MERS virus is likely close to 1.0, or perhaps even higher, and wrote:

We conclude that a slowly growing epidemic is underway, but current epidemiological data do not allow us to determine whether transmission is self-sustaining in man. Our analysis demonstrates that the transmissibility of MERS-CoV in man is close to the critical threshold of R=1 required for self-sustaining transmission. If R is greater than 1, then the number of human cases we estimate to have occurred to date make it highly likely that self-sustaining transmission has already begun.

Skipping ahead to February of this year, in mBio: Spread, Circulation, and Evolution of MERS-CoV, we looked at a study (also co-authored by Ziad Memish), that warned:

MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.

So far we’ve not seen the kind of exponential growth in MERS cases that would indicate that this virus has achieved a high enough basic reproductive number to spark a major epidemic. Cases are rising, but more in a linear fashion.

Whether that equates to an R0 of <.5 or something approaching 1.0, I’ll leave to the epidemiologists of the world to sort out.

I would only note that there are still a lot of unknowns with this virus, including the incidence (and causes) of community transmission. Surveillance outside of the hospital environment is spotty at best, and we really have no idea how many cases go unidentified.

The bottom line is that past performance doesn’t guarantee future behavior of this, or any other virus.

Which means that as long as the MERS coronavirus continues to circulate in humans and animals in the Middle East, its potential to spark a larger epidemic should not be ignored.