Combined interferon and ribavirin therapy an option for early MERS-CoV intervention?

Falzarano and colleagues write in Nature Medicine that the combination of ribavirin (an antiviral) and interferon-a2b (a cytokine key to our antiviral defenses) improved the health of MERS-CoV (EMC/2012) inoculated rhesus macaque monkeys. 

This builds on the March Study by Falzarano et al, which reported  the usefulness of this drug cocktail in reducing virus production in a cell culture system.

Treated infected animals did not suffer from increased respiratory rate, breathing difficulties or increased white blood cell counts (mostly due to neutrophils). Treated infected animals also showed no X-Ray changes in their lungs 1-day after infection and little change beyond that. Untreated animals showed mild to marked evidence of pneumonia and also lower levels of markers of inflammation and copies of viral RNA genome.

The macaques were inoculated with 10⁶ tissue culture infective doses (TCID₅₀) by combined intratracheal (lower respiratory tract), intranasal (upper respiratory tract), oral (ingestion) and ocular routes. That seems to represent a fairly "shock-and-awe" cocktail of inoculation routes compared to how humans may get exposed. Viral RNA was detected in spleen, kidney, lymph nodes, upper and lower respiratory tract and airways in the untreated animals - and many of those sites in the treated ones. The relevance of this study to MERS-CoV transmission is probably limited, but then it's not a transmission study, it's a treatment study. There is another article cited as in press from part of this group. It may further address tissue replication; Novel human betacoronavirus causes a transient lower respiratory tract infection in a rhesus macaque model. Proc. Natl. Acad. Sci. USA.

Interestingly, disease in the macaques is at best mild to moderate in severity, so how the drug cocktail would work when faced with severe human disease...which may take longer to develop...remains unclear. Also unclear, is what disease would look like in macaques with a similar degree of comorbidities to those seen in the most severe human MERS cases.

The main proviso is, the cocktail must be administered early; it was administered 8-hours after infecting the monkeys here. 

With a 5-working day to 2-week turnaround in testing for MERS-CoV, treatment would have to be started at first suspicion and even then might not meet this window. Given the Qatar GP story yesterday, that window would be long shut, painted over and boarded up.

Nonetheless, this is a very encouraging finding and a very nice piece of work that adds an important step in the path to providing a therapeutic option to MERS-CoV infections.

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A memo to the Saudi Minister of Health...

Crawford Kilian has written a memo to Abdullah Abdulaziz M. Al Rabeeah, MD, Minister of Health, Kingdom of Saudi Arabia.

It is brilliant. 

Please read the entire thing. I have an excerpt below, but it is only a fragment of the whole glorious piece.

Your government, Minister, is now risking a similar problem. Both medical experts and the media are growing impatient at the erratic flow of information on MERS, and I hear rumours that Saudi hospital staff are as alarmed as those in Canadian hospitals afflicted with SARS ten years ago. And well they might be, when this virus seems to thrive in healthcare settings.

An aggressive, open communication policy is now urgently called for. Rather than indulge in a litany of past problems, I would like to recommend some steps your ministry could take right now to ease concerns around the world while also ensuring solid support from Saudi professionals and public. 1. Frame a detailed, standard format for reporting each case. At a minimum, this should include:

1. Frame detailed, standard format for reporting each case. 
At a minimum, this should include:

• the age, gender, and occupation of the patient;
• mention of specific underlying medical conditions, if any;
• place and date of onset;
• a description of treatment and place of treatment;
• the specific relationship, if any, to previous cases;
• tests administered and results of those tests;
• if possible, a statement by a Ministry spokesperson putting this case in the context of recent events.

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Saudi Arabia takes the initiative on MERS research

A coronavirus virion schematic.
IanM, Virology Down Under.

In what many might describe as well overdue, an independent Saudi Arabian scientific organization, the King Abdulaziz City for Science and Technology (KACST), has called for grant proposals to conduct research on coronaviruses (CoVs). 

The Arab News reports that several areas of research will be considered, as well as CoVs.

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MERS cases jump by 8 today...biggest 24-hours in 15-months?

Distribution go cases by site of likely acquisition.
Based on publicly available data.

The Kingdom of Saudi Arabia's (KSA) individual list of Middle East respiratory syndrome coronavirus (MERS-CoV) cases that have been acquired within its borders (and that's just to the best of my knowledge) is at 101. It's just a number but its also 81.5% of all laboratory confirmed cases to date. And it rose to 124 by a jump of 8 cases today (VDU time that is).

The latest KSA cases continue to pop up in Hafr Al Batin (Batin) Medinah (Medina) and Riyadh. Contacts (~4/8), healthcare workers (~1/8) and comorbidities (~3/8) feature heavily - and that's just among the ones with those details included. We're missing sex on most and dates of onset have been getting more rare since May.

Within those 8 cases are 3 deaths (37.5% of those cases). Are these the first reports of these people? How long is the turnaround time for testing currently? This proportion is below the global proportion of fatal cases (PFC) which as of just now stands at 46% (57 deaths have have data available to use in this calculation)

The other thing we should factor in is co-infections with other respiratory viruses, and with bacteria. The viruses, as noted in my previous post, may now be starting to increase in prevalence as the "cooler" months affect the region. None of the broader testing data (presumably they were screened for other pathogens as well) are available on recent cases and few details available on earlier cases. 

Some things that are unknown on this topic:

1. How MERS-CoV interacts with other viruses - has any virus just finished up its seasonal peak? Something that may have interfered with MERS-CoV circulation at a population level?
2. Are we seeing more MERS-CoV cases now because of a change in environmental conditions? His could be anything from temperature to humidity to impact on animal movements to festivals to dust storms

8 cases in 1 day. I think the first time I have seen so many cases in a row on my list in a 24-hour period (not actually at 24-hours yet). Many questions start arising without answers.

Even with Prof Memish's 2nd personal update through ProMED yesterday, it feels like cases are starting to appear faster than the local health authorities in these regions can manage them. Or has something changed with the virus itself?

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Flu-like symptoms on the rise in Qatar...

The Gulf Times notes a rise in cases of "flu-like symptoms" in Doha, Qatar. Dr Sameer Kalanden, a general practitioner (GP) notes a rise on cases coming to the clinic. He usually prescribes medication  or "an injection" to reduce the fever (please don't let it be antibiotics..oh. It is antibiotics). 

If there is no sign of improvement, even after a 2nd visit, he refers the case to Hamad General Hospital (managed by Hamad Medical Corporation; HMC).

Another GP confirmed the recent rise in cases with symptoms of "flu and common cold" rising "these days". He also refers cases with more severe respiratory disease to HMC.

So from that we might be able to conclude:

1. HMC may be the testing lab for Middle East respiratory syndrome (MERS) coronvirus (CoV) in Qatar. We also know that may/all MERS-CoV cases are confirmed by UK collaborators
2. That only the most severe cases of illness will be tested for MERS-CoV
3. GPs do not refer any other acute respiratory illnesses for MERS-CoV testing routinely
4. There is considerable concern about MERS in Qatar - but not a lot of structure to resolve that concern

This sort of anecdotal report is a great way to bring attention to what isn't being done, but it would be much more helpful to know what is being done in Qatar, given its recent local cases and deaths. 

As I understand it, Qatar is entering it's cooler months. Looking through the literature, there are not a lot of papers on respiratory viruses from Qatar. In one paper by Wahab and colleagues in 2001 in the Journal of Tropical Pediatrics, we see that HMC testing defined the peak season for respiratory syncytial virus (RSV) in children as November-January in Qatar (data from 1996-1998 combined, included 257 previously healthy children). 59.9% of these cases were diagnosed with bronchiolitis, 17.6% with pneumonia and 35.8% had an infiltrate in their lungs. RSV cases start rising from September though. The authors note this seasonality is similar to other temperate countries in the Gulf region. And this is just 1 virus of 200.

In another study, this year, in Archives of Virology, Althani and colleagues (Qatar University and HMC) tested 200 adults with asthma or chronic obstructive pulmonary disease (COPD) across winter (October 2008 to March 2009). While virus detections were relatively few (18% of patients), most seasonal viruses were present during this period - more so in asthma than in COPD. These included rhinoviruses, HCoV-229E, NL63 and OC43, parainfluenza viruses 1-3, RSV, adenovirus, influenza B virus and human metapneumovirus.

So this rise in cases noted by the GPs above may be nothing more than the usual start to the respiratory virus season, made to look more scary because of the recent MERS-CoV outbreak. Or it may be more than that.

I believe its time to be seriously considering what local laboratory testing capacity exists on the ground in the Arabian peninsula.

If the hajj stirs up case numbers, as many suspect it will, having limited to no ability to quickly resolve a flood of potential cases will result in a management crisis. Cases will accrue quickly and "probable", rather than "confirmed" will become the word of the day while trying to prevent spread in hospital environments.

If it looks like a duck and quacks like a duck, it may be just a rhinovirus. 

Case numbers will also be added to, as they always are when surveillance is heightened for a new agent, because seasonal endemic human respiratory viruses are circulating as well and those infections cannot reliably be discriminated from mild to moderate MERS-CoV using patient observation alone. 

Currently, MERS-CoV results in the Kingdom of Saudi Arabia may take up to 2 weeks to turnaround (if you follow me on Twitter you will have seen this time frame suggested to me last night). 

If the cases seen by the GP today were MERS-CoV positive, they would 1st need to return with a continuing fever before being tested and then that result would be revealed either too late to reduce the risk of a transmission event, or perhaps too late to be of use in applying novel antiviral treatments on that patient.

Time is of the essence. And more testing is paramount.

Thanks to @makoto_au_japon and @dspalten for bringing this to my attention.

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Hafr Al Batin MERS-CoV cluster grows...

Click to enlarge. The red circle indicates Hafr Al Batin in the north east of the
Kingdom of Saudi Arabia.

Apart from Riyadh's latest flurry of cases, Hafr Al Batin (Batin) has been hosting cases in healthcare workers (HCWs) since July. Lately though, we've seen seeing more HCWs - with reports suggesting as many as 10 in the cluster, and the possibility - raised via numerous local media and other reports - of more in this cluster. As with most clusters, cases seem to include human-to-human transmission events.

Is this a hospital based outbreak, a change in the virus to something more transmissible  or some particular activity that is exposing people in this region to more animal host infections?

Those long-awaited MERS-CoV full genome sequences we heard about recently are still not here, but if they were, they likely won't include recent strains like the ones in Batin. We really need to get over his whole-genome fetish and get some subgenomic sequencing going to reduce turnaround time. 

There are already PCR primer sets published by Corman et al that could monitor some smaller genome (subgenomic) regions of MERS-CoV and this should be able to be done locally, perhaps in , gasp, a collaboration with local Universities  But this does not seem to be happening for some reason.

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