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.

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.

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?

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.

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.

Death of a young adult Qatari MERS patient who presented with flu-like illness...

So that last post is out of date already.

The Qatari Supreme Council of Health, as it does, has issued an announcement through the media (it has yet to update it's technically troubled website) announcing the death of the previously described 29-year old male with asthma who had been confirmed by an international (presumably UK-based) reference laboratory.

Asthma occurs in about 5% of the world's population, but in higher proportions in particular countries and regions.

This moves the deaths up to 54 with data, possibly 56 in total (see earlier post today for what that means) with a PFC of 48.3% for 56 deaths.

The presentation of this case on August 17th, was of "flu-like illness" which can be anything from fever + cough to much more. What this case highlights, and it is only a single case, is that cases can present with standard upper respiratory tract infection (flu most often starts off that way) which will make it devilishly hard to discriminate from that caused by many other non-MERS-CoV respiratory viruses. In a study of pilgrims leaving the 2012 hajj, 41% had flu-like symptoms (cough, sore throat and fever). I mentioned this in an earlier post (see #3 in the Prof Memish lit review) and the paper in Feb this year from Clinical Microbiology and Infection can be found behind a paywall here. A subsequent article published in Clinical Infectious Diseases this July, also paywalled and by the same group showed that a number of respiratory viruses were lab-confirmed as acquired while in the Kingdom of Saudi Arabia (showed symptoms of  illness), fewer were brought into the country and fewer were taken out. Not much can be concluded from that as I would expect this in any group tested in this way under these circumstances (travelling to a gathering of lots of people from around the world and from different climates  experiencing different respiratory virus seasons). It is not surprising that when you throw people together, they transmit respiratory infections and the the number of cases spikes.

This will be a big challenge if observation alone, rather than prospective laboratory testing, is used as a method to diagnose MERS among hajjis (thanks to AtRG for this phrase), in the coming weeks.

Tunisian father was MERS-CoV positive...

A retrospective diagnosis by the US CDC has confirmed that the father of a MERS-CoV-positive brother and sister in Tunisia (FluTracker's Cases: #42-35-year old female; 34-year old male) was indeed positive for the CoV as well. 

There was also a mention in BMJ of this cluster.

Earlier testing had not been able to confirm that the father, despite him being a probable case, had transmitted the virus to his children.

This raises the MERS-CoV case tally to 116 based on what has been reported by official Ministries and Councils. I assume we add the 2 deaths for which we have no information - they have been floating around for some time now - to this to make a total of 55 deaths (PFC of 47.4%). Not having the specific details makes these 2 very hard to confirm they are not just clerical or media release errors from the past.

The WHO count (based on what they have been officially told I assume) is at 110 cases with 53 deaths. This number of deaths agrees with what I actually have data for; PFC for the 53/110=48.1%).

More MERS molecular masterfulness: Egyptian camels contain lots of anti-MERS-CoV antibodies [AMENDED]

UPDATE #1: 23NOV2015

Perera and colleagues from China, Japan, Egypt and the United States report in Eurosurveillance that they
have found a high prevalence of Egyptian camels which have antibodies to a piece of the Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein.

The group looked at 1,343 human sera (815 from Cairo as part of influenza study; 528 archived from Hong Kong) and 625 animal sera (from goats, sheep, water buffalo, cows, camels, pigs and birds) from Egypt and China (no MERS reported there, so this acts as control population; unfortunately no camels tested from there either). 

A positive control serum was provided by Prof Drosten from an earlier MERS case.

The novel assay does not need to be used in a biosafety level 3 containment environment (BSL2 is fine) because it does not use whole/live MERS-CoV to capture the human/animal antibodies, rather it uses just a piece of the virus; the spike protein, which is known to attract the lion's share of antibody attention. 

The spike protein was merged with HIV (non-infectious) proteins to create a pseudoparticle of proteins that could enter cells, and also bind to MERS-CoV antibody which would act to prevent such entry by the virus-like particle. If there was no antibody, the pseudoparticles could enter cells and this entry could be measured using a marker enzyme reaction. This novel assay (pseudoparticle neutralization test; ppNT) was run in parallel with a more standard micro-neutralization (MNT) test; the two tests agreed well but the standard MNT test needed to be carried out in a BSL3 laboratory).

The more traditional MNT test pre-incubated infectious MERS-CoV with serum and then measured whether the live MERS-CoV could still infect and damage cells. If there was antibody in the serum, it blocked infection (as it presumably can in us during a second or third infection). 

Pseudoparticle/virus will be more or less blocked from cell entry if more or less antibody is present in the serum. One can determine how much antibody was in the serum sample too. These type of tests measure the ability of antibody in a patient/animal to block virus entry; it's neutralizing ability. 

A high proportion (103/110; 93.6%) of dromedary camels from Egypt had antibodies that could block cell culture infection by a lab strain of the MERS-CoV (MERS-CoV/EMC from Erasmus University Medical Center). 

No humans had antibodies. No animal sera from China (Hong Kong) were positive - this included pigs (n=260) and wild birds (n=204). 

Numbers were sometimes very low but no goats (n=13), sheep (n=5), water buffalo (n=8) or cows (n=25) were antibody-positive in Egypt. Only the camels.

The authors specify that this does not exclude cross-reactivity with a closely related, but non-MERS, CoV that has at some previous point infected the camels. If only there was some sort of plan to do this sort of virus hunting in mammals.

Click to enlarge.

So how does this fit in with the human acquisition model proposed 1-week ago? Pretty well. It supports previous findings from Omani camels too. 

Camels could be part of the chain of infection. It says nothing about how they may then go on to be a source of human infections that start off as a respiratory illness, presumably requiring, at least in most cases anyway, inhalation or self-inoculation (I'm looking at you, nose-pickers). For that we'd need to know anything about survival of MERS-CoV in excreta and on surfaces. I'd also like to see some more animal test results. 

Nonetheless, it looks as though we have some very useful antibody detection assays shaping up, and they can do just that.

Here's hoping for a KSA study next.

UPDATE #1: Fixed some typos and grammar.

MERS-CoV and deaths rise....[UPDATE]

The latest Kingdom of Saudi Arabia (KSA) Ministry of Health (MOH) announcement (Arabic only for now) provides scarce detail on 4 new cases including 2 deaths.

1. 30-year old, Riyadh, health care worker (HCW), in an intensive care unit (ICU)
2. 47-year old, Hafr Al Batin, multiple comorbidities, contact ("Mkhalt") of another case, in an intensive care unit (ICU)
3. 41-year old, Riyadh, HCW, fatal infection
4. 79-year old, [construction worker=Harf al Batin-place name], multiple comorbidities, contact of another case, fatal infection

The last case on that list is particularly interesting* for their role as a contact, who died. Generally, the second "passage" of infection to a new human host has not been as severe as the first. This once again draws attention to the role of underlying disease (comorbidities) in making any infection, even one that has gone through a human host, fatal.

There are no data on the sex of cases, when the fatal cases were admitted to hospital, or any indication at all of a date of disease onset.

After Wednesday's post of the plateau that ceased after umrah, I would be very interested to know how many recent cases has recent travel with a common destination.

The MERS-CoV lab-confirmed case tally now sits at 115 with 54 deaths (proportion fatal 47%)


*It's very sad that there are real people in these numbers who have died from MERS. You may have noticed that I try and stick with the cold number-crunching aspect of these outbreaks. It's not because I'm a heartless b&^$# but because that is not what this blog is about. That and my editorialisation and expositionary writing consume what little time I have spare. But I don't feel that I have enough information to make any other comments about these or any other lives lost to infectious disease. I personally feel that any unexpected and acute loss of life (if I had to scale loss of life) is the worst kind of loss; it's a waste of potential, a source of great sorrow for all involved and it's something we should all strive to prevent, if we can. I know that's not much to convey, but it's all I can offer from my kinda comfy chair in Brisbane. 

H7N9 in wild birds...a review of the literature

Not by me though., This was a review just published in EID

Bird flyways that may contribute to H7N9 spread.

by Olson and colleagues.

They found 48 published studies that listed findings of influenza A virus haemagglutin type H7, or neuramonase N9 viruses as well as H9N2. The prevalence was calculated as the number of positive samples divided by the by number tested.

H7N9 has been rarely reported from Delaware (USA), Alberta (Canada), Guatemala, Spain, Egypt, Mongolia and Taiwan but has not been reported from Russia, Japan, South Korea or China from birds sampled between 1976-2012.

The outcome? If you were planning wild bird surveillance to track H7N9 spread in these non-poultry animals, you'll need to sample >30,000 wild birds to find 1 positive for H7N9 (its Asian prevalence was 0.00931%). 

That's a rare bird.

This is just a rough gauge of course because it is entirely dependent on when, where and how thoroughly bird populations were sampled, how they were sampled, what they were tested with and how the sequencing methods performed. It also focuses on HA and NA genes, at the expense of other internal influenza gene segments which also have an important role in the assemblage of new viruses. 

But its a gauge nonetheless.