MERS-CoV among healthcare workers: no longer identified or the end of a hospital cluster?

Just looking at @maiamajumder's vast array of MERS-related charts on Twitter and had a thought.

She and I and others have been wondering for a while if perhaps the Kingdom of Saudi Arabia's (KSA) Ministry of Health (MOH) reporting has decided to simply no longer identify healthcare workers (HCWs) as such. That would not be the strangest thing to occur with these data, believe me (deaths that have been "previously reported" that actually haven't, people who were discharged from hospital who were previously not described as being hospitalised, and of course, some instances of HCWs in KSA being identified as MERS-CoV positive by their country of origin and not by the KSA MOH). Perhaps not identifying HCWs is a way of attempting to stop pointing to what was a huge problem in infection prevention and control just last month?

But perhaps that is not entirely what is happening. 

Perhaps there is another reason and there may be some precedent to support it; HCW numbers have in fact realistically decreased because they are no longer being infected as often. Why not? Perhaps because April's Jeddah hospital-based MERS-CoV outbreak is under control. Have a look at the chart below. Some things to note afterwards:

Click on image to enlarge

1. HCW numbers have stopped accumulating so rapidly. That mirrors total MERS-CoV detections of course. See some recent posts on the now receding wave of April's MERS surge here and here.
2. The precedent I mentioned? When the Al-Ahsa hospital-related outbreak stopped in May 2013, so did the number of HCW positives/week dropped away. 
3. There have clearly been a bunch of other HCW peaks which may also have been related to hospital-clusters that were not so obviously publicised (I'll have a loo over this some time in the future). Those spikes of HCW infections have narrower bases and higher peaks than does the Jeddah outbreak, so perhaps that can be used as an indication of them being short-lived clusters that were better controlled than Jeddah. Not rocket science I guess and probably stating the obvious to the experts out there.
4. Infections in HCWs serve, as we already know, as a kind of sentinel system for identifying a spike in overall cases since more severe disease shows its face in hospitals and most likely represents the presence of other cases out in the community. His statement is much more believable now that we ;can look back and know that milder signs and symptoms of disease, or none at all, do not infrequently follow MERS-CoV infection).

I hope that our original hypotheses - that the KSA MOH has quashed identifying HCWs - was wrong. Heading towards Hajj-2014, it would be best to be polishing the very tarnished reputation of of the KSA MOH on matters ;of communication, not further damaging it.

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The impact of cell culture on virus as highlighted by deep sequencing..[UPDATED]

Alignment of complete or near complete MERS-CoV
genomes made using Geneious v6.1.7.
The Neighbor-Joining tree was made using MEGA with
1000 bootstraps. Red stars indicate virus from same patient. 
Vertical bars to the right indicate Clade A (dark blue)
and B (pale blue). Sequences from the the 2013 Al-Ahsa
hospital outbreak are boxed in pink. GenBank
accession numbers are indicated at the end of
each sequence name which also includes region
of detection, host and date of sample collection.
Click on image to enlarge.

Just a quick post to note the difference that "passage" in cell culture (isolation of an infectious virus using lab cells inoculated with the original virus-positive patient material, some of which is taken off and added to a new flask of cells and this process repeated as needed)  can do to the virus as it changes to grow most effectively in the new environment...this is akin to the adaptive changes seen when a virus first jumps to a an entirely different species.

Apparently the 2 starred (red stars in the figure) virus genomes are from the same 60-year old male patient [1,2,3; ] but the original variant, EMC/2012, was sequenced from material after 6 rounds of cell culture [3] while the Bisha_1 variant was not [1]; it was subjected to deep sequencing directly after nucleic acid preparation using an original respiratory sample aliquot (nasopharyngeal swab)[1]. 

Given that cell culture passage seems to be related to the positioning of EMC/2012 in Clade A versus Bisha_1 in Clade B (indicated by a pale blue line), does this mean there is no Clade A (dark blue vertical bar) and that it's just an artefact??

Probably not. Why? Because the Jordan-N3/2012 virus that is also found in Clade A and it also originates from a human specimen collected in 2012. It is listed as having been sequenced from a bronchial sample. There is no mention of cell culture on its GenBank record - which does not mean there was no culture. But when that sample was passaged through culture and sequenced (N3/2012 MG167; sequence not shown in this tree) it remained 99.95% identical to the original sequence; just 2 nucleotide differences out of 30,028nt. 1 difference in the spike gene and 1 Open Reading Frame 1a). These are unlikely to be enough to switch its clade  but I'm realigning with this sequence included just to be sure about that!

I thought that was kinda interesting.

NB. There may be some concern over the specimen labelling used to identify samples for sequencing of EMC/2012 or Bisha_1. I'm attempting to sort our by following this up with the lead author.[1]

Reference...

1. Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Cotten et al. Lancet 2012;382:1993-2002
2. 60-year old man from Bisha who died in a Jeddah hospital (EMC/2012 variant)
   Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. Zaki et al. N Engl J Med 2012; 367:1814-1820
3. Genomic workup on EMC/2012
   Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans. van Boheemen. mBio 2002; 3(6): e00473-12

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MERS by day, testing by night...

Now that we can look back over more than a month (from 20-April to the latest Kingdom of Saudi Arabia [KSA] Ministry of Heath [MOH] report of 7 cases dated 22-May), we see that the downwards trend in MERS-CoV detections  has been pretty consistent.

Click on image to enlarge.

I noted it looked likely to be dropping at the beginning of May, but it's much more clear now. 

So now we wait and see what happens next. 

None of the pressure is off the KSA to try and reduce animal-to-human exposures, to determine how those exposures lead to human infection/what bits of animal are virus positive, to tighten hospital infection and prevention protocols, to see how much of the community has been exposed to or is currently infected by MERS-CoV, to sample more of 2014's MERS-CoV variants and determine how the virus is evolving with more time among, and passages through humans...and other things! 

It was interesting to read recent Lancet articles on Mass Gathering Medicine which, apart from a backgrounder to its "Father", Dr Ziad Memish, make note of the preparedness required each year by the healthcare sector in the KSA to ready hospitals to receive and treat ill pilgrims during their mass journey for Hajj. Clearly the hospitals, having played such a central role in the spread of most human MERS-CoV detections to date and so they have a lot of work ahead them, in a very short period, to ensure a much bigger MERS-CoV outbreak does not result from Hajj-2014. And of course MERS-CoV is neither the only nor the major respiratory virus in town when people descend on that town from all seasonal corners of the globe.

Respiratory virus testing, as I understand it from discussions on Twitter, is not a regular nor a routine tool to support clicnial decision-making in the KSA. Not like it is in the UK, USA or Australia for example. If that's true, then it really should be. he fund exist to support it and clearly Central labs is capable of getting good RT-rtPCR results. It's perhaps just a mater of scale then. Such testing supports and complements a modern healthcare system. And it's important for public health. Respiratory viruses are one of the most common causes of hospital visits. Among the elderly and those with comorbidities, as we have seen with MERS-CoV, these viruses play a big role in stressing or damaging an already damaged tissue/organ/system and spreading among individuals with underlying disease (e.e. those undergoing dialysis) conveniently gathered under one roof within range of each others aerosols. Some disease can be prevented (flu vaccines, which are already used in the KSA), some can be quarantined but knowing which virus is present may lead to better patient management, cohorting and understanding of prognosis. Such a testing system would devolve to the MOH to initiate, organize and manage I suppose.

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Snapdate: Avian influenza A(H7N9) virus...

There seem to have been more announcements of late than previously so I thought I'd plot this and see. 

These are a little adrift as the last 7 or so have not been through the WHO scrubbing process (which adds extra bits of data) so we will see a little shifting the last 2 or so blue dots on the chart below.

Click on image to enlarge.

Guangdong and Anhui provinces have the most active case generators in May.

Anhui province has reported 3 cases in a week and there seem to have been a constant stream of cases in May, but they they don't, in reality, seem to be out of what's become the ordinary in 2014 for a virus that is happily ticking over in several provinces.

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Snapdate: MERS-CoV detections by where they were probably acquired...

...yeah its "probably" because sometimes it's just not clear to anyone. I've about 14 (554 in total) more cases attributed to a likely source in the Kingdom of Saudi Arabia (KSA) compared to the Ministry of Health tally on their website (540), but such is life.

Anyway, I haven't updated this chart for 17-days (woah - sorry about that). The latest version now has the two major hospital-related outbreaks shown in pink - I'm still liking the Janadriyah festival as the possible source of community cases that then filter back throughout the country as visitors and tourists return to different areas or travel afterwards for other reasons. That would be on my 2015's "festivals that need to be tweaked to avoid camel contact" list.

As per yesterday's post, these accumulation curves highlight that new detections of MERS-CoV have slowed right down in the KSA and in the United Arab Emirates (UAE). However, the UAE are now the reporting slow pokes, if the last batch posted by the World Health Organization is anything to go by, so we should stay tuned to what's happening there (and also stay tuned to the extent of upper respiratory tract signs and symptoms in those cases which continue to bug me).

Click on image to enlarge.

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Camels at the centre, aerosol all around...

v2 12JUN2015

A droplet (and perhaps airborne)-centric view of how the camel could be a source of sporadic human infection by MERS-CoV, a virus that is genetically very similar whether found in camels or humans.

The inner ring (orange) is more about bigger wetter droplets and aerosols-if you must differentiate on size. 

These are potential routes by which a human in contact with, or near to, camels might acquire virus from them, when those camels are actively infected. Keep this in context though- because of a number of large hospital-based outbreaks, most cases of MERS seem to have occurred by virus transmission between humans and their environments rather than from camels to humans.

Camels are not all infected all the time. This is probably why there wasn't a rash of camel herdsmen coming down with MERS after the YouTube camel-kissing outbreak...at least as far as we know there wasn't.

Camels have been found to be actively infected more often when young, but adult camels have also been found actively infected by MERS-CoV as well so there is risk of exposure to camels at any age, when they are infected.

Sometimes camels do not show signs of illness (e.g. no runny nose) but other times they do, so illness alone cannot be used as a warning sign.

There are also some data to suggest adult camels can be reinfected. This makes sense if you remember that MERS-CoV is well entrenched among camels spread over large areas of the Arabian Peninsula and Africa. The virus would disappear if there were no susceptible hosts left among the adults to maintain it in the herds between camel breeding seasons. Plus, there is nothing to physically stop a new infection anyway. That's a conversation about whether that infection leads to notable or debilitating disease or not.

The outer (Blue) ring in the picture above is more about consumption of camel products. As you can see in the inner ring, some of these activities could also generate aerosols and it is important to think about, and recognize, that avoiding consuming of camel products may still be about reducing your risk of exposure to virus that you can breathe in during the process of preparing the camel products to consume, when the camel is infected.

We don't yet have any evidence that the virus can infect after eating/drinking material contaminated with it. Or whether many camel products are contaminated with it. I tend to think that if eating/drinking were a route to acquiring MERS, then a lot more people would be infected by such a deliberate process of viral delivery. Plus. the disease almost always shows up as a respiratory tract illness with gut issues thrown in sometimes, not the other way around. And the physiology underpinning a virus being ingested, disseminating systemically and mostly showing up as pneumonia? Plus the few exported cases that have forward transmitted probably weren't consuming camel products at their destinations. Meh. Droplets. Respiratory

So we still need to find out which bits of the camel actually have virus in them. No milk testing has been done yet but nasal swabs and faeces have been positive for MERS-CoV RNA and have had infectious virus grown from them.

On cleaning this blight from the camels, I'd like to see more talk about quarantine and isolation processes now. Can camel herds be kept separated for long enough that the virus is "burned out" of each herd by limiting its ability to infect new herds? It would be a huge job but it may be a way to rid areas, countries and perhaps the Peninsula of MERS-CoV while routine animal testing can be put in place for imported camels. Just a thought. In the meantime, finding ways to perhaps do this on a small scale for the incoming pilgrims so that they could still visit with "safe" camels, might be a matter of priority.

Make no mistake, camels host this virus and they have done so for at least 20-years.

That's not the end of the story - but it's one chapter of it and it's written in stone.


Version history.

• v2-changed some use of the term 'airborne' as my understanding of the word has mutated over the past year

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MERS-CoV detections: The April wave recedes...

So welcome to the 114th Week of MERS-CoV among us. That week numbering may change shortly. Stay tuned if week numbering is your thing.

We currently have a tally of 649 detections of MERS-CoV or viral antibodies in humans. I don't list camel numbers. My count says 192 fatalities among infected people, resulting in a proportion of fatal cases of 29.6%. That seems high. Because, until very recently, the Kingdom of Saudi Arabia's Ministry of Health did not regularly report deaths alongside their date of illness onset, it has been an interesting hobby to try and link them. The number is solid so along as the MOH has not been doubling up in the reporting or coming back later to re-report deaths. You'll be familiar with these issues if you follow me on Twitter.

I made a point of saying antibodies earlier because I am going to be including these sorts of laboratory data in my tally when produced by trustworthy laboratories who have described their methods and shown some validation data and an understanding of what the cross-reaction issues are when dealing with MERS-CoV serology. This will be despite the current WHO MERS case definition not allowing for inclusion of people who only have antibody but no virus or viral RNA detected in their samples. There may be some hiccups with MERS-CoV antibody testing along the way, but we need these data in humans and it's good to see the wheels rolling on this at last.

[One of those hiccups occurred 28-May-2014, when the test result from an Illinois man who had originally tested positive in an Ab test, was retracted.]

In my estimation though, serology (the testing of human sera for antibodies against a virus here, the main target being IgG which takes a couple of weeks to become detectable after infection) is a much more reliable way of defining an infection by MERS-CoV virus than by relying on patient recall bias of symptoms 2-weeks ago, or from directly observing signs and symptoms that are nondescript and difficult to distinguish, alone. The latter approach has been the mainstay of identifying cases of human infection for a very long time; still is. This approach is especially important during times of outbreak and pandemic when labs are swamped by testing requests and it must be assumed that cases are due to the bug of interest; if it looks like a camel, slobbers like a duck and walks like a duck, then it is a MERS-CoV infection yeah? No. If you can clinically characterise and laboratory test then you will more often know the virus the patient has/had than if you don't test. But I'm sure that's clear to everyone anyway.

For MERS, as for H1N1pdm09 influenza and perhaps SARS, finding a reliable pathognomonic set of signs or symptoms capable of reliably distinguishing a respiratory virus of interest from another virus capable of the same disease is not possible. These viruses cause a spectrum of illness. Testing is paramount if you want to know what's there and to address other aspects relevant to public health during an infectious disease cluster/outbreak/pandemic. There are a couple of issues here (at least!)...

From a patient management perspective, who really cares what is making my patient very ill anyway? It really doesn't matter right now if it's this respiratory virus or that one; there are few vaccines and I don't have an antiviral for most of them anyway. I and my healthcare team are already taking respiratory infection precautions and I just want to direct my supportive therapy and resources to the problems they have, right? I'll be (well...you, experienced medical types of which I am not one) doing that before many lab results show up anyway. 

From the perspective of interrupting and understanding viral transmission however, nondescript signs and symptoms are a nightmare. And in the early days of a new virus where we seem to know very little about what path(s) transmission is taking (and perhaps we're also learning some more about those possibilities in general), any infection by whatever method it is empirically determined should, I believe, be recorded as an infection in order to provide the biggest picture possible; a process we have seen unfolding in the United States with its 2 3 detections (1 locally transmitted) of MERS-CoV or its spiky little footprints.

THIS RESULT WAS RETRACTED 28-May-2014 FOLLOWING A NEGATIVE NEUTRALIZING ANTIBODY TESTING.

Given that many viruses cannot be distinguished by signs and symptoms alone, a clinical diagnosis to define a case is less reliable than any pathogen-specific laboratory test. I hope the WHO alters their case definition in the near future. Infectious disease is always teaching us - seems we learned a heap from SARS but even the relatively a few cases of MERS are presenting interesting issues and testing us in new ways. 

[While the US antibody-positive result above has since been retracted, I stand by these comments-Ab testing requires rigor, but that can be provided using several assays and applying a good understanding of Ab technologies and limitations to produce reliable results]

Anyhooooo...been stewing on that for a few days apparently. Let's move on and have a look at the 3 updated charts below. 

We are definitely through to the other side of the Jeddah outbreak (see weeklies chart). While cases do keep accruing each and every day (see dailies chart from 20-March), the downward trend of smaller numbers of illness onsets each day also continues. 

Weekly MERS-CoV detections.
Click to enlarge.

Daily MERS-CoV detections from 20-March.

Click to enlarge.

For perspective on the size and the influence of what 1 hospital cluster can turn into and how that can influence how a virus "looks", take a gander at the extent of the April outbreak. Case are still falling out into April as we get more data. If you look at the monthlies chart at the bottom, I've readjusted that y-axis scale again such that it's maximum value is now 10x higher (350 vs 35) than the scale used for 2012 or 2013's charts. May's tally is currently 4x greater than any month from 2012 or 2013. 

What does MERS-CoV hold for us in the coming months? 

Daily detections of MERS-CoV, 2012-current.

Click to enlarge. 

Monthly detection of MERS-CoV 2012-current.
Click to enlarge.

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Thoughts on two weeks of rural primary care in Mexico

Update: I go to Jaltenango today enroute to Refoma, the second community that I am working in.  From what I understand, it is both more rural and yet closer to Jaltenango.  It is apparently also a community of many Jehovah's Witnesses.  

My last night in Laguna was marked by an after-dark walk to the pantheon/cemetary to try and get phone reception in order to talk to the main office about a case.  All the lights are gone, which is unsurprising after the three days of gloomy cold rain.  It also means that I haven't showered in two days because it is too cold to envision an icy bucket bath.

I've learned a tremendous amount about how I have (mostly subconsciously) learned to practice medicine by being here.  Today, we had a female patient who has a history of gallstones and who clinically seems to have progressed to pancreatitis.  As usual, the question arises of whether she is safe to stay here in the community until Monday, when her family can take her to the local hospital with surgical capabilities.  And the answer as to whether she is safe, as with so many things here, is that I haven't a clue.  I know how to risk-stratify pancreatitis in a hospital, where I can get labs and imaging.  I can fearlessly quote mortality statistics.  Here, I'm fairly certain of our diagnosis, but without the laboratory confirmation that I've learned to rely on, I feel paralyzed with doubt on how to treat people.  My pasante is so much more fearless, having gotten used to trusting her instinct without needing multiple (or any) forms of confirmation of her clinical instinct.  Somewhere in the middle is probably best for patients.

How can I tell how likely it is that our patient's chest pain is angina without ever getting an EKG, or lipids?  What is the pretest probability in a rural Mexican farmer who has never smoked but who probably inhaled tons of smoke in an indoor kitchen?  How do I treat him without access to a stress test?  How applicable is the Framingham Risk Score (or pick your favorite) to him?

I've learned that, in the absence of the screening tests that the majority of my patients get, I tend to suspect cancer at every turn.  I blame this in part on three years at BWH, with all our Dana Farber patients.  But in every abdominal pain in an older man, I see colon cancer and I fret about every woman with pelvic pain having cervical cancer.  I hadn't realized how much comfort I personally take in having an easily accessible screening panel.

In addition, so much of my practice at home is based on not missing anything.  We will get chest x-rays and labs for the lowest probability events.  So often, we use the language of 'ruling something out.'  Here, as testing is so hard to come by, you have to be pretty darn sure that you need something before you make someone travel.  

In my last day, we had two children who clinically looked like they had hepatitis A (one of whom's mom actually said, "his urine looks like coca-cola and his eyes are yellow."). How many kids in the past two weeks with diarrhea and abdominal pain actually had hepatitis?  Are we sitting on an outbreak?  Do you need the serological confirmation?  All these questions are new ground for me.

On an unrelated note, here's my pasante, myself, our neighbor's daughter and one of a thousand local dogs.

-Sarah Kimball, MD

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Health related graffiti in Jaltenango, Mexico

I'm a total sucker for health-related graffiti.  There seems to be an HIV educational campaign in Jaltenango, which makes for some amusing artwork.

"HIV/AIDS.  Bring me, look for me, use me!"

"HIV/AIDS can only be aquired by means of sex and blood.  And a mother can transmit the virus to her child during pregnancy, delivery and breast feeding."

And my personal favorite:

"If you want to have sex, you should protect yourself with a condom."

-Sarah Kimball, MD

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Primary Care in Chiapas, Mexico

Some of these posts are backdated, due to poor internet access in Chiapas.  But in short, thanks to funding from the Partners Center of Excellence, I'll be spending the next month in rural primary care clinics in Chiapas, Mexico with Compa�eros en Salud, the Mexican arm of Partners in Health.  While I work on my Spanish (starting from a place of fumbling with many years out of practice), I'm hoping to get a sense of how primary care is practiced in a place where routine health exams are not the norm, and where people come without good access to the health care system.

My role here is as a medical consultant to the Mexican pas antes who are stationed here for a year.  They do six years of schooling, including a year of hospital training.  As a payback to their community (because medical school is paid for by the government), all pasantes do a year of community service.  My first post is in Laguna de Cofre, high up in the mountains of Chiapas, and about two hours from Jaltenango.  We have a small house next to the clinic where my pasante and her nurse live along with anyone else who comes along and needs a place to crash, like me.

On our first day, we left Jaltenango at 7am and headed straight for clinic, as the line was already getting long by the time we arrived at 9:30  From what I understood from my broken, aching Spanish, today's clinic included (in semi-medical speak)

Pts 1-4: pregnant mother and there kids, there for HIV testing.  Kids negative, mother positive.  Presumably from father, who travels back and forth to Tiajuana for work, as HIV rates are quite low here. 

Pt 5: well pregnancy check

Pt 6:  woman with pain in multiple parts of body, likely from stress.  IUD placed. 

Pt 7: woman with RA, who was getting dexamethasone injections and developed Cushings Syndrome and diabetes.  Now off steroids, but in lots of pain.  No clear other medication options available.

Pt 8: 60 yo man with exertional chest pain. No EKG or stress test easily available.  No clear idea of protest probabilities without lipid testing. Opted for nitrate trial diagnostically.  

Pt 9: 70 y.o. man with hypertension and vision changes.  As a side note, he was as tall standing as I am sitting.  

Pt 10: 70 y.o M with hemorrhoids and hearing issues.  Clearly no colonoscopy, but they have hydrocortisone suppositories with lidocaine in them.  Brilliant!

Pt 11: hypertension and sore throat

Pt 12:  well pregnancy check.  23 year old with three other children

Pt 13: sick kid (eeek! I don't know what to do with kids!) with diarrhea.  Fortunately, the wonderful

Pasante that I am working with knows kids may better.

Pt 14: teenaged boy with facial dermatitis

Pt 15: urosepsis in a 70 y.o. man with a permanent supracatheter.  Looked bad.  IV fluids, abx, monitored, no labs.  Will see tonight and tomorrow (he lives across the street) to make sure he doesn't need to be shipped to a local hospital (which he almost certainly does, but it is such an issue here to make happen)

Pt 16: told by a naturalist doc that he had bladder inflammation that he healed.  Wanted to talk to someone else, which is good because the story didn't make sense.

Pt 17: young girl with diarrhea

Pt 18: very depressed 15 y.o. girl who walked 2 hours to get to clinic.  Her problem is, in short, that she is a female in a a village in Chiapas without the ability to get out.  Not something sertaline will help, but that was what we had,

Pt 19: 19 y.o. lady with constipation

Pt 20: 15 y.o who was pregnant.  Wanted an abortion, but it is illegal in this state.  More about that later, which I find baffling and angering.

Off to this spot, which is my bed for the next ten days.

And our kitchen, which is barely functional but doesn't really need to be.

-Sarah Kimball, MD

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