Are we testing enough?

I had written this as part of my last post but it didn't fit in with that topic...

Yes there was a case of pneumonia in the Kingdom of Saudi Arabia that apparently went untested for all possible/emerging/out-of-the-box pathogens - does that never happen elsewhere?

In defence of the current CORONA-CoV hotzone's testing, there are plenty of research and review papers in the scientific literature that show pneumonia is one of those diseases that could really do with better testing and characterisation. Acute brain inflammatory diseases are another bunch. They are scary diseases, they have an immediate impact and sequelae that may not yet be well defined and they are likely to be triggered by 1 or more viruses and or bacteria. And all that sits on top of the highly variable milieu of our genetic (immune defects?), physiological (prior predisposing tissue damage or changes?) and immunological (previous exposures or lack thereof) background.

Is it possible to effectively manage disease prevention and ill patients if you don't know the cause of the disease? Sure, there are no treatments for most viral diseases - but that's an excuse not to uncover the agent likely causing a patient's ills and not a reason. One can never learn the cause if there has been no testing for the most pertinent bugs. Its a vicious and really annoying cycle that seems to be part of a disconnect between the bed and the lab. At least in some places. I'm deliberately leaving aside being unable to prove causality through detection alone. That's for another day.

In the case of diseases that are poorly tested, that list of bugs should include everything relevant and everything that could be relevant. 

It feels (oh very scientific) like its been a while since we've really looked hard at the testing of some acute diseases - we tend to stick with what we knew when it comes to testing panels. Over time new technologies have been developed (PCR - kinda old now) and a lot of new bugs have been (and keep being) found. Are we in need of a shake up? I think "paradigm" should really be a dirty word in the testing for infectious agents right now.

I would personally love to get some good collaborations going and do some comprehensive testing for everything under the sun, plus some next-generation sequencing to find things we don't yet know of, on a large number of such cases (and controls). Finding the funding - and the interested collaborators - now there is a trick worthy of Loki and one I have yet to attain.

Kingdom of Saudi Arabia is CORONA-free...is it CORONA-CoV free though?

An article on news site France24 notes that no CORONA cases are to be found in the KSA ahead of the imminent commencement date of the hajj; a gathering of pilgrims that is already well under way.

Great. And may that remain the case for the next few weeks.

And I tend to agree that there will not be any "mass spread" of a virus that still does not show that potential.

But the story avoids an important fact - while inadvertently spelling it out. 

There have been no severe cases of CORONA - the disease - in the KSA in the lead up to the hajj. Severe enough to warrant triggering the strict measures...

"Employees have been given strict orders to isolate any suspected case and carry out the necessary laboratory tests" to ensure the safety of pilgrims on the hajj. 

To suspect, the Ministry of Health employees will first have to eyeball a fairly sick individual.

What about mild and asymptomatic cases of CORONA-CoV infection? We know that they happen. We know that means at some point the person is likely to be shedding virus (at some level for some time period). We know transmission between humans is possible, albeit limited. We know of millions of pilgrims visiting the KSA so while the chance of a limited transmission event happening may remain the same, the total number of such events could rise. We know that we don't know where CORONA-CoV is coming from. We know we have no idea how much, or little, CORONA-CoV infection is in the "normal healthy" population in the KSA because that testing has not been done. We don't know much about the circulation or proportion of cases due to the other endemic CoVs in the KSA because epidemiology publications about general respiratory virus testing is limited.

So why is testing and isolation of patients still limited to severe cases? We don't yet know that mild/asymptomatic cases don't shed virus. So what we may potentially see in the coming weeks is many ambulatory new cases walking around shedding virus until they transmit to one of those older males who have 1 or more comorbidities. Then we see a 2:5 chances of that person dying from an infection they cannot explain getting because they were not in contact with a severe case or a likely animal.

While we do not know the primary source of the CORONA-CoV - we do know that testing less ill people would let us answer an important secondary question; are the sporadic infections actually due to human-to-human transmission events that are simply not being identified or sought? This method of spread doesn't discount the viral genetic diversity we've recently learned of either. There could still have been multiple spillover events from animals - each may simply have spread more widely throughout the community than we know.

Please, please do some prospective testing. It would be an answer - and we have too few of those for CORONA.

Thanks to @makoto_au_japon fr posting the link to the France24 article.

Happy 1st birthday Middle East respiratory syndrome coronavirus (CORONA-CoV)

A coronavirus schematic. The spiky bits give the virus
its name(corona=crown) and represent the
receptor binding, antigenic Spike protein. 

...I can remember when you were just a novel little thing.
How you have grown young prince and how clever of you to emerge in a Kingdom of all places (corona=crown, named for it's spikey appearance). You've certainly garnered attention worthy of a King given the relatively few cases of disease you gave been associated with in the first year we've known of you.

It was September 20th when Dr Zaki 1st alerted the world to the death of a Saudi man due to what looked to be a new coronavirus (CoV). Today we have over 135 cases 58 deaths (43%).

I've previously covered Zaki's disocvery and the problems posed for the Kingdom of Saudi Arabia (KSA) by the way in which he announced that discovery, apparently without the Ministry of Health's (MOH) foreknowledge. The way in which the sample was exported from the KSA without their prior consent was also problematic for them.
Soon after we heard of it, we had virus-detection assays with which we could seek out new cases. Were they used as they might have been in the days of the SARS-CoV? Nope. And there still seems to be only a single laboratory in KSA testing for CORONA-CoV (despite reports of 3), with Dr Abdullah Al-Aeeri (a director of hospital infection control) claiming a 72-hour reporting turnaround time.

Is there an antibody detection assay that has been validated using a panel of known positive sera? Nope. There are some innovative antibody-detection methods around but why do they only include a single positive control? Is there no collaboration at all? Why is the KSA not leading the charge to develop these diagnostics and to hunt for an animal host? Why wait on advice from external organizations to screen samples? Why has the necessary testing capacity not been built well before now? Is it to do with that pesky material transfer agreement? I hope not because there is little evidence for that being a real block to anything from a public health standpoint.

At least we have some new CORONA-CoV sequences to celebrate the birthday with. Although they and the 9 preceding them represent less than half of the relatively small number of cases described to date. Why can't the typing region sequences be released? That should really be part of the diagnostic process. Okay, those may not inform us about the evolution of key regions of the virus but they do confirm it is the strain we know. Why not focus on full or subgenomic Spike gene sequences? They might be a better sentinel for keeping tabs on CORONA-CoV change over time.

Most of the detail about CORONA-CoV and cases of CORONA has come through the peer-reviewed scientific literature. That is pretty normal for respiratory viruses that are not notifiable. But it's generally a slow medium. Is CORONA infection a notifiable disease? It is in some countries (e.g. the US and New Zealand), but is it at the epicenter of the outbreak, the KSA? I'm not sure. It's not obviously stated as such anywhere I looked on the KSA MOH website.

The World Health Organization politely notes:

WHO encourages all Member States to enhance their surveillance for severe acute respiratory infections (SARI) and to carefully review any unusual patterns of SARI or pneumonia cases. WHO urges Member States to notify or verify to WHO any probable or confirmed case of infection with CORONA-CoV.

How's that been working out? In a nice summary of the lack of communication, Helen Branswell and Declan Butler highlight that, as usual, everyone  who was asked agreed that it's not working out well at all. In fact it's pretty woeful. And to add to matters, the latest WHO Disease Outbreak News (DON) takes the form of a summary of 18 "new" cases; no extra or confirmatory detail to be had from it. SO the KSA MOH is now the source for detail.

If we were talking about wanting more data on the monthly proportion of rhinovirus infections, the KSA would be justified in saying that the world doesn't need to know (I'd like to but that's my thing). 

If we were talking about influenza, then there are plenty of international public health sites publishing these notifiable data on the internet; here's Queensland, Australia's for example.

But we're talking about an emerging disease which kills half of the people it infects, is caused by a novel virus for which no host is known, which transmits between people in a way we don't yet understand, which is shed from ill (or well) people for an undefined period of time (if at all), which remains infectious in the environment for who knows how long, which jumps to other countries, which may only cause severe disease in those who are already ill with another disease, which may be endemically spreading within the community as mild or asymptomatic infections, for which there is no vaccine or proven antiviral therapy available..I'd say it's a no-brainer that at the very least the WHO deserves regular and detailed updates of what's going on. Reading between the lines, that does not seem to be happening even behind closed doors.

The mass gathering of pilgrims known as the Hajj is fast approaching. This may trigger a large increase in CORONA cases or, in the worst case, a pandemic. I personally believe it won't go that far. We shouldn't forget is the 2nd Hajj for CORONA. But perhaps the virus is much more widespread than it was in October 2012. But without testing data, we can only guess.

So, it's your 1st birthday CORONA-CoV. But instead of wishing you a happy birthday you opportunistic, spiky little killer, I'm wishing Dr Zaki well and congratulating him on co-parenting the birth of this novel coronavirus. Going by what we've seen to date, his actions may have been the only way we would have ever heard of this virus otherwise.

And, as noted previously, but not given much air to in the above rant (thanks to @MicorbeLover for straightening me out)...

It's very sad that there are real people in these numbers who have died from CORONA. 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. 

The MOH says it better in anyway; May Allah have mercy upon the deceased.

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 CORONA, 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.

Helix...a show about dual use research of concern (DURC), black goo, pretty people and an absence of grounding in good virology [EDITED]

I'm not really here to critique TV shows but this one has some "virology' in it, so I'm making an exception. 

Plus, I've been yelling at people about it. So time to rant in print and get it out of my system.

I was really looking forward to this show turning up. 

Let me start by saying that I really enjoyed the tension and the creepiness of the first 3-episodes. I really liked the old school music counterpoint and the potential paleovirology which could make for a great premise for some really mystical creepy virus stories. I'm enjoying the 70s-style Arctic accommodation, somehow made made modern, and I'm a fan of Billy Campbell, Hiroyuki Sanada and Ron Moore's work. I've had many hours of enjoyment and great story telling from Lost, Contact, The X-Files, 24 and BSG. But Helix is not any of them because it doesn't convey respect for its audience.

But mainly? Dude. The "virology" is a major fail and really pulls me out of any willing-suspension-of-disbelief I'm trying (hard) to get going. I think that may also be a problem for a (majority) non virologist audience. A general audience knows what "feels" like professional science and what feels just plain flaky. 

I guess I'd been hoping for something more Contagion'esque; grounded in today's reality, well informed, taking itself seriously and telling interesting stories using believable characters. Having watched 3 eps, I sum it up as more Outbreak-meets-28-days-later with dual-personality-but-still-angry zombies. I reckon it needs to make the material stand apart or at least do more to improve on what's come before. We probably have enough zombie+virus variations to not need another one unless it stands out. Maybe that's what the unmoving snow-plough is for. Or maybe there are some huge twists coming that will make me look like like an idiot (or perhaps the typos have already done that). Hope so.

Some (by no means all) nerdy comments and questions follow. Spoiler alert also, if you haven't seen the 3 eps that have gone to air so far.

• What is it about this, or any retrovirus outbreak for that matter, that shouts "hey, I'm a retrovirus and I'm breaking out" to Arctic non-virologists? What retrovirus symptoms are so acute and worrying that a CDC team would have been called in? What retrovirus causes you to bleed out and die? Oh, and melts the flesh from your bones as well? How did the Arctic guys identify it was a retrovirus before asking for help?
• A "Spherical" worm virus? Clearly nothing like a retrovirus.
• "The cells are heavily damaged almost totally deformed, it's like..Armageddon down there." says senior post-doc.
                      "But no sign of a virus?" says junior whizz-kid post-doc. Ouch. C.P.E. I'ma geddin outta here.
• 15nm (?could have been 5 or 150 - was hard to hear) on an electron microscope (EM) screen...that clearly shows a scale of 8,000nm...pretty good on-the-fly size estimation young whizz-kid post-doc.
• Portable, real-time, high-magnification scanning electron microscope (SEM), adjustable with a focus knob, that can also show CG wormy virus entering cells that then instantly shrivel without the SEM killing/breaking down the cells or the virus? Also totally unlike the Helix show logo which looked more like the cell, but was black yet not shrivelled. I'm so confused.
• What's with the unofficial CDC logo - or lack of the official logo? The show is not even supported by the CDC but uses "CDC" a lot?
• "...screened for all current viral structures..", "...even icosahedrons". What are the chances that they even looked for icosahedrons??? Its not like they are a hugely common presence in the virus world or anything...Oh.
• This unknown illness caused by a "retrovirus" or whatever, is to be worked with under Biosafety Level 4 conditions (BSL4) and yet considerable work is done on open benches without any significant personal protective gear. Of course that's all after the pathogen is defined as not being capable of spreading via an airborne route. Apparently there is just one type of airborne spread and droplets and aerosols generated by a number of techniques and procedures...and gunshots...don't count.
• You take off your BSL4 suit because a mouse doesn't what? Die in a matter of minutes...perhaps hours? If wormy virus is enacting annihilation upon it's human hosts then I'd like to at least see a monkey if not some decent primary human (because that's the host we're most worried about it annihilating) cell-culture results and inflammatory marker data before I started breathing that air! We do see a (creepy, angry) monkey later, but the protective gear doesn't go back on, or ever get put on in some cases, and then in later episodes it does, then it's off again, then a non-sealing surgical mask turns up...argh! BSL4 being optional must be part of the working-without-regulations mantra up there in BigPharma Arctic world 
• In a later Ep we develop a test using green fluorescent protein. GFP is  from the jellyfish Aequorea victoria our over-sharing young whizz-kid post-doc states; although she states nothing about how this bloody rapid bedside test works nor how she produced it without any cloning at all. It gets combined with an infected patient's white blood cells. A huge volume of the GFP-containing, virus-sensitive, previously infected patient cell solution glows green (under normal light) just seconds after a huge volume of the infected patient's sample is added. 96-well plate guys? Mind you this was all developed without validation and within half an hour or so; exemplifying how great the 26-year old whizz-kid post-doc with 2 Masters degrees is in the lab. She told us she was earlier. Later we see why unvalidated tests based on poor science and rushed to market fail so spectacularly. More on that in Ep 4 I suspect.
• Hey, anyway, let's go conduct a monkey autopsy with just a face shield that is in no-way sealed to our face. And what the hell, why even bother doing up that lab coat? It would just ruin the belligerent devil-may-care researcher vibe we're aiming for. Aerosolized bits of diseased freaky-monkey tissue in your eyes/mouth/nose/lung anyone?

Where World War Z succeeded in providing a great story about a virus wanting to transmit by driving its host to infect more potential hosts, Helix fails by clubbing us over the head with a show that feels like it's leveraged science thawed from an Arctic vault constructed in the 90s. 

While I don't expect the general audience to know that centrifuging a drill core of frozen solid monkey butt will not just transform it into a homogeneous black liquid in 5-sec (or ever), I do think they will notice something is amiss. Off beat. Out of  sync. Even if it is set 5-min into the future or something.

Try making Helix smarter. I like that there is a story about DURC that may get to a wider audience. That and the suspense are probably the biggest draw-cards for me. 

This needed/needs an infectious disease expert on the advisory team. A virologist in this case. Just as disease outbreaks do in real life. Just as the movie Contagion had - and for that movie, it really paid off.