Thursday, 8 May 2014

Pressure testing...

Comments in the recent ScienceInsider article (a great read by the way [1]) interview with Prof Christian Drosten got me to thinking.

What follows is a stream of consciousness around the need, or not, to expand laboratory testing capacity during times of an acute rise in cases such as during a viral cluster / outbreak / pandemic situation (COP; just made that up-it's not an official acronym or anything).

During a COP, the workload in a diagnostic virology/microbiology/pathology laboratory is dramatically increased. More samples, more often. And this is due to the testing of just 1 added virus. Often, the biggest impact on service delivery comes from the need to add a new test for this virus which may not have been part of any existing testing menu or panel; it adds to the number of tests already being run. In one major Australian laboratory, routine diagnostic testing for non-influenza-related diseases runs at ~1,000 tests/day.[2] In winter, Australia's peak season for influenza, this lab (Victorian Infectious Diseases Laboratory or VIDRL) would normally test ~100 samples per day for that 1 pathogen, but during the influenza A(H1N1)pdm09 pandemic, one day saw 1,401 tests done for it alone.[2] Impressively, these guys kept to their usual result turnaround time (TAT).

Such a response requires coping with extra paperwork, quality control, and the creation and implementation of new protocols, perhaps overcoming special specimen reception issues and specimen handling requirements. There may be delays in getting specimens to the lab and a need to enrol other (previously quality assured) COP assistance laboratories to cope with the load. Less urgent testing and research may be halted and even expanded lab space may be sought in adjoining areas. This all create some real impact. It can affect other results, it may impact on the TAT for a lab (although prior planning is aimed at coping with the strain of COPs and keeping the result TAT in check as happened in the example above). A COP strains nucleic acid extraction robots, centrifuges, bio-hazard safety cabinets, labelling machines, pipettes and thermal cyclers - all of which break down when you least need them to. Reagents may become rare and if not stockpiled could create a bottleneck in assay performance - basic PCR assay reagents may be hard to come by or slow to receive, especially during a global and/or sustained outbreak or pandemic. And very importantly, there is a real toll on staff and managers. Hours may be extended, tiredness and stress will set in and a shortage of expertise may be an issue for maintaining quality and TAT...and sanity

In other words, test results don't magically appear and diagnostic labs are nowhere near as automated as you might think.

All this adds up to a system that can reach its capacity and thereafter shows signs of stress. The influenza A(H1N1)pdm09 pandemic did this. Now we hear of that MERS-CoV may be creating a similar circumstance in the Kingdom of Saudi Arabia (KSA). Why is the KSA Central Laboratory, which does all the PCR testing for MERS-CoV, under such stress now? According to Prof Drosten, it's because of changes in the testing which may be a driving factor underpinning April's Jeddah surge of viral detection.
Something dramatic changed, and that is the case definition.
Prof. Drosten to ScienceInsider

This change led to a jump in testing from 459 samples for all of 2014 prior to the outbreak, to 4,629 in just 1 month. As the number of MERS-CoV tests being performed in each (daily) report of new cases is no longer part of the KSA Ministry of Health's (MOH) message, a thumbnail sketch is that 154 sample per day are being tested for that month (divided by 30 days). And then there was this comment..
"The question of whether there is a mild, short-lived infection in some people is scientifically interesting. But in cities like Jeddah, it is bringing the health system close to collapse. That is the big problem. So many samples are being tested that the lab capacity won’t suffice for the real cases."
Prof. Drosten to ScienceInsider

An entirely fictional map of MERS-CoV spread including
severely ill, mild/moderately ill and prodromal /
asymptomatic infections. Simply intended to be
something to think about when discussing the
impacts of limiting PCR testing. Reduced PCR
testing should not happen until until we know which
parts of this map are real, and which are a load of rubbish.
With this background and these comments in mind I have some thoughts and questions...


  1. I know almost nothing about the KSA's pathology laboratory testing capacity generally nor its approach to respiratory virus testing in particular. I do know that the KSA is are a country of around 29 million people while Australia has around 23 million. I refer to the numbers above when I say that 4,629 samples in a month, for what has become an epidemic that seems to have exposed major flaws in infection control across multiple hospitals around the west, south and central regions of a wealthy country, should not be threatening the KSA's testing capacity unless it did not exist in the first place.
  2. Why wouldn't pathology testing which is robustly designed to cope with a worse-case-pandemic, not exist in the KSA? I don't know. Does testing exist for standard virus screening and if so what sort of throughput is the norm? The KSA healthcare systems seems to be laden with western-influenced medicine, and with that influence comes our compulsive need to create protocols and preparedness plans and to learn for the misfortune of others. The WHO have all this sort of information publicly available and always seem available for a chat.
  3. The reality is, and I am not on the ground to see whether this is a real factor in the KSA, laboratory capacity needs to be such that it can cope with a surge in cases such as that during a COP. It also needs to manage other endemic respiratory virus testing and whatever is coming next. It seems highly likely to me that the same at-risk older male population with kidney and heart disease, diabetes and obesity issues that get hit so hard by MERS, is also suffering badly from influenza and other viral infections. Back in August we heard about additional laboratories coming on line. It looks like they may not have. They need to.
  4. Am I especially naive (probably) to expect wealthy countries to make sure something as important as pathology testing is not in danger of falling over when it's particularly needed? We expect our electricity to be quickly reconnected after a storm, out SUVs to be easily refuelled no matter what wars or disaster befall the worlds, we take for granted that water is just there and we'd riot if our shop were not stocked with food 24/7. Why would testing your population to make sure you have a real-time knowledge of the pathogens infecting them, not be given an equal measure of attention and support? Especially if that pathogen has never been seen before, is transmitting without your understanding and is killing 1:4 of those it infects?
  5. Prof. Drosten noted that he has been working to get good MERS-CoV antibody testing in place within the KSA to get a better idea of how widespread prior exposures to MERS-CoV is. That will be a very helpful piece of knowledge to have. But it will not tell the MOH what is happening now in Hospital X (an apt name since we no longer know names of the hospitals where cases are being treated; that dropped off the new MOH messaging format last night). We're not even sure MERS-CoV antibodies are produced if the PCR-positive person only had a mild or asymptomatic case. PCR testing must remain in place until the MOH or whomever it looks to for advice, can be sure they have seen all the faces of MERS and the MERS-CoV. We're some way off seeing that yet I believe.  Don't get me wrong - an antibody test is great and we should roll it out alongside PCR. But in context - it will tell us information about the status of the KSA population in terms of how many have been exposed to MERS-CoV. And then it will have done its job as a research tool. Routinely, we need to test with the gold standard; PCR. And I think we should keep testing widely. 
  6. Prof Drosten also suggested that instead of continued PCR testing of contacts (the source of asymptomatic cases presumably), the KSA should consider a home isolation approach. Would that be  for up to 2-weeks, away from work, school - away from family too? Seems like a lot of hassle and disruption for the sake of a PCR test. Perhaps a shorter period once we know more about the dynamics and shedding during the diseases prodrome or from asymptomatic people. That will require PCR to define a person was initially MERS-CoV positive in order to study whether virus is shed.
  7. Let's also keep in mind that antibody testing is labour-intensive too. Perhaps not as intensive as PCR, but it would still increase the workload on a pathology laboratory.  It's a new tool not a better one.
  8. Why do I think the KSA should keep testing widely? Because if we don't we might be missing mild and asymptomatic or prodromal cases which may (and we have no data to support the argument in either direction right now, so its much better to be safe and test as the World Health Organization advise) contribute to the spread of MERS disease. Who knows how much virus an already old ill male needs to become severely ill? Perhaps much less than a healthy young nurse with lots of previous exposures to other viruses, including some that may provide cross-protective immunity I suspect. 
  9. If the KSA had not switched gear and accelerated into more testing, we would still only know the face of MERS that is pneumonia and death. It is clearly a lot more than that-as are all respiratory viruses. It would be a great shame in my opinion, to do things the way they were done with SARS, just...because. We always need to look afresh with the knowledge and tech we have to hand on the day.
Now more than ever with new measures being instigated to educate the KSA public (a bit more anyway), reduce camel exposures (although it's clear many don't see a link to camels as justified) and improve hospital infection control (too late for the majority of MERS cases that seem to have occurred in linkage with healthcare facility outbreaks) and hospital triage of MERS cases, testing efforts must not wane.

And while that goes on in the background, it really is past time to sort out some transmission details. How is the virus spread (a) from and between camels and (b) to and between people? These are fundamental questions and all risk reduction hinges on their answers. 

At least now that we know the virus hasn't changed, we shouldn't be seeing any more cases during the upcoming multi-million person Hajj pilgrimage, than we saw last year. Right? Last month was all about an infection prevention and control breakdown that can be fixed before October. Yes? And the few instances of Umrah pilgrims that seem to be popping up positive this year that we didn't see in 2013 and the bunch of single export cases? Just increased testing? Yup. Some of that even kinda fits in with what I wrote about Umrah 2013

Oh look. 10 new cases tonight, just like on 2013. Oh wait. No it wasn't like tat in 2013. We didn't have any 10-detections/day days in 2012 or 2013. Guess these will be because of all the pesky asymptomatic people? Let's see...ICU, hospitalised, ICU, symptomatic but home isolated, ICU, ICU, asymptomatic, ICU, asymptomatic, hospitalised oh and in two most likely unlinkable previous cases: death, death. 2 out of 10 with no symptoms. 

Definitely keep up the testing guys. MERS isn't SARS but then 2014 isn't 2013 either.

Sources...
  1. http://news.sciencemag.org/health/2014/05/mers-virologists-view-saudi-arabia
  2. Reality Check of Laboratory Service Effectiveness during Pandemic (H1N1) 2009, Victoria, Australia | Emerging Infectious Diseases. 2001. 17(6):963-
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358210/pdf/10-1747_finalS.pdf
  3. http://www.nccid.ca/files/Evidence_Reviews/NCCID_H1N1_impact_04.pdf