VDU's blog: lab testing

Showing posts with label lab testing. Show all posts

Monday, 11 April 2016

Colombia...no recent confirmed Zika virus positives or reporting lag or...?

UPDATE #1: 24APR2016

Okay. Let me rephrase an issue I had from one of my posts yesterday-the one looking over the Colombian data. The relevant text was...

"I'm still not clear how the tally of confirmed cases is rising, but not showing up on the Colombian NIH graph (the red bars; the grey ones are clinical suspected cases).

I've excised and posted the Colombian NIH graph to the left. 458 cases this week should show up clearly using that axis - it was the second biggest tally, just below Week No. 8 (also missing?) and 1.6X bigger than Week No. 4 which has been plotted and shows up clearly. I'm just assuming that the graph person has forgotten but would love to know if there is something else going on."

Below I've excised the relevant graphs from the most recent epidemiology report (Week No. 13 [2]) and also the one that first plotted confirmed alongside suspected Zika virus (ZIKV) cases (Week No. 11 [1]).

You can in fact see that the red bars have grown over the 3 week period - but that none of the 700 confirmed cases reported over that time have visibly made it into a bar after Week No. 5. So my question is whether that means:

no newly confirmed ZIKV cases have been detected/become ill during the past 8 epidemiology weeks (keeping in mind that Week No. 13's report only reports data to 02APR2016)
there is an 8-week lag in getting lab data into these reports?
Someone forgot to update the graphs
Colombia is no longer testing for ZIKV

..or perhaps something else altogether?

Week No. 11.
Data from [1]

Week No. 13.
Data from [2]

The lag seems to be the leading theory so far (see Tweet below)...but that's quite a lag.

@MackayIM @INSColombia graph reflects adjusted reported cases per wk. not #s on table. "New" confirmed may be old. Wk12 only 1,100 on graph
— Gabby Molinolo (@gabby_molinolo) April 10, 2016

I find it strange that no-one seems to be critical of the testing lag here and yet it was the topic du jour for MERS in the Kingdom of Saudi Arabia.

Is it simply about the perception of resources - the Americas are perceived as resource-poor and the Saudis as resource abundant?

In the area of lab testing, I'm not at all convinced that the Saudis were at all resource rich though. I don't think they were in any better position at the start of their outbreaks. Especially if the resource we measure is understanding about testing to understand the aetiology of an emerging infectious disease.

References...

Updates...

Added a new 3rd option which was not carried over from the orginal post 10APR2016 - and pushed the previous 34rd to 4th

Sunday, 27 March 2016

Zika virus is a testing problem for science...

Edited by Katherine E Arden, Ph.D.
UPDATE #1: 30MAR2016
UPDATE #2: 08APR2016
UPDATE #3: 30MAY2016

I need to get this off my curmudgeonly chest.

I've watched the Zika virus (ZIKV) "event" since January 2016, back when I said this...

I think Zika might be my 2016 virus.
— Ian M Mackay, PhD (@MackayIM) January 3, 2016

...and wrote a small overview while on holiday.[1]

Since then I've been, on an almost daily basis, alternately and in no particular order disgusted, amazed, shocked, horrified, stunned, disappointed and flabbergasted by the quality, type and amount of detailed information available, about the discussion around that information as it comes out, about the language used and the assumptions underpinning the discussions that have occurred. In short - too many assumptions, too little virus testing data and too many people impatiently rushing to conclude that correlation is the same as causality.

The communication of being sure, or unsure...

There was a confusing comment from the Director General of the World Health Organization, Dr Margaret Chan. Keeping in mind that this is the organization that suggests how to communicate risk to the community in their document Risk communication and community engagement for Zika virus prevention and control: A guidance and resource package for country offices for coordination, planning, key messages and actions.[2]

Dr Chan: Though the #Zika-fetal malformations association is not yet scientifically proven, the circumstantial evidence is now overwhelming
— WHO (@WHO) March 22, 2016

So we are overwhelmed by non-evidence, despite the evidence not being available yet? How far from actual evidence is that?

Before this, WHO has been good at saying "looks like something different is happening with ZIKV but we don't know much more yet. In the meantime we're doing things that facilitate reducing the known vector, the mosquito, and bites from them, we're ramping up the testing and the science and we're moving things along on the vaccine front, but we're not putting all our eggs into one basket just yet."

Why are so many so hell-bent on jumping the gun on ZIKV?

WHO's science meeting reviewed evidence linking ZIKV infection with foetal malformations and neurological disorders and advised that the implication from the evidence was that the link between microcephaly and ZIKV was looking real.

Dr Chan said "If this pattern is confirmed beyond Latin America and the Caribbean, the world will face a severe public health crisis" - absolutely true.[22] But this still remains an "IF" for now.

Lab testing and reporting from Brazil needs work...

Among the 6,671 suspected diagnoses of microcephaly in Brazil - the rapid rise for which WHO called a Public Health Emergency of International Concern (PHEIC) - just 122 (1.8%) have any current laboratory evidence identifying that ZIKV infection - past or present - occurred. If there are more laboratory testing data from Brazil to fill this huge gap, they need to be talked about.

Brain injuries...

Microcephaly diagnoses and congenital brain malformations, which are rare diagnoses overall, have been occurring worldwide for a long time.[4] I don't know for how long - perhaps throughout human history? So if the epidemic of ZIKV is actually driving a sudden rise in microcephaly and foetal brain deformity diagnoses, plus meningitis and Guillain-Barre syndrome cases, those diagnoses should be higher in number than what is normal for Brazil.

Finding a baseline on which to base the official line...

The rate at which microcephaly diagnoses have been reported in Brazil still awaits some type of overall agreement.[13] In the north east, individual reports quote doctors, such as the van der Lindens, who have personal experience in seeing dozens more examples of microcephaly and brain malformations from August 2015 onwards than they had been used to seeing.[11,12,26,27]

This widely reported evidence is hard to deny despite being anecdotal-the doctors and their collaborators are yet to publish their observations.[25] NB: New paper describing 105 microcephaly diagnoses infants born in Pernambuco State, Brazil was released after this post, including a van der Linden as author, but has no ZIKV testing.[29] A second study with a van der Linden finds ZIKV IgM in 7/23 microcephaly diagnoses.[30]

In this extrapolation, 2 and 12 are the limits of the

range of microcephaly diagnoses

reported by the US CDC.[24]

Publications still appear which use the initial rates of ~150 microcephaly diagnoses in Brazil per annum - about 0.005% of 2.9 million annual live births.[5] This is despite data and others' analyses suggesting that these may not be realistic rates. [6,7,8,9,10,14]

The reported 'spike' in diagnoses might not be above, or as drastically above, normal figures for Brazil, or certain regions of Brazil, as at first thought. But even this fundamental knowledge remains unclear.

The vector in Brazil is probably something...

No mosquito species in Brazil has yet been identified as a carrier of ZIKV.[3] Testing is being done but no report of a mosquito testing positive for ZIKV have emerged as yet.[3]

It's not clear whether this extra information would have any impact on the more general mosquito-reduction measures that have been rolled out - spraying, fogging and poisoning.

However, might this knowledge gap have an impact on some species-specific anti-mosquito measures, such as those involving interfering with mosquito mating or reproduction?

We assume that the Brazil vector is Aedes aegypti because that's what's been the culprit elsewhere and because they can ingest and become infected by ZIKV.[17,18,19,20,21] Other Aedes species also stand accused, as does Culex quinquefasciatus.[23] So this too remains unclear.

Some clarity falls out from between the gaps...

From among all these gaps has recently fallen an article that makes sense.[15]

No, it didn't support any causal link between ZIKV presence and any sort of brain damage in foetuses.

It just describes the genetic findings from analysing 7 ZIKV genome sequences from 4 human cases and made a modelled estimate suggesting that ZIKV was in Brazil from May-December 2013. This may sink the canoe hypothesis.[28]

That date could still change if other sequences are found of course - such as older ones in stored specimens. But it's a nice estimate for now. It may also explain why microcephaly diagnoses were predicted to have been high prior to 2015 according to the Mattos report,[6] if ZIKV is indeed a new and sizeable cause of the burden of these diagnoses. While this paper tells its story with lots of dense detail - as befits a paper in the journal Science - it takes a little bit of extra time and space to clearly and plainly state what the data do not mean (see the quote above).

This sort of extra detail is so very important. It shows that the authors have thought through their work and placed it in a bigger picture and it helps those who may be looking to paraphrase the study to see that it has limitations that should be mentioned.

This really shouldn't be something to praise - it should be the norm - but in many of the Zikaglyphs put into print this year, care has not been taken, too many assumptions have been made and too little thought has gone into the complexities of trying to associate the presence of a pathogen with a disease that is occurring at the same time, or some days, weeks or months later on.

So maybe there is still some hope to be had that science and the media will start talking more frequently and clearly about what we don't know, what we haven't looked for and what other possibilities exist, instead of what we almost know.

"Yes, Zika infection during pregnancy can lead to brain-related birth defects in a fetus".[16]

Or maybe not quite yet.

In summary...

We do not yet have definitive scientific evidence of a causal link between increased microcephaly diagnoses, brain malformations and ZIKV infection.

That is not to say there is no such link, just that we have not yet gathered the evidence to confirm one.

Given the potentially severe consequences of the link being real, it is entirely appropriate that measures are being taken now to reduce exposures to ZIKV by potential parents of either sex.

Until data show otherwise, it remains possible that ZIKV is not to blame and so we need to keep an open mind, keep searching and keep carefully examining strong evidence, because if the cause is not ZIKV alone, or it is ZIKV working alongside some other factor(s), we are missing the boat and failing in our duty to help halt a severe public health crisis.

References...

Updates...

Added reference to a van der linden publication [29]
Added a reference to a second Dr van der Linden publication [30]
Repaired typos to Crawford Kilian's name

Sunday, 21 February 2016

508 confirmed microcephaly diagnoses in Brazil...let's just say they're all Zika virus related because...belief?

This comes from the 13th Brazil Ministry of Health's (MOH) Health Portal epidemiological reports on microcephaly [1] which spans from when microcephaly diagnoses began sometime during 2015, to the 13th of February 2016.[2]

With the aid of Google translate, the report states that 5,820 suspected diagnoses have been logged to 13FEB2016 of which 1,345 (25.5%) have been finalised as:

508 confirmed (37.7% of the finalised suspects)
837 discarded (62.2%)
60.1% were recorded in 2015 and 39.9% are from 2016 so far
The previous MOH report noted that 41 of the then 462 confirmed microcephaly diagnoses were somehow (mum or foetus or baby?) laboratory confirmed as being aligned with a Zika virus infection [4]

Geographic distribution of 508 confirmed microcephaly cases from 2015 and 2016.
Data and graphic from the Brazil Ministry of Health.[2]

But what absolutely flummoxes me is this translated text (highlights added by me) from the end of the report,[2] found in a big red "Heads up" box. In particular that highlighted in yellow:

The Ministry of Health believes that there was infection zika virus mostly mothers who had babies whose final diagnosis was "microcephaly and / or changes in the central nervous system, suggestive of infection congenital ".

Therefore clarifies that from this Report Epidemiological No. 13 concerning the epidemiological week 06, 2016, will disclose these confirmed cases, without specifying the laboratory diagnosis to Zika virus, because these data do not adequately represent the number of observed cases (magnitude).

Furthermore, from that moment, consider that all confirmed cases are related to congenital infection Zika virus.

All cases are individually assessed and submitted to a laboratory set of diagnostic tests and imaging (ex .: ultrasound transfontanellar etc.). A very small proportion of these cases, after monitoring and Specific analysis is confirmed for other causes, but they are so few children that does not change the assessment the trend (increase or decrease) the number of cases (magnitude). It is important to inform that the Ministry of Health participates in and supports the entire national effort directly and international for better understanding of this new disease and that every effort is being made to improve diagnostic methods and strengthen assistance to children and families affected.

I'm presuming this is because the MOH cannot get any samples from earlier diagnoses and thus cannot test them. Or perhaps they were negative and it has a "feeling" that they should have been positive.

No idea.

I have felt nothing but unease about the way Zikacephaly has been settled on via a process of accusation, summary judgement and instant public conviction during 2016 - via instances in both the media and the scientific literature.

I'm now in complete disbelief that a national MOH is relying on a 'belief' without further data or discussion, to officially communicate a message about the cause of a severe disease.

Why not rely on a careful analysis of extensive testing data? Do such data exist? Are they bottled up in the publication pipeline? Why not employ a more reasoned public engagement strategy whereby careful and balanced description of the the risks and all the knowledge gaps, is communicated to a rightfully worried community? And to the world, because no outbreak or epidemic affects the host country in isolation any more.

The battle to cull the mosquito vector and avoid bites was under way quickly, so why the need to point the finger so urgently when nothing additional can be done right now anyway? So we can get a vaccine underway? What if...heretical at this point I know, but what if Zika virus is not the cause of the surge in microcephaly cases? Gasp!! What a gigantic waste of resources and public faith in science we will have burned through because-belief?

Wouldn't it be better to undertake a more careful investigation and analysis before putting any more eggs in the single, lonely Zika virus basket?

Just to be clear, I don't for second discount that Zika virus could be the cause of microcephaly - but I'm not just going to put that in a text book until the studies have been done. Those studies have not been done yet and neither have any studies been done that discount anything.

As we can see in red above, there are clearly other causes of microcephaly being found in Brazil. Presumably these are some of the better known causes like in utero or at birth infections by the Toxoplasma gondii parasites, Treponema pallidum bacteria, rubella virus, herpes simplex virus, cytomegalovirus and human immunodeficiency virus or due to chemical exposures in the mum, including to arsenic, mercury, alcohol, radiation, and smoking or perhaps genetic abnormalities including Down syndrome or even severe malnutrition during development. Even if in small numbers-one or more of those things (which were not detailed by the MOH report) are clearly present and though to be acting.

Everything is still on the table as a cause of microcephaly in the north east of Brazil-as it always has been since probably much earlier than October of 2015.[3]

References...

Monday, 12 May 2014

VDU Quote for the night...

From:

Z.A. Memish et al.

Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study.

Clinical Microbiology and Infection, 2014.

"Surveillance studies also help in defining and monitoring transmission rates, case load, and epidemic risk assessment, and assist in instituting infection control measures with new diagnostic methods and treatments."

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...

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.
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.
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.
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?
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.
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.
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.
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.
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...

http://news.sciencemag.org/health/2014/05/mers-virologists-view-saudi-arabia
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
http://www.nccid.ca/files/Evidence_Reviews/NCCID_H1N1_impact_04.pdf

Sunday, 27 April 2014

If this is what MERS-CoV detections look like with more testing...what is the "normal" community level of virus?? [UPDATED]

The bar along the top depict how much time passed between each 100 cases.
Click on chart to enlarge.

For a virus that is chugging along without the aid of any new genetic changes, and perhaps showing up more often (a) because of enhanced testing and/or (b) because of a large-scale breakdown in infection prevention and control (IPC), this curve sure does depict the possibility that we had no idea how much MERS-CoV was transmitting among the population. Still a poor transmitter compared to an influenzavirus, because we have seen a few larger MERS-CoV studies than show few to no MERS-CoV positives, but still more people positive than we thought.

Can we really lay this rate of climb at the feet of poor IPC alone? Wouldn't that also mean that every other respiratory virus would do this too? Perhaps not if MERS-CoV was the only one capable of causing acute pneumonia. It isn't. So shouldn't all hospitals always be full of acute pneumonia and respiratory disease among older males with comorbidities? These are modern hospitals after all. Also modern doctors with great training and skills acquired from all over the world. Perhaps poor IPC plus enhanced testing is an option? Maybe. Probably most likely when combined with an outbreak that starts in April for an unknown reason.

What about this option, which focusses on testing alone? Better levels of testing are at last showing it like it really is in the Arabian peninsula? This options proposes that we've been underestimating the ability of MERS-CoV to travel from person-to-person, all along. An underestimation driven by testing only the "tip of the iceberg" of disease and just watching the rest of the iceberg from a distance? What if severe disease is only found in already ill older males and most (granted, not all) of the rest get milder or unnoticeable disease but do get infected? Yes, in the past 2 weeks 5,000 samples have been tested in the Kingdom of Saudi Arabia (KSA) to yield ~140 MERS-CoV detections (~3%). After the 2012 Hajj, 154 pilgrims were tested by Gautret et al and, despite a high proportion with respiratory symptoms (83%), none were found positive for MERS-CoV. At 3% in Jeddah, testing of the Hajjis should have yielded ~4 detections among this cohort if the distribution of MERS-CoV was at this level all the time. In screening 5,065 cases and their contacts (family and healthcare workers) over a year from 1st-Oct-2012, Memish et al reported 106 detections (~2%) and no significant rise in case detection rates over that year. So a very similar proportion of positive cases, and both Jeddah and this larger study have similar numbers and a roughly similarly broad population being tested. Of course, even endemic human CoVs are not always detectable every year at the same site. Some have a biennial periodicity.

So perhaps 2-3% prevalence, similar to endemic CoVs, is the magic number for MERS-CoV positivity? Which just leaves the question, why weren't more Hajjis positive last year? Or was that just a testing thing too?

Just wondering out loud here.

Wednesday, 9 April 2014

Ebola virus disease and lab testing...

This post has been moved to the new Virology Down Under platform on Wordpress.

You can get to this specific post by clicking on the link below...

https://virologydownunder.com/ebola-virus-disease-and-lab-testing/

Please adjust your bookmarks.

Apologies for any inconvenience.

Friday, 14 March 2014

Google Flu Trends: not so perfectly predictive?

I'm no expert at the algorithms that go into the search giant's Google Flu Trends (GFT) predictive website so take what follows as a very superficial opinion. It does not surprise me at all that a recent paper in Science [1], backing up previous chatter on this subject [2], finds GFT is is not very accurate. Specifically, it has been overestimating peak influenza levels compared to more traditional laboratory-confirmed cases (itself only a subset of all cases) and influenza-like illness presentations to Doctors (a non-specific method of trying to identify influenza from a swarm of other ILI-capable viruses).

A note: this recent paper is more a look at big data and whether it deserves our complete trust yet (it doesn't, is the message) than it is an analysis of how best to predict influenza virus activity in the future.

It would be fantastic if we could have a predictive system that could work around the need for actual testing of sampled people and give us an informed guess as to what flu was doing, how long it would be doing it, how severely it would do it and when it might start and stop doing it...I just don't have a lot of faith in predictive things like this. Perhaps I've just entered into a grumpy middle-aged male phase of my life....but I think that if we want to find out what's happening, we don't need to look too much beyond simply (not so simple when it comes to lab capacity and funding of course) upping the level of testing and typing that we do.

Even now, the current situation in Queensland of a 2-fold increase in influenza virus notifications compared to the mean of the past 5-years does not really show up so clearely on GFT.

Given that so many variables will contribute to a person's choice to search for "flu" (or whatever related text GFT includes in its algorithms), it makes perfect sense that a website showing flu activity in your area that is based on that component of the results, will be an over-estimate, especially during the peak times of flu activity. Why then? Imagine the impact on search when the media is most active in trying to get your pageviews using headline banners with "killer flu" or "early flu season" in them. People don't just chat over the back fence in response to those headlines any more, they go looking to the internet to provide their answers, news and sometimes poorly communicated facts. This will not just indicate that the have the flu, it will reflect concern that they may get it at some point in the future.

GFT also taps "real" flu data from real testing labs and Doctors clinics. This means its performance is probably not "off the rails" wrong, just overly influenced by non-infectious factors at peak times.

Are the inflated results positively affecting flu vaccine uptake I wonder? That would be a good thing. Might even have an impact on the size of the peak season.

Of course, no one knows what the actual numbers of flu cases in the community are; because flu is not always a serious disease that leads us to get a sampled collected and tested. The serious disease gets to a hospital and does get tested. these get added to notifications. Sure, influenza virus can cause a more serious outcome than many other respiratory virus infections, especially in certain groups, including death on occasion. There are also many mild infections that fly "under the radar". Those numbers won't be accounted for anywhere except through modelling. Perhaps the overestimate isn't that much of an overestimate; very hard to actually know that.

It's that damn iceberg tip again.

References...

Saturday, 1 February 2014

Neither market nor farm poultry all that positive for H7N9; songbirds the culprit...?

Following on from yesterday's post, "If not poultry then what?", I thought it worth noting the impressive numbers from the Chinese Ministry of Agriculture.

From 2013:

1,630,000 poultry and environmental samples tested

88 POS; all from live bird markets
None from poultry farms

From 2014, to date:

33,400 poultry and environmental samples

8 H7N9 POS; all from live bird markets
None from poultry farms

The other alternative to answer the question in my heading; the testing methods are at fault.

No detail of what approach has been used to obtain these numbers in the links below. Viral culture and serology with some PCR have been noted before. I'd wager culture yields chicken scratchings compared to PCR for detecting virus in he wild; but serology has successfully been a pillar upon which animal testing rests. So that's why the numbers above are such a quandary for the epidemiologist who reads about the high frequency of links between human disease and exposure to poultry.

It would be nice to see some technical papers on antibody test testing (development and validation) at some point. If only to reassure everyone that the testing methods are doing what testing methods should be doing.

See #3 below for influenza PCR discussion at WHO.

Sources..

Monday, 13 January 2014

H5N1 case in Canada had been diagnosed with pneumonia...testing at the source would have been helpful

And now, from a fantastically detailed post onto ProMED by Fonseca and colleagues, we see that the H5N1 case was diagnosed with pneumonia.

On 28-Dec, the patient presented to a local emergency department.

"A chest X-ray and CT scan revealed a right apical infiltrate. A diagnosis of pneumonia was made; the patient was prescribed levofloxacin and discharged home."

One sad point made in the ProMED post which supports the need for constant viral vigilance the world over, coupled with the dissemination of those surveillance data, so that patient management anywhere in the world can be armed with the best possible decision-making information...

"The index of suspicion was low as travel was to an area in China where there have been no recent reports of the circulation of this virus, and coupled with no obvious exposure to poultry, the diagnostic work-up and consideration for A(H5N1) infection was very low"

As a recent J Virology article by Yu and colleagues highlights, when a sensitive testing method like the polymerase chain reaction (PCR; in this case RT-PCR because influenza viruses all have an RNA genome, not a DNA one) is applied to the search for a virus, it yields the kind of data that can:

Explain from where a virus emerges
Inform the search for disease aetiology - where are human cases getting infected from and if a zoonotic infection (from animals to humans), which animal(s) is the culprit?
Alert the world to any risks of infection when travelling to a certain area(s)
Allow the local health departments to mitigate the risk of their population acquiring infection by instigating controls (like live bird market closures). This has implications for the world since respiratory viruses have the potential (thankfully not realized for H7N9 or H5N1 to date) to spread more rapidly and efficiently that blood-borne or mosquito-borne or sexually transmitted viruses.
Permit understanding of how widespread (over what geographic area is it detected) a novel or emerging virus may be and how entrenched (is the same site repeatedly positive) it is

Not doing such testing, or using less sensitive methods will not yield this information.

In Yu's study, testing of 12 poultry markets, mostly urban, and local farms linked to 10 human infections in Hangzhou, Zhejiang province around 4th to 20th April 2013 yielded signs of H9N2, H7N9 and/or H5N1 viruses in all markets. Poultry were often positive for H7N9 and H9N2 (this finding from individual RT-PCRs was confirmed using next generation sequencing), whereas human specimens were not. These levels hadn't been turned up when 899,000 bird were tested in 2013 using (perhaps) less sensitive methods.

I think with influenza, it may be safer to presume its everywhere until that presumption can be discounted. Clearly the conditions for influenza viruses to swap gene segments and sort themselves into new subtypes and variants are commonplace and frequent; these aren't just chance occurrences of different birds passing in the night via overlapping flyways. These feathered vectors are co-infected by 2 or more viruses at a time. Luck and the constraints of viral fitness are presumably the only things keeping H7N1, H5N9, H7N2 cases from dialing up in humans? What seems to be lacking is more molecular testing at the farms supplying the markets. Not just in Zhejiang, but all over the region.

As the authors noted, 100,000s of people visit these live bird markets each day and very few influenza cases seem to be due to them. Long may that last. But it's a tinderbox for which matches are already being struck; if the viruses should bud of that one-in-a-million variant that is enabled to readily spread from person-to-person, whooshka.

More testing guys, keep testing.

Tuesday, 22 October 2013

Hajj pilgrims return around the world...is lab testing happening?

Media and Ministry reports are filtering in from many different countries that their Hajj pilgrims have been safely returning from their pilgrimage.

To date there have been no reports of Middle East respiratory syndrome (MERS) disease in any pilgrim.

I presume this is all observational diagnosis? It would be very interesting to read whether any actual laboratory testing is occurring in any of these States. If it is, are the pilgrims PCR-negative?

What observation alone cannot tell us is whether a pilgrim infected but not showing signs.

Self-reporting of mild disease without overt signs, can be problematic and may bias away from capturing all cases in the absence of laboratory testing. If cases do enter a State "under the radar" they may still shed virus to others in their new locale. Some of those others may be older males with comorbidities; the MERS coronavirus's (MERS-CoV) highest impact population. Of course we don't really know if mild and asymptomatic cases can transmit effectively. We might if their was more widespread testing. Since we haven't seen that level of testing coming from the site of most MERS-CoV infections, the Kingdom of Saudi Arabia, perhaps there is an opportunity for other States to step up and test not just returning pilgrims but their families and other contacts and see whether their upper respiratory tract's are free of MERS-CoV RNA?

These media reports also don't tell us what definitions are used by each State to define a pilgrim as being free of MERS-free. It may be the absence of any sign of any respiratory disease, or it be just absence of severe signs and symptoms, or perhaps a combination of signs and symptoms e.g. fever+cough or cough+difficulty breathing.

Too many knowledge gaps.

One thing's for sure. The headlines are only scratching the surface.

Static pages