Wednesday 30 March 2016

Plotting the Brazil microcephaly data...

These data are obtained from the Brazil Ministry of Health microcephaly reports, which you can also find here.

Above we can see a cumulative curve (black line, yellow dots read using the left-hand axis) which adds each week's cases to the total from the week before. The curve appears to be rounding off in in the last few weeks which might suggest a slowing of the rise in number of microcephaly diagnoses. 

Or it might be too early to say. 

The vertical orange bars (read against the right-hand axis) are the differences between reports. The first bar is the total diagnoses in week 54 of 2015, minus the total from week 46, 2015, and so on. There seem to be fewer new cases each week over the last 3 epidemiological reporting weeks.

In the second chart things get a bit more crowded - but follow the same basic layout  as the first - lines read on the left-hand axis, bars one the right. Colours go together. Lines are totals, bars are differences between weeks. 

We see the rise in discarded suspected microcephaly diagnoses (blue; they were classified as not being microcephaly cases) which became a little steeper between Week 7-10.

Confirmed microcephaly diagnoses (red) did not rise as steeply and seem to have slowed in the last 2 reporting weeks.

The number of laboratory confirmed Zika virus positives (green) among the confirmed microcephaly diagnoses is much smaller and oscillates.

This chart also shows that these extra details didn't start appearing until around Week #2 of 2016.

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... 

...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]

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.

  15. Zika virus in the Americas: Early epidemiological and genetic findings
  16. 5 things the world has learned about Zika so far
  1. Added reference to a van der linden publication [29]
  2. Added a reference to a second Dr van der Linden publication [30]
  3. Repaired typos to Crawford Kilian's name

Editor's Note #25: 3rd birthday...

3 years ago I posted my first blog thingy. 

It was on MERS-CoV.

863 posts, >735,000 recorded views and a continuous run of viral outbreaks and epidemics later - here we are.

Happy 3rd birthday Virology Down Under!

Thanks to all of you for reading and chatting and asking and thinking.

Roses are red
Violets are blue
When I talk on viruses
I use VDU

I also use Twitter and LinkedIn and Facebook a bit too.

Colombia posts new data on Zika...

In the latest epidemiological report, which includes data on Zika virus disease (ZVD; week #11), has been produced by the excellent Colombian National Institute for Health team.[1] It's a small one this week - only 94 pages.

We see a new format to the graph which more clearly depicts how many of the ZVD cases are in fact only suspected (grey) of being Zika virus infections. 

Very few ZVD cases are confirmed (red) as being Zika virus infections and it appears as though no new laboratory confirmed cases have occurred in the past 7 reporting weeks. 

I've looked at the numbers used in this graph a little differently by calculating the differences between weekly cumulative reported tallies of laboratory confirmed cases. We can see that new confirmations seem do still be occurring. I presume the weeks with zero confirmations just reflect a delay in getting the lab testing data to the reporters on time.

I'm not sure why they are not plotted in red. Perhaps someone familiar with this report can clue me in?
  • This Report (#11): 2,361 (+6 from previous week)
  • Report #10: 2,355 (+265 from previous week)
  • Report #9: 2,090 (+0 from previous week)
  • Report #8: 2,090 (+478 from previous week)
  • Report #7: 1,612 (+0 from previous week)
  • Report #6: 1,612 (+108 from previous week)
  • Report #5: 1,504 (+173 from previous week)
  • Report #4: 1,331 (+281 from previous week)
  • Report #3: 1,050 (+252 from previous week)
  • Report #2: 798 (+22 from previous week)
  • Report #1:  776
In graph form, those values look like...
So total suspected cases - the bulk of what is being reported by Colombia in relation to ZVD - are still declining, however the number of confirmed ZVD cases are not showing that same consistent downward trend. What does that mean?

Wednesday 23 March 2016

Microcephaly: diagnoses and discards and those with Zika virus...Report #18 from Brazil

The latest Brazil MOH report on microcephaly diagnoses was released 22-MAR-2016 – Report #18 which extends the data to 19-MAR-2016; epidemiological week #10.[1]
The following is a summary of key numbers, after translation via Google.

  • There have been 6,671 (+191 since last week) reported suspected diagnoses of microcephaly since some unspecified date in 2015
    • 4,293 (+25; 64%) remain under investigation
      • 2,378 (+166; 55% of those under investigation) cases have been investigated and classified  
      • 907 (+44; 21% of those classified, 14% of all reported) have been confirmed as microencephaly diagnoses
        • 122 (+28; 13% of confirmed microcephaly cases; 2% of suspected cases) have been laboratory confirmed as Zika virus infections (PCR or serology but no specifics on which or whether mum/foetus/infant/samples etc)
      • 1,471 (+122; 60% of those investigated, 22% of all reported) have been discarded

Tuesday 22 March 2016

SNAPDATE: MERS by the years...

When it comes to Middle East respiratory syndrome coronavirus (MERS-CoV) infections, the years  and the comorbidities - really do take a toll. 

The graph below helps to highlight how the median and average ages of MERS-CoV positive cases and deaths are distinct from the median age of the total Saudi Arabian population - among whom most MERS-CoV infections have been reported. ...although there is the issue of expatriate workers who also get infected - do they contribute to the Kingdom's median age?

Click on image to enlarge.

SNAPDATE: MERS-CoV around the world...

A quick snap update to show how the Middle East respiratory syndrome coronavirus (MERS-CoV has been travelling around the world in the pat 4 years, using a cumulative curve.

Click on image to enlarge.

Sunday 20 March 2016

Colombia updates the numbers..

The latest epidemiological report, which includes data on Zika virus disease (ZVD; week #10), has been produced by the excellent Colombian National Institute for Health team.[1] But people - 97 PDF pages long this week? You're making us all look bad!

Keep in mind that this, as with any report, only captures what it captures. Reports miss a lot of infections because a lot fo inectsion do not get tetsed or seen by a Doctor - espcially with a virus that reportedly only cuses symptoms in 1 of 5 people.

 Fast forwarding to Zika (Its a searchable PDF and "Zika" in Spanish translates into "Zika" in English) we find some interesting things.

Colombia reports 55,724 suspect, probable and confirmed ZVD cases since confirming the virus in epidemiological week 40, 2015.
  • 2,355 (4.2%) of those have been confirmed as positive via a laboratory test 
  • 46,556 (83.5%) have been "clinically confirmed" - which equates to a suspected case according to the World Health Organization (WHO) case definition I've copied out below. It is not clear to me from the Colombian report, whether any IgM testing has been conducted among these 46,556 - I am working under the assumption that it has not (please correct me if you have evidence otherwise)
  • 6,813 (12.2%) are reported as suspect cases

The downward trend in notifications I wrote about last week continues into the past week.

Reported Zika virus disease cases by epidemiological; week, 2015-2016.
The distributions were performed with n = 55,261 corresponding to the records
in the SIVIGILA notified. Image captured from [1] 
Since the beginning of the epidemic phase in Colombia, 10,319 ZVD cases have been reported in pregnant women

  • 995 (9.6%) of those have been confirmed as positive via a laboratory test (RT-PCR)
  • 8,229 (79.7%) have been "clinically confirmed" - which equates to a suspected case as discussed above
  • 1,095 (10.6%) are reported as suspected cases

Most of the "cases" in pregnant women have been notified during 2016's 10 epidemiological weeks, there have been 8,782 cases described in pregnant women (85.1% of the 10,319 total if I interpret the report correctly:
  • 845 (9.6%) of those in 2016 have been confirmed as  positive via a laboratory test (RT-PCR)
  • 6,997 (79.7%) in 2016 have been "clinically confirmed" - which equates to a suspected case as discussed above
  • 940 (10.7%) in 2016 are reported as suspected cases
The report notes 352 instances of neurological syndromes (248 are described as cases of Guillain-Barre syndrome) among mostly (57.1%) males. There is also a report of an increase in reports of acute flaccid paralysis in children under 15 years of age. 31 instances have been reported in children with a "documented" history of ZVD.
World Health Organization (WHO) interim definition for a case of ZVD [2; 12FEB2016]...

Suspected case
  • A person presenting with rash and/or fever and at least one of the following signs or symptoms:
    • arthralgia; or
    • arthritis; or
    • conjunctivitis (non-purulent/hyperaemic).
Probable case
  • A suspected case with presence of IgM antibody against Zika virus[a] and an epidemiological link[b]
Confirmed case

  • A person with laboratory confirmation of recent Zika virus infection:
    • presence of Zika virus RNA or antigen in serum or other samples (e.g. saliva, tissues, urine, whole blood); or
    • IgM antibody against Zika virus positive and PRNT90 for Zika virus with titre ≥20 and Zika virus PRNT90 titre ratio ≥ 4 compared to other flaviviruses; and exclusion of other flaviviruses
[a] With no evidence of infection with other flaviviruses
[b] Contact with a confirmed case, or a history of residing in or travelling to an area with local transmission of Zika virus within two weeks prior to onset of symptoms.

So while I adore the sheer amount of data in these reports from Colombia, there are - as is has ever been the case with Zika virus data in the Americas - some significant gaps. Here we see that most of the ZVD "cases" are suspect - not probable and certainly not confirmed. There is also no mention of brain malformations or microcephaly diagnoses among babies born to mothers with a confirmed history of ZVD - of which there have been a few. Perhaps they have not been confirmed yet?

We await more information from Colombian authorities on this issue because this is the next biggest outbreak of ZVD outside of Brazil and we expect to learn some things about the brain malformations and microcephaly diagnoses we have been hearing about from Brazil which may help us understand more of the role played by Zika virus. Or perhaps by other things that are Brazil-specific.
My thanks to Jorge Pontual for the early alert to the release of this reports-and the chats about it.

  2. WHO interim guideline for defining a ZVD case - 12FEB2016
  1. Noted that these figures are only based on people who present to a Doctor and will this miss many uinstances of ZIKV infection; stressed that the second part of the report was for pregnant women; highlighted that the Zika content is only part of the 97 page PDF - thanks DB

Friday 18 March 2016

Back to the bats for MERS-CoV...

It's a smoking bat. Get it? Hmm.
In late February Munster and a team of United States' researchers infected bats with MERS-CoV. 

The aim here was to seek out information about a possible origin for MERS-CoV in bats and perhaps find an animal source from which camels may have first been infected. This path is suspected because of the genetic similarities between MERS-CoV and other bat coronaviruses which make bats an attractive reservoir for MERS-CoV...or an earlier form of MERS-CoV.

It's worth reinforcing that there is as yet no "smoking bat" - no bat species has been found to harbour infectious MERS-CoV in the wild or more than a diagnostic PCR fragment's worth of genetic material. To date.

The team used a bat species called Artibeus jamaicensis - the Jamaican fruit bat. 

They first tested whether the bat's version of the molecular known to be the human MERS-CoV receptor,  dipeptidyl peptidase 4 (DPP4), could act in that role. To do this they cloned the relevant bat sequence and introduced it into some some cells that usually didn't permit MERS-CoV to infect and replicate wihtin them. When the introduced DPP4 material was expressed, the cells permitted MERS-CoV infection and replication; Jamaican fruit bat DPP4 could act as the MERS-CoV receptor, just like human DPP4 does.

From the Histology Lecture Image Gallery at Yale
Medical Cell Biology.[3]
Next the team infected 10 A.jamaicensis bats via the nose and body cavity; none showed signs of disease, lost weight or were found to have a rise in their temperature but 8 shed virus - moreso from their respiratory than their gastrointestinal tracts.

When the bats were killed at different times and examined, the lower respiratory tract was found to contain the highest level of virus, but MERS-CoV was also found throughout the bodies of the bats, possibly spread via a blood-borne path since viral RNA was detected in the blood 2 and 4 days after inoculation. 

Signs of mild tissue damage could only be found in 2 bats - both in the respiratory tract with signs that virus infected Type I pneumocytes. Type I pneumocytes form part of the alveolar gas exchange barrier. In humans, Type II pneumocytes were identified as MERS-CoV targets in the only human autopsy conducted to date.[2] Type II pneumocytes are responsible for secreting surfactant which helps stop the lung's air sacs from sticking to themselves, they metabolize drugs, move water across epithelium (tissues that line the body's hollow cavities in this case) and repair injured alveoli.[4]

Only 1 bat developed a MERS-CV a specific antibody response.

The discussion had some interesting points including....
  • A.jamaicensis may be a good model system for studies of how bats and their coronaviruses co-exist
  • MERS-CoV "maintains the ability to efficiently replicate" in bats which the authors take to support the hypothesis that bats are the ancestral reservoir for MERS-CoV. Or maybe its ancestor?
  • Because bat coronaviruses are usually bat gut pathogens, but MERS-CoV was a bat respiratory pathogen, this might suggest MERS-CoV evolved to be so in camels. might not.
  • In the absence of disease, a detectable antibody response may not occur in humans as was found in bats, or it may be delayed in humans as has been previously reported. 
  • In most bats and bat tissues, MERS-CoV RNA could not be detected beyond a 2 week period after inoculation - but in 1 bat, the small intestine was still positive at day 28

I'll get back onto the camel literature reviews next.

  1. Replication and shedding of MERS-CoV in Jamaican fruit bats (Artibeus jamaicensis)
  2. Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates, April 2014

Thursday 17 March 2016

Microcephaly: diagnoses and discards and those with Zika virus...Report #17 from Brazil

The latest Brazil MOH report on microcephaly diagnoses was released 16-MAR-2016 – Report #17 which extends the data to 12-MAR-2016; epidemiological week #9.[1]

The following is a summary of info after translation via Google.

  • There have been 6,480 (+322 since last week) reported suspected diagnoses of microcephaly since some unspecified date in 2015 
    • 4,268 (+37) remain under investigation 
      • 2,212 (+285; 52% of those under investigation) cases have been investigated and classified 
      • 863 (+118; 39% of those investigated, 13% of all reported) have been confirmed as microencephaly
      • 94 (+6; 11% of confirmed microcephaly cases; 1% of suspected cases) have been laboratory confirmed as Zika virus infections (PCR or serology but no specifics on which or whether mum/foetus/infant/samples etc) 
      • 1,349 (+167; 61% of those investigated, 21% of all reported) have been discarded
Notified and confirmed microcephaly diagnoses by municipality, Brazil.[1]

Population density in Brazil by State, 2014.

My thanks to Jorge Pontual for the early alert to the release of these MOH reports-and the chats about them.


Monday 14 March 2016

Middle East respiratory syndrome coronavirus kicks off...

Click on it.
It gets bigger!
The next wave of MERS-CoV cases is well underway in the Kingdom of Saudi Arabia (KSA). 

Since 2012, 1,702 MERS-CoV detections have been reported in humans from 26 countries around the world.

Click to expand.
Graph captured from [3]
The first reported MERS cases appeared on our radar via an eMail to ProMED sent September 20th 2012.[1] That person became ill in April 2012 and some others, found later, were ill in March 2012 [2] - so we're smack dab into our 4th "disease onset birthday" right now. 

Each year we news and number watchers, wonder aloud about the course that MERS-CoV might plot. We don't predict it though - that would be dumb. No-one can know where things may go because that's all based on human behaviours, oversights and mistakes. And who knows how, how many, how often, why or when those will occur?

MERS-CoV is very much a human problem - it's a particularly opportunistic virus which causes it's biggest impact when we create the conditions for it to spread among vulnerable people in health care settings.  Whether or not that whole process will play out again in 2016 is anyone's guess. As I noted in my last post, it has already happened to some degree in Buraidah in the Al Quassim province of KSA. The KSA is - if you are new to MERS-CoV - the country in which 80.4% of infection have been acquired. Word oen the Tweet is that the outbreak is under control now.

I've updated my graphs, tallies and charts with the latest numbers now, so feel free to click on the MERS-CoV tab above to see where we're at.

And don't forget - an outbreak of an infectious disease in one country has the potential to be an outbreak in any country. Just add human behaviour.


Tread carefully when MERS-CoV stirs in hospitals as it can spiral out of control quickly..

In 2014 a stepwise increase in Middle East respiratory syndrome coronavirus (MERS-CoV) cases preceded the largest healthcare facility outbreak of MERS to date. 

If you look at the most recent daily Kingdom of Saudi Arabia (KSA) Ministry of Health report below,[1] you could be forgiven for thinking that there is currently a threatening rise in cases which could easily spiral out of control once again unless it is quickly stepped on.

Adding fuel to the fire is the fact that in Buraidah, in the province of Al Quassim , there has clearly been a healthcare-associated outbreak ticking over since November 2015 - patients, healthcare workers and relatively little camel contact make for a pretty clear picture.
When these fires are let smoulder in this way, they can quickly spread embers across the region and then cases fly out to other ports.
A week ago there were 8 cases reported in a day. That's far from the biggest reporting day we've seen in 3 MERS years (around 31 cases in a day n April '14), but it's still high. There have been 11 consecutive days with 2 -8 cases reported each day. The region in the map above has been the hotspot, but in the 12-March report there were 4 cases, each in a different city

There have also been an usually high number of camel mentions so far this MERS season. We do not usually see so many consecutive cases reported to have some form of camel contact. These are from cases across the KSA but also from United Arab Emirates- and Oman-acquired cases too. Is this because of a better understanding and acceptance of the role of camels in spreading MERS-CoV to humans, after research really hammered home the facts, or is it that more camels are infected, or there are more infected herds this season, are other animals becoming infected, or is it that, for some unknown reason, there is more contact between humans and infected camels/other animals this season?

There have been no viral gene or genome sequences from 2016 arriving on the interwebs yet, so we are left with a few of the old questions...again
  • is this all normal or is something different this time around?
  • has this season's MERS-CoV undergone a significant genetic change(s), affecting stability, tropism or transmission?
  • has infection control and prevention slipped again?
  • is there more contact with infected camels this year?
  • are increased camel descriptions an indication of better surveillance and questioning about camel contact?

Time to start watching and plotting MERS-CoV again.