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.

References...
  1. http://virologydownunder.blogspot.com.au/2016/01/zika-virus-briefly.html
  2. http://www.who.int/csr/resources/publications/zika/community-engagement/en/
  3. http://www.theglobeandmail.com/news/world/who-may-be-leading-brazil-down-wrong-path-on-zika-virus/article29390468/
  4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1716566/?page=3
  5. http://adc.bmj.com/content/early/2016/03/14/archdischild-2016-310590
  6. http://www.who.int/bulletin/online_first/16-170639.pdf
  7. http://crofsblogs.typepad.com/h5n1/2016/01/is-microcephaly-surging-in-brazil-or-just-efforts-to-find-it.html
  8. http://northshorejournal.org/microcephaly-and-zika
  9. http://www.nature.com/news/zika-virus-brazil-s-surge-in-small-headed-babies-questioned-by-report-1.19259
  10. http://www.nature.com/news/zika-and-birth-defects-what-we-know-and-what-we-don-t-1.19596
  11. http://www.theguardian.com/global-development/2016/jan/25/zika-virus-mosquitoes-countries-affected-pregnant-women-children-microcephaly
  12. http://www.wsj.com/articles/the-brazilian-doctors-who-sounded-alarm-on-zika-and-microcephaly-1454109620
  13. http://www.thelancet.com/pb/assets/raw/Lancet/pdfs/S0140673616002737.pdf
  14. http://virologydownunder.blogspot.com.au/2016/01/microcephaly-in-brazil-is-it-occurring.html
  15. Zika virus in the Americas: Early epidemiological and genetic findings
    http://science.sciencemag.org/content/early/2016/03/23/science.aaf5036.full
  16. 5 things the world has learned about Zika so far
    http://www.statnews.com/2016/03/25/new-understanding-zika/
  17. http://www.ncbi.nlm.nih.gov/pubmed/26527535
  18. http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001792
  19. http://www.ncbi.nlm.nih.gov/pubmed/25299181
  20. http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004543
  21. http://www.ncbi.nlm.nih.gov/pubmed/26527535
  22. http://www.who.int/emergencies/zika-virus/mediacentre/webcast-22-3-2016/en/
  23. http://www.reuters.com/article/us-health-zika-brazil-idUSKCN0W52AW
  24. http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html
  25. http://time.com/4202262/zika-brazil-doctors-recife-investigation-outbreak/
  26. http://www.nature.com/scitable/blog/scibytes/the_new_ebola_zika
  27. http://www.newsweek.com/2016/03/11/zika-microcephaly-connection-brazil-doctors-431427.html
  28. http://wwwnc.cdc.gov/eid/article/21/10/pdfs/15-0869.pdf
  29. http://wwwnc.cdc.gov/eid/article/22/6/16-0062_article;
  30. http://www.nejm.org/doi/pdf/10.1056/NEJMc1603617
Updates...
  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