Brazil's microcephaly and CNS disorder (M&CD) monitoring: Report No. 32, 2016-Week No. 25...

These graphs are made by me using data obtained from epidemiological week (EW) number 25's Brazil Ministry of Health microcephaly and foetal and infant microcephaly and central nervous system (CNS) disorders (M&CD) report.[1]

Brazil last reported a total of 120,161 suspected Zika virus detections some weeks back. Around one thousand of these have been confirmed.[2,3]

Suspected M&CD cases...

The total number of suspected M&CD cases increased by 126 to 8,165 this EW (compared to last).

The graph above shows the number of suspected M&CD diagnoses in Brazil up to 25-June-2016. The cumulative curve (yellow dots; left hand axis) is growing, but slowly. 

This was another weekly rise (orange bars; right-hand axis). These bars are based on the difference in total suspected cases reported this EW compared to that reported in the last EW. This method may not reflect the diagnoses that occurred during the past EW (some may have come from days or weeks earlier), but that level of detail is not available in the MOH report.

Confirmed and discarded M&CD diagnoses...

M&CD cases under investigation increased by 54 to 3,061 this week.

In the graph above, we can see that 50 (blue bars; right hand axis) suspected M&CD diagnoses were discarded upon closer investigation with a current total of 3,466 removed.

The rate of these resolved diagnoses (line with blue dots, left-hand axis) seems similar to the rate of the smaller overall number of confirmed M&CD diagnoses (red dots, left-hand axis).

As of this EW, 20% of suspected M&CD diagnoses have been confirmed while 42% of suspected diagnoses have been discarded-a percentage that has been steady for 4 EWs.

The cumulative number of confirmed M&CD diagnoses does continue its climb this EW, growing by 22 new diagnoses (red bars; right-hand axis) to total 1,638.

The number of these M&CD diagnoses to be confirmed with a Zika virus infection also grows (green dots; left-hand axis) by 37 new detection (green bars; right-hand axis) to 270 this EW after rising by 7 the preceding EW.

Those confirmed Zika virus infections represent 16% (an increase for the first time about 11 weeks) of all confirmed M&CD diagnoses and 3% of all suspect diagnoses.

References...

1. http://portalsaude.saude.gov.br/images/pdf/2016/junho/30/Informe-Epidemiol--gico-n---32--SE-25-2016--27jun2016-16h18.pdf
2. http://combateaedes.saude.gov.br/images/sala-de-situacao/informe_microcefalia_epidemiologico26.pdf
3. http://combateaedes.saude.gov.br/images/boletins-epidemiologicos/2016-013-Dengue-SE16.pdf

Lab virus in lab cells, kill lab cells...

Tang and colleagues from Johns Hopkins University School of Medicine and other Universities have just described what Zika virus (ZIKV) can do to cells in culture.[1] That is, cells that have been tweaked to appear and behave like human brain cells - of a sort. Some very complex, expensive and expert work is needed to chemically drive cells to become other cells. But the question is - how much does this reflect what happens in a developing foetus whose cells harbour ZIKV?

The human neural progenitor cells (hNPCs) in this study were developed from human induced pluripotent stem cell (iPSC) lines that had previously been generated from skin biopsy material. This is an interesting origin because we do know that ZIKV can grow in skin cells (dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells).[2] The authors do not address whether the new hNPCs inherit any skin cell features that may help ZIKV infect them and perhaps give an inaccurate picture of the ZIKV in the developing human brain. I'm no expert on these methods however and may well be missing many issues.

These new laboratory findings may begin to unearth some possible mechanisms by which ZIKV infects and damages brain tissue in humans, but they are one step on a long path to understanding the mechanism in humans and should be considered with care and in context. The use of "primary" human tissues would be a useful addition to this study-cells or tissue not chemically matured, but as found in foetal tissues. No, I do not know how those tissues could be obtained-it would certainly require a lot of effort.

The particular ZIKV used in this study, which the authors identify as the MR766 variant (which originates from a sentinel primate from Uganda in 1947),  has been extensively grown in animals, mosquitoes and cell culture [3] although to what extent is unclear from the authors or from the information provided by the company they bought the virus preparation from.[1,3] It is unclear whether this lab-adapted virus still "behaves" in the same way as do ZIKVs currently circulating in Brazilian mosquitoes and infected humans. It may be an accurate ZIKV representative, or it may infect cells more easily, cause cellular damage or changes more effectively - or it may do the opposite.

Cell culture studies are a fast and relatively easy starting point to understand which cell types may host a virus and to see what the virus does in those cells and under those laboratory conditions. Certainly compared to clicnial studies. Cell cultures derived from one tissue type that have then been extensively manipulated and chemically treated in the laboratory to develop in certain ways, to be prepared for infection and possibly requiring ongoing chemical care to retain their state or health, may not yield infection results that accurately reflect disease processes in humans or other animals.

While this article is a useful insight into ZIKV and human-derived immature neural cells, a lot of work remains to be done to understand how ZIKV could cause the brain injuries or diagnoses with which it is being presumptively associated, predominantly in Brazil.

And that work appears to be proceeding apace.

NOTE #1: this post was based around bullet points I wrote in response to a request for comment by The Scientist.[4]

NOTE #2: There was another paper in this space that went online at PeerJ Reprints 04MAR2016 [5] - it has yet to be peer reviewed and does not have the detail describing the development and maturation of the stem cells that the paper reviewed above does. My thanks to @Ammer_B for pointing this out.

References...

1. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth
   http://www.cell.com/cell-stem-cell/pdfExtended/S1934-5909(16)00106-5[Extended article contains information of the laboratory maturation of the human stem cells]
2. Biology of Zika Virus Infection in Human Skin Cells
   http://jvi.asm.org/content/89/17/8880.long
3. ZIKA VIRUS Infectious Culture Fluid
   http://www.zeptometrix.com/docs/PI0810092CF.pdf?1457038294
4. Zika Infects Neural Progenitors
   http://www.the-scientist.com/?articles.view/articleNo/45506/title/Zika-Infects-Neural-Progenitors/
5. Zika virus impairs growth in human neurospheres and brain organoids
   https://peerj.com/preprints/1817/

Jon Snow is remarkably well informed compared to us...

...because we clearly know almost nothing when it comes to the specifics of where Ebola virus (EBOV) can, in some portion of survivors, hide. 

What triggers EBOV to come out of hiding? If indeed that is what it has done within PC, the United Kingdom nurse who seems to have recently become ill while (or due to) hosting a reappearance of EBOV in her blood - 9 months after her blood was defined as containing no detectable EBOV. 

This is not a new infection - but a return of a virus that had not been cleared from its hidey hole(s).

There are obvious concerns to be discussed around this, including:

1. What triggered its re-emergence
2. Is this a strange and rare event or a more common one?
3. Was the virus hiding in PC's central nervous system (she has meningitis-like symptoms reportedly) or in another place or places? 
4. Is the thyroid a site of persistence? 
5. Did the mysterious antiviral treatment she was given alongside a plasma treatment in 2014/15 act to push the virus into hiding? 
6. Has the activated virus mutated in any significant way during its holiday out of the bloodstream? 
7. Can EBOV become truly latent or at least dormant (still producing proteins, but not infectious virus particles) when off the beaten track, or is it constantly replicating?
8. Is PC suffering from full-blown Ebola virus disease (EVD) now, or a disease due to tissue or organ damage from her earlier infection - although if she has detectable EBOV in her blood, one would assume it is EVD. 
9. What the hell are a "lucky set of genes" in the context of a return to systemic EBOV infection? 

Below are some known and some proposed/possible/unproven sites at which EBOV may linger, avoiding or not exposed to clearance by the full force of our immune response.

In the future, perhaps tomorrow, in a non-rich nation, will others become infected from a convalescent patient who experience a return of EBOV long after they were declared virus-free based on a their blood test results. Has that happened already? Will they be our colleagues, friends or family members? The sooner we hear more about what is going on with PC, the better prepared those on the ground will be to intervene. Also, those tending to convalescent health workers in countries around the globe. 

Communication has always been a key issue for EVD and other emerging diseases. Have we been listening?

We know nothing but we can learn. Will we?