Sunday, 28 February 2016

Avian influenza A(H7N9 virus...a primer...

Influenzavirus taxonomy
OrderUnassigned
FamilyOrthomyxoviridae
GeneraInfluenzavirus A, Influenzavirus B, Influenzavirus C
SpeciesInfluenza A virus, Influenza B virus, Influenza C virus
Genome(-)ssRNA, 7 (IFCV)- 8 (IFAV/IFBV) segments (~14kb total length)
GenesPB2, PB1, PA, HA, NP, NA, M, NS
VirionEnveloped, approximately spherical, 80-120nm
NB-this has just been transferred from my old VDU website to this blog and so is out of date. I'll update in the future

One of the most recent avian influenzavirus strain added to the list of agents causing "bird flu" is called avian influenza A(H7N9) virus - a colourfully exciting reference to its key surface proteins (see influenza background). H7N9 is considered a low pathogenic avian influenza virus (LPAIV)...at least in its feathered hosts. Avian influenza A(H7N9) virus (which I may shorten to H7N9 to save my fingers) was once considered a relatively rare cause of infection although how extensively and routinely it was looked for in the past is unclear. Avian influenza A(H7N9) virus is similar to its closer cousins, H7N2, H7N3 and H7N7 and its more distant cousin H5N1 in that they are all IFAVs and they usually infect birds. However, they are each quite distinct and made up of different genes.

Avian influenza A(H7N9) virus is an IFAV (see the adjacent schematic) that has evolved in birds. The virus has 8 single-stranded RNA segments that encode 11 proteins. However, when cases of infection by it were reported for the first time in humans (China, March 2013; very general locations of confirmed cases to date are shown in the map), it was linked to its first two deaths in this host (an 87 year old male [87M, sick 19.02, died 04.03; 2 family member(s) also reported ill with pneumonia but H7N9 negative] and a 27 year old male butcher [27M, sick 27.02 and died 10.03], both in Shanghai, China) or critical illness (35F in Chuzhou city). 


Since 2013, cases have slowly but continuously climbed.

Because there is a delay between illness onset and laboratory confirmation of 10-13 days, the newest cases started have illness onset dates some way back making it is still hard to judge the impact of control measures like live animal market closures and animal culling, on interrupting transmission. A timeline of the early events shown below. 


Use images freely but please cite this blog and Dr. Ian M Mackay as their source.
Click on image to enlarge.









The chart to the left divides the H7N9 outbreak into its 2 Waves based on laboratory notifications made public starting from March 31st (Chinese CDC notified WHO). 


In the graph of the accumulating confirmed cases to the right (blue mountain), fatalities (red) and the rolling proportion of fatal cases (grey-PFC calculated using public data, yellow using media reports of totals), we can see that the total proportion of fatal cases (PFC) sits around 30%. Please don't go nuts and draw any major conclusions based on extrapolating the PFC to the global population - this figure is solely meant to show you the numbers and trends at the site of the outbreak among those people being affected. It cannot be translated widely. What it does show us is how the outbreak came to be noticed - fatalities. The PFC remained fairly steady though 2013, although its calculation is at the mercy of the availability and extent of public data. For an update on the most recent epidemiology, please visit my blog, virologydownunder.blogspot.com.au  and use the search box to find recent “H7N9” posts. 


H7N9 Fataliaties by week. Use images freely but please cite
this blog 
and Dr. Ian M Mackay as their source. Click on image to enlarge.


The various H7N9-positive municipalities (Shanghai and Beijing) and provinces (e.g. Henan, Anhui, Zhejiang, Guangdong, Jiangxi, Hebei, Fujian, Hunan and Jiangsu) in southeastern China have had different numbers of cases reported and the reports started at different times. The first cases were confirmed from Shanghai on March 30th and included the first case who showed signs darting back to February 19th. Jiangsu's first confirmed cases occurred 30-March-2013 (although they were not announced until 2-April-2013) then Anhui province followed (confirmed on 31-March-2013) then Zhejiang province (1st April-2013), Henan province (11-April-2013) and Beijing reported its first case 13- April-2013. Guangdong province confirmed its first case 6-August-2013; Fujian province, 26-April-2013; Hebei province, 20-Jul-2013; Shandong province, 22-Apr-2013; Guangxi province 29-Jan-2014; Jilin reported its first detection, 21-Feb-2014. Most cases in Wave 1 were from Zhejiang province which was also a major site of virus activity in Wave 2, along with Guangdong province.


The denominator problem...


You may remember from your early maths classes that fractions have both a numerator (the number on on top or before a slash/line, that represents a portion of the whole) and a denominator (the non-zero number on the bottom or after the line that represents all the parts of the whole).  avian influenza H7N9 flu cases by area of China The avian influenza A(H7N9) virus outbreak in March-May 2013 mostly manifested as severe disease - those people being admitted to hospital needing help to breathe (requiring oxygen or mechanical ventilation) - and we did not see many mild or asymptomatic cases (virus positive but no obvious feelings of signs of illness). This might be because there were no mild cases (although a couple popped up in children and adults) or because only the worst cases were tested. In favour of the former hypothesis, enhanced surveillance in China found few H7N9-positive cases of mild disease - the most notable being children. 

Many milder respiratory diseases look the same based on signs and symptoms but can be caused (and I use that word with caution) by many, many different respiratory viruses. There may be cases of respiratory infection going around in China that are H7N9-positive but not severe enough to warrant a admission to hospital or even a trip to the Doctor. Until we know more about this part of the H7N9 story, we won't know the total number of avian influenza A(H7N9) virus infections that are occurring, so we can't calculate the true denominator. More info on this in a recent article.

If the denominator is small (like it is now with so few H7N9-positive cases and those being from mostly severe illness or deaths, then we see a high proportion (percentage) as our Proportion of Fatal Cases  (x severe cases over a small number of total cases is a high proportion). If there are mild cases of avian influenza A(H7N9) virus infection out there (as we saw early examples of 15-Apr-13) and they are in large numbers, that denominator could be much larger and the severe disease cases will be "diluted" down to a smaller proportion (x severe cases over a large number of mild and severe total cases is a low proportion).

Saturday, 27 February 2016

Microcephaly: diagnoses and discards and those with Zika virus...Report #14

The latest Brazil MOH report on microcephaly was released earlier in the week – Report #14. 

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

·         There have been 5,640 reported suspected diagnoses of microcephaly sometime unspecified  in 2015
o    4,107 remain  under investigation
o   1,533 cases have been investigated and classified
  • 583 (38% of those investigated, 10% of all reported) have been confirmed
    • 67 (11% of confirmed microcephaly cases; 1% of suspected cases) have been laboratory confirmed as Zika virus infections (no detail provided on method or whether mum/foetus/infant/samples etc.
  • 950 (62% of those investigated, 17% of all reported) have been discarded

·        The MOH notes that if a diagnosis of microcephaly was confirmed, then the mother is to be considered ZIKV positive whether laboratory data are available/provided or not

References…
  1. http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/23/coes-microcefalia-informe-epidemiologico14-se07-2016-fev2016-14.pdf
  2.  http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/secretarias/svs/noticias-svs/22296-casos-suspeitos-chegam-a-4-107-em-todo-o-pais#

Wednesday, 24 February 2016

Line by line for H7N9...

My thanks go to the team at the World Health Organization for adding a downloadable line list for avian influenza A(H7N9) virus cases to their website.

This a great addition and will make following the seasonal outbreaks so much easier. 

I don't know when in 2016 it appeared, I just noticed a referral to it in the latest ProMED post and its seem that both go 2016's disease outbreak news posts (19-Jan and 10-Feb have attached lists. I had been bemoaning the lack of detail for a while so this really is fantastic.

There don't seem to be any lists from 2015. Should I push my luck further and ask if any of 2015's cases will be added to a list retrospectively?

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...

  1. http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/197-secretaria-svs/20799-microcefalia
  2. http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/17/coes-microcefalia-inf-epi-13-se06-2016.pdf
  3. http://www.who.int/csr/don/20-november-2015-microcephaly/en/
  4. http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/12/COES-Microcefalias-Informe-Epidemiologico-12-SE-05-2016-12fev2016-13h30.pdf

Tuesday, 16 February 2016

Human parechovirus (HPeV) may be spread with the help of well kids...

UPDATES: #1 17FEB2016 AEST
#2: 10AUG2016 AEST

The first human parechoviruses (HPeVs) were initially called Human echovirus 22 (HPeV-1) and Human echovirus 23 (HPeV-2).[11,12] These guys were discovered in the summer of 1956 but they weren't officially renamed, and put into their own genus, until 1996.[1]

This very month the genus was officially split into two species, Parechovirus A (containing the 16 human parechoviruses) and Parechovirus B (containing 4 Ljungan viruses).[2,3]

HPeVs are usually summertime viruses and they are not that unusual although there is still plenty to learn about them. They usually show up, or make the news, when more severe infections drive small children to hospital with central nervous system disturbances.[6,7] It has been assumed that they're spread by contact and also by droplets via the respiratory tract and the faecal-oral route. HPeVs can be detected in the nasopharynx, throat, blood  as well as cerebrospinal fluid and in faeces - usually using RT-PCR technologies.[8]

After a study last year,[4] its authors found that within families in Japan, genetically identical HPeV variants could be identified among both sick and well members. They speculated that aymptomatic infections might be a source of spread of infectious HPeV to others in such a close quartered environment. 

While HPeVs were sometimes found in the absence of any signs of illness in this study, some family members showed the more serious end of an HPeV infection - encephalitis, septic shock as well as fever, vomiting and diarrhoea.[4]

There are no specific antiviral drugs available to treat HPeV and no vaccine exists. Supportive treatment is recommended for serious illness and most, although not all, serious cases reportedly recover without any later problems, although long-term studies are needed.[9,10,8] The best prevention is consistent hand hygiene after nose wiping, going to the toilet or changing nappies and coughing and sneezing into a tissue which is then discarded.[5]

Once again we see that a virus found in patients with severe disease, can also be found in a person without any disease. The outcome from a virus infection is best considered as sitting somewhere along a sliding scale and which will vary from animal-to-animal. Just don't lump the outcome into any one particular box.

References...
  1. http://www.picornastudygroup.com/taxa/genera.htm
  2. http://www.picornastudygroup.com/taxa/species/species.htm
  3. http://www.ictvonline.org/proposals/2014.016aV.A.v1.Picornaviridae_spren.pdf
  4. http://www.ncbi.nlm.nih.gov/pubmed/26305831
  5. http://www.health.nsw.gov.au/Infectious/factsheets/Pages/parechovirus.aspx
  6. http://virologydownunder.blogspot.com.au/2013/12/what-to-watch-for-with-human.html
  7. http://virologydownunder.blogspot.com.au/2013/11/parechovirus-infections-in-babies-in.html
  8. http://www.ncbi.nlm.nih.gov/pubmed/21736976
  9. http://www.ncbi.nlm.nih.gov/pubmed/25301212
  10. http://www.ncbi.nlm.nih.gov/pubmed/23810613
  11. http://www.ncbi.nlm.nih.gov/pubmed/13785166
  12. http://www.ncbi.nlm.nih.gov/pubmed/13538681
Updates...
  1. Added 2 references
  2. Note that one Echovirus 23 (CT86-6760) is not an HPeV-2, but a misclassified HPeV-5 - Al-Sunaidi et al. J Virol 81;2. 1013-1021

Monday, 15 February 2016

Zika virus: pathology, postulates and questions...

UPDATE #1: 16FEB2016 AEST
Zika virus (ZIKV [1]) infection usually results in a mild outcome for the mosquito-bitten human host. 

Only 18% of probable infections had related symptoms in a previous outbreak.[24] Despite 82% having no obvious disease, virus replicates happily enough in us for there to be enough of it circulating in our blood (a viraemia; vy-ree-me-yah) that from around a week later (3-12 days), another protein-seeking female mosquito can consume some of it and become infected herself. And thus the cycle continues.

There may be some much less frequent possible methods of human-to-human infection. These may include sexual transmission,[2,16,17,18] perinatal infection [3] and blood transfusion.[4] Recently, viral RNA had been detected from the amniotic fluids of two pregnant mothers [3] and from the brain of at least 5 foetuses as well as the placental tissue of 2 of those.[13,14]

Bigger outbreaks meant more chance to see rare diseases...

While usually mild - a feature entirely based on relatively few confirmed cases up until 2013 - understanding and awareness about what constitutes ZIKV disease (ZVD) begun to change after this. At this time there were concomitant outbreaks of ZIKV infection and Guillain-BarrĂ© syndrome in French Polynesia,[5,8] first noted in October 2013.[7] This outbreak was estimated to have involved 19,000 cases, making it the largest outbreak recorded to that point; 294/584 patient sera (50%) contained ZIKV RNA.[7]

Size does matter here because when there are only a few or even a few hundred cases, less frequent disease complications may not show up. This point is very relevant to the complication that is today being "linked" and "associated" with the epidemic of ZIKV in Brazil; a diagnosis of microcephaly.[1] These two separate, or perhaps linked, events have been co-occurring in Brazil during 2015 and there are now data to suggest that microcephaly diagnoses of 150 prior to 2015 were an underestimate, with diagnoses occurring in much greater numbers, well before Brazilian health authorities declared an emergency.[9,10,25] 

In fairness, ZIKV may also have been present well before 2015 - but laboratories may not have tested for it. This is also a question for other countries reporting their "first" local transmission of ZIKV. Phylogeography estimates suggest that ZIKV may have arrived in Brazil around 2013-2015,[11,12] but these are based on the sequence data to hand and could be affected by the discovery of genomes from months or years earlier from stored sample material for example. Also, some existing gene and genome sequences come from viruses that have been passaged though cell culture and animals so many times that they may not accurately reflect the virus that comes out of a mosquito.

Associating infection with disease means more than the dictionary definition..

In the olllld days (ya know, before smartphones) a thing called Koch's postulates was used as a guide to whether a bacterial infection (these weren't developed with viruses in the picture) was the cause of disease in an infected person. A 1976 summary by Alfred S. Evans [15] noted that these postulates were a check-list requiring that...
  1. The parasite occurs in every case of the disease in question and under circumstances which can account for the pathological changes and clinical course of the disease.
  2. The parasite occurs in no other disease as a fortuitous and non-pathogenic parasite.
  3. After being fully isolated from the body and repeatedly grown in pure culture, the parasite can induce the disease anew.
A few obvious problems may jump out to some of you - for virus infections at least. For example..
  1. Detection methods today are mostly based upon the detection of viral genetic material (polymerase chain reaction [PCR]-based techniques) which can detect virus at levels which could never be detected using culture-based methods. But these are not detection of infectious virus. They are detections of bits of genetic material. Also, many viral pathogens discovered in recent times have not grown, or not grown easily, in the cell culture and other culture-based techniques used. On top of that, virus isolation in cell and tissue culture has become a dying art form, with broad speciality left mostly in reference laboratories
  2. We now know that the many viruses may cause a spectrum of disease ranging from severe disease states through to infection that does not yield any obvious or measurable sign or symptom of disease at all
  3. We simply cannot replicate disease using humans, and often it is hard to find an animal model that accurately represents the disease course experienced in a human. This can mean that the results we get from infecting an animal are misleading or just plain irrelevant
Once viruses were discovered and more became known about our immune system, then that original check-list of Koch's became more of a wishlist.[19]

Moving to the molecular..

Some "Molecular" postulate variants emerged from the late 80's onwards (still in the ollllld days!). In 1988, Stanley Falkow highlighted that Koch's postulates were not meant to be taken as dogma and liberally applied to everything, rather they were intended as a starting point for broader conversation, to encourage more rigorous thinking and evaluation and to convince the sceptics of the day that bacteria caused disease at all.[20,21] For example this version to which I've added some comments about how well this has been addressed for the proposed ZIKV/microcephaly...

  1. A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found preferentially in those organs or gross anatomic sites known to be diseased (i.e., with anatomic, histologic, chemical, or clinical evidence of pathology) and not in those organs that lack pathology.
    We're nowhere on the first part-too little testing, but in a very few instances we have seen evidence f ZIKV in brain tissue - the site of damage in microcephaly diagnoses 
  2. Fewer, or no, copy numbers of pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease.
    Fail. 80% of infection are without noticeable disease if it couple of studies are to be believed
  3. With resolution of disease (for example, with clinically effective treatment), the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.
    There is no resolution of microcephaly disease as the major structural changes are permanent. In "normal" ZVD, viraemia resolves in a week, urine clears in 20 days and while semen may harbour ZIKV genetic sequences for 62 days or more, there does not seem to be accompanying disease.[26,16] Relapse has not yet been documented.
  4. When sequence detection predates disease, or sequence copy number correlates with severity of disease or pathology, the sequence-disease association is more likely to be a causal relationship.
    Perhaps - it is usually the case that higher viral load correlates with overt disease but more work is needed to investigate these correlations for ZIKV. There was at least as much viral RNA in brain tissue from a terminated foetus, as is usually found in blood.[13]
  5. The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms. When phenotypes (e.g., pathology, microbial morphology, and clinical features) are predicted by sequence-based phylogenetic relationships, the meaningfulness of the sequence is enhanced.
    Little is known about ZIKV lineages and whether they impart change in virulence or clinical course so this is not able to be ticked off either.
  6. Tissue-sequence correlates should be sought at the cellular level: efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible micro-organisms or to areas where micro-organisms are presumed to be located.
    Not been done yet.
  7. These sequence-based forms of evidence for microbial causation should be reproducible.
    As described above, only a few cases have been thoroughly examined - and even they have significant gaps in testing. There has not been any study controlled by testing of a population of non-disease individuals to date.
Postulates can help discussion but have they found an association...?

Sadly, neither the original nor the modified postulates help us find the path to proving ZIKV can, or cannot, cause microcephaly. This is because we have seen little confirmatory testing data from Brazil, we most often detect ZIKV in mild or asymptomatic people, we have yet to develop a clinically relevant animal model and there is no way a pure culture of ZIKV is going to be injected into any mums-to-be to replicate any chance of seeing central nervous system disease in their foetus/infant. Plus those reason in red.

Finding answers will not be an easy journey, but in the meantime a lot of important responses addressing the ZIKV threat - if one exists - have been mobilized. How much work is being done by and within Brazil remains to be communicated more clearly. There is not a lot of information coming out to fill in the blanks and of course that leave idle the tinfoil-encompassed minds of some. Voids get filled by whatever fits. 

Questions remain...

There remain a few of voids around the ZIKV/microcephaly topic that I can and have listed below...
  • How long has ZIKV been in Brazil and in what numbers?
  • What are the real (not affected by extra attention/poor reporting) rates of microcephaly in Brazil?
  • Do real rates of microcephaly diagnoses vary by region/state?
  • What are the real rates of microcephaly in countries other than Brazil?
  • How many microcephaly diagnoses have been infected with ZIKV? How many infections by other viruses including Dengue virus (DENV)?
  • Is microcephaly a seasonal diagnosis? What other possible causes of microcephaly also occur with a seasonal pattern? Are DENV and Chikungunya virus (CHIKV) and other mosquito-borne virus infections seasonal? Is ZIKV seasonal?
  • Is mosquito treatment and/or mosquito breeding in this region seasonal?
  • Apart from Pyriproxyfen, what other pesticides are in use and are they all equally safe?
  • What has been excluded from having a role in causing a GBS or microcephaly diagnosis so far? What are the data supporting this?
  • What about other chemicals that have been associated with microcephaly, for example Isoretinoids in cosmetics [22]
  • What is the tissue distribution of the ZIKV receptor(s) and are we happy we know what that receptor(s) is/are [23]?
  • Does ZIKV cross the blood-brain and placental barriers in the absence of microcephaly?
  • What does ZIKV do in foetal, or infant/child/adult, brain tissue? Is it destructive or inflammatory and does it constantly produce new virus or does it enter some type of latency?
  • How long does ZIKV persist in foetal tissues?
  • Are there long-term disease consequences from ZIKV infection of brain tissue that stretch into adulthood?
  • Does ZIKV persist in the adult central nervous system or anywhere else apart from semen (and what is the upper limit of persistence in semen)? Do DENV, CHIKV, JEV etc persist?
  • Are the mutations observed between ZIKV lineages and within lineages important for viral virulence, transmissibility or for the clinical course of disease?
  • Is ZIKV present in and/or able to persist in the eye (during or after conjunctivitis) or in other organs?
  • Are there mums with evidence of past ZIKV infection who have delivered completely healthy babies? Do these babies have any other issues?
  • How has the study of ZIKV infection in mums been done - by unbiased selection and testing or testing only those with symptoms?
  • When would we expect to see signs of microcephaly among pregnant mothers in Colombia and other countries with large outbreaks of ZIKV?
I'm sure you have your own questions as well.

References...
  1. http://virologydownunder.blogspot.com.au/2016/01/zika-virus-briefly.html
  2. http://wwwnc.cdc.gov/eid/article/21/2/14-1363_article
  3. http://virologydownunder.blogspot.com.au/2016/01/zika-virus-in-amniotic-fluidbut-is-that.html
  4. http://www.eurosurveillance.org/images/dynamic/EE/V19N14/art20761.pdf
  5. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20720
  6. http://virologydownunder.blogspot.com.au/2016/01/zika-virus-disease-zvd-14-cases-until.html
  7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036769/pdf/14-0138.pdf
  8. http://www.ncbi.nlm.nih.gov/pubmed/25001879
  9. http://www.who.int/bulletin/online_first/16-170639.pdf?ua=1
  10. http://www.the-scientist.com/?articles.view/articleNo/45297/title/Brazil-s-Pre-Zika-Microcephaly-Cases/
  11. http://virological.org/t/phylogeographic-analyses-point-to-a-single-introduction-event-responsible-for-the-2015-zika-virus-outbreak-in-the-americas/211
  12. http://virological.org/t/strong-dependence-between-zikv-molecular-rate-estimates-and-host-source-of-viral-sequences/212/21
  13. http://www.nejm.org/doi/full/10.1056/NEJMoa1600651
  14. http://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm6506e1er.pdf
  15. http://www.ncbi.nlm.nih.gov/pubmed/782050
  16. http://wwwnc.cdc.gov/eid/article/22/5/16-0107_article
  17. http://wwwnc.cdc.gov/eid/article/17/5/10-1939_article
  18. http://www.ncbi.nlm.nih.gov/pubmed/26848011
  19. http://www.ncbi.nlm.nih.gov/pubmed/3055197
  20. http://www.nature.com/nrmicro/journal/v2/n1/full/nrmicro799.html
  21. http://cmr.asm.org/content/9/1/18.long
  22. http://drdhesi.weebly.com/blog/-microcephaly-is-zika-the-culprit
  23. http://www.ncbi.nlm.nih.gov/pubmed/26085147
  24. http://wwwnc.cdc.gov/eid/article/22/5/16-0107_article
  25. https://www.washingtonpost.com/news/to-your-health/wp/2015/12/23/brazil-declares-emergency-after-2400-babies-are-born-with-brain-damage-possibly-due-to-mosquito-borne-virus/
  26. http://wwwnc.cdc.gov/eid/article/21/1/14-0894_article 
Updates...
  1. Some text colour and formatting corrections

Debugging the recent claim that Pyriproxyfen is the cause of microcephaly in Brazil...

I've copied the text below, in it's entirety, from the Science Media Exchange (Scimex; [4]) site run by the Australian Science Media Centre (AusSMC). I asked A/Prof Batholomaeus if he would be okay with this and he was.

The AusSMC had asked for local expert opinion on the recent claims by some physicians from Argentina that a pesticide, Pyripyroxyfen, could be causing microcephaly rather than Zika virus (ZIKV).


As those who read me know, I'm also not convinced that Zika virus is causally linked. For what that's worth. But should better data appear, I will certainly support them here.

This pesticide issue is the latest outcry generated by people seeing two events occurring at the same time - microcephaly and Zika virus epidemic/genetically modified mosquitoes/Tdap vaccine use - as linked events rather than just as events that have co-occurred in time and space. Just coincidence. The only way to rule out coincidence is to do a lot of hard work - which takes time and patience. And is hopefully being done. As ever though, it would be great for more of that progress to be communicated publicly.

_________________________

EXPERT REACTION: 
Is a pesticide, not Zika virus, causing microcephaly?

Read some other comments from https://www.scimex.org/newsfeed/expert-reaction-is-a-pesticide-not-zika-virus-causing-microcephaly

Adjunct Professor Andrew Batholomaeus is a consultant toxicologist from the School of Pharmacy, University of Canberra and the Therapeutic Research Unit, School of Medicine, University of Queensland


"Pyriproxyfen is an insect growth regulator with a mechanism of action that is highly specific to insects. Pyriproxyfen is used on a wide variety of crops and is recommended by the WHO for addition to drinking water storage vessels to prevent the spread of deadly diseases such as malaria.

Studies in rats and rabbits have shown pyriproxyfen to have no reproductive or developmental effects at doses up to at least 100 mg per kg of body-weight every day. This intake would be equivalent to an average human female consuming 6 grams of the compound per day. The acceptable daily intake of pyriproxyfen set by the WHO is 100 micrograms per kg of body-weight per day for a lifetime.

This equates to approximately 6 mg per person per day. By contrast the WHO recommended addition of pyriproxyfen to drinking water storage is a maximum of 10 micrograms per litre which would deliver a daily dose of 20 micrograms. A microgram is one millionth of a gram. Thus, the intake of pyriproxifen in Brazil from treated drinking water is of the order of 300 times lower than the safe limit set by the WHO.

All of this information is readily available to any genuine scientist looking dispassionately at the potential causes of the Zika virus outbreak or the rise in malformations in Brazil. Also readily available is the knowledge that the use of pyriproxifen is driven by WHO recommendations and not the marketing activity of any multinational or other corporation.

The potential human health consequences of discouraging the use of pyriproxyfen in drinking water storage and other mosquito-reduction programs is catastrophic with potential deaths and serious disease from otherwise avoidable malaria, dengue and other mosquito-borne diseases numbered in at least the hundreds of thousands. If these reports and suggestions are motivated by anything other than ignorance and poor scholarship they are deserving of the most strident condemnation.

Journalists covering this story would do well to research the background of those making and reporting the claims as the underlying story and potential public health consequences may be far more newsworthy than the current headlines"


_________________________

Further reading...
  1. Pyriproxyfen in Drinking-water
    World Health Organization
    http://www.who.int/water_sanitation_health/dwq/chemicals/pyriproxyfen.pdf
  2. PYRIPROXYFEN AS A MOSQUITO LARVICIDE
    J.F. INVEST AND J.R. LUCAS
    http://www.icup.org.uk/reports%5CICUP886.pdf
  3. Pyripyroxyfen general fact sheet
    National Pesticide Info
    rmation Center , USA
    http://npic.orst.edu/factsheets/pyriprogen.pdf
  4. The science media exchange (Scimex)https://www.scimex.org/ 
  5. Australian Science Media Centre (AusSMC)
    http://www.smc.org.au/

Friday, 12 February 2016

Risk to the community of Zika virus after >insert detail< in Australia....unchanged at LOW

To my fellow Australians,

Despite this latest detection of Zika virus 

>insert day< 

in a 

>insert age, sex, whether pregnant, weeks pregnant, emotional status and any other information considered for inappropriate for publication by any group of reasonably minded people< 

in 

>insert street, hospital, city, state<, 

there has been no change to the level of risk to the Australian community.

>insert image of very distressed baby<

Overturn any water containers outside your house and sleep well.

Sweet dreams,

Virology Down Under.

#Zikasteria #ZeekOfNoTesting #Zikafied

Thursday, 11 February 2016

Not testing for the virus you are trying to associate with a disease is really dumb...

I quickly skimmed over two new papers last Friday (AEST) and was appalled.[1,2] 

In their current format, these papers really just should not have been published at all. 

Any respectable peer review would have sent them back for additional results, to be completely re-written as a letter or more simply - and what I would have recommended to the Editor - that they be rejected outright. 

I was asked if this was just a lost-in-translation error, but complete absence of laboratory data is not that. And that's what these lack - any testing for the virus they name - Zika virus. 

How can you publish something even hinting that a disease is caused by a virus infection, when you present no data to show that person was ever infected by that virus? How can you seriously have that conversation at all?

And using "presumable"and "clinically diagnosed" doesn't get you out of jail either. 

You need some evidence that the virus is or was in the tissue(s) in question (viral genetic material or infectious virus isolated in culture), or was present at some point in the past (antibodies or cells tat respond to the virus when challenged by it in the laboratory) in the person. Neither of the papers here do that. Which astounds me.

Sadly today, there seems to be a journal willing to take any manuscript so that even had the authors been rejected, they most likely would have had their paper appeared elsewhere. 

Or perhaps they had been rejected - and this is that "elsewhere".

I think this sort of publishing sets a hugely dangerous precedent. If the "scientific and medical" literature cannot be relied upon to present its results accurately and with necessary context, how do we expect the community to be able to accurately judge risk and respond reasonably, or our public health experts to find the extra time to sort the signal from the background noise, or the media to get the story straight? 

The Zika virus epidemic of 2015/16 has made much more background noise than signal to date. I hope that changes soon because its hugely disappointing to see so many responding to noise as if it were fact, and fact as if it was hiding conspiracy.

References...
  1. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection.
    Arquivos Brasileiros de Oftalmologia
    http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27492016000100002&lng=en&nrm=iso
  2. Zika virus-related hypertensive iridocyclitis
    Arquivos Brasileiros de Oftalmologia
    http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27492016000100020&lng=en&nrm=iso&tlng=en