Where do we stand with #Zika causing #microcephaly?

Early 2016, WHO, supported by CDC and following reports published in NEJM, concluded that Zika virus is causing microcephaly. The evidence based medecine was referring to outbreaks which occurred both in Brazil (Spring 2015) and Colombia (Fall 2015).

As of today, Zika outbreak in South America is (temporary?) over and we may start a review of the risk factors and address lessons learned:

  • Zika virus has been found and localized in fetus and new born; Virus is capable to pass through placenta and brain barrier of the fetus.
  • In vitro studies are reproducing nerve cells damages caused by zika virus.
  • There is a close relationship between microcephaly and zika virus.

Here are some of the key points demonstrating that Zika virus is one condition leading to microcephaly; but question is to consider if it is the only one? In other words, does microcephaly resulting from a unique cause or multi-causal?

Zika Map BrzailSince the beginning of the outbreak in Brazil, some Doctors and Scientists, mostly South-american, were pointing out the possible role and responsibility of a larvicide (Pyriproxyfen) used in North-East Brazil and poured in water tanks/reservoirs where water pipe system does not exist. But recently a study reported the lack of effect of Pyriproxyfen on the human being.

So, what do we need to address today by reviewing the Zika outbreak in South-America?

NTD_zikaWe have found People who were co-infected by Zika and Dengue and for a few of them, co-infected by Chikungunya, ZIKV+DENV.

Researchers also found that Dengue antibodies can initiate a specific reaction through antibody dependent enhancement (ADE) of infection with zika virus, leading to autoimmune diseases like Guillain Barre syndrome and which might be explaining pathophysiology of microcephaly.

WHO reported a study case in Martinique:Mother infected by DENV,CHIKV and ZIKV

zkv-martinique

Eipdemio Brazil_ZIKV_DENV_CHIKVSaying that, back to real life, in vivo, by looking at what happened in NE Brazil; starting with Dengue outbreak then followed by Zika and finishing by Chikungunya outbreak. In other words, the zika outbreak occurred on a population which was acute immunized for Dengue and a ADE might have happened in this region of Brazil explaining the discrepancy with the other regions of Brazil.

Now and looking at the numbers of microcephaly in Colombia, it is interesting to analyze prevalence of Zika related cases compared to the entire microcephalies: zika-related-microcephaly-numbers-colombia60/752 = 8%.

Where are coming from the others? That means 92% of microcephaly cases are not related to zika virus but might be related to either infectious diseases including but not limited to Rubella or Cytomegalovirus. Another source might be socio-economics in these regions of NE Brazil and some locations in Colombia in link with poor resources for sanitation and poor quality of food leading to a lack of hygiene and Vitamines deficiency.

As an Health risks manager, always tracking root causes analysis and trying to understand 5 Why, I have to admit that I have not been convinced by the double statement posted by WHO & CDC on Zika virus causing microcephaly but still looking for multi-factors, multi causal including possible co-infection and ADE.

#zika in Colombia: still waiting for a peak of #microcephaly in September…

October 3rd 2016; updated on January 9th 2017

Early September, Minister of Health in Colombia declared end of Zika outbreak. With 78.000 suspected /7166 confirmed cases ; 21 microcephalies and 398 Guillain Barré Syndrome (GBS). It means prevalence for microcephaly estimated in a range of 2.7/10.000 to 29/10.000 at the time being. As of today we have 42 microcephalies recorded leading from 2.7/10.000 to 5.9/10.000 for the confirmed cases.

from @thelonevirologi

 According to data, 7.9% microcephaly cases are linked/caused by Zika virus so far.

According to evidence based medecine, taking into account tested ZIKV + microcephaly cases, we get 17% of the entire microcephaly tested for ZIKV.

Question: if we all agree to say that Zika virus is involved in the immunological process leading to neural defect and microcephaly, we have to cope with other causes (83%) responsible for microcephalies. On a Global Health issue, it appears more and more obvious that studies are required to build a full picture of the root causes tree regarding microcephaly outbreak in South Americas. By comparing Brazil with Colombia, we might discover different paths to follow, especially by studying what happened in NE Brazil.

colombia-and-zikvdenvchikv_2016

Colombia recorded a lot of GBS (>398) compared with microcephaly (>21). A interesting paper is just released in J.Autoimmun 2017 by Colombian researchers pointing out the role of Dengue antibodies. Socio-economics factors are also interfering in the process leading to neurological defects.

“All GBS patients were positive for IgG antibodies against both ZIKV and Dengue virus, and 69% were positive for Chikungunya virus.”

Some time ago, CDC and WHO have posted a statement on microcephaly caused by Zika virus. May be they jump the gun?

Is #zika (alone) really causing #microcephaly in Brazil?

For the second time, US CDC declares publicly that Zika virus causes microcephaly (M) and other Central nervous system diseases (CD):13% of zika tested positive could lead to microcephaly if occurring at the early stage of pregnancy (<3 months).

In his excellent blog, VDU’s blog, Pr Ian Mackay is monitoring epidemiological data coming from Brazil on a weekly basis. For his 27 report, week 20, he is pointing out that 15% of all confirmed M&CD diagnoses and 3% of all suspect diagnoses are reported as positive for ZIKV testing . Question: what are the causes of the 85 to 97% M&CD?

Eipdemio Brazil_ZIKV_DENV_CHIKV

If we now refer to another paper on causes of microcephaly in Brazil, in Pernambuco State (2015), it is amazing to notice that based on a cohort of 104 newborns with microcephaly, we observe plenty of cases related to TORCH infection, some of them due to co-infection. It is mentioned that ZIKV test was not available at that time, between April and December 2015. Compared with previous records 2010-2014 with 7 cases/year, Brazil health authorities have recorded 874 cases in Pernambuco State in 2015. Taking into account that Zika outbreak started in April 2015 in Brazil with a peak around October, the question raised to consider Zika virus (alone) causing mincrocephaly. In this survey, Dengue does not appear to be a co-factor as suggested by other case review studies and confirmed by In Vitro experiments.

Danger ZikaSaying that, it is obvious that 2015 recorded abnormal increase of microcephalies, especially in NE Brazil: 7 ->874 microcephalies (x125). If highly significant, the question behind is to understand the root causes, focusing on the role and responsibility of Zika virus. Cytomegalovirus and Rubella are the two main identified virus related to these microcephalies without the capability to link with Zika virus (not tested).

Last, not least, it remains an unclear statement with regards the use of pesticides/larvicides during the same period of time in the same region of Brazil. Notwithstanding, we have to address the question of huge differences in the numbers reported in NE compared with other regions in Brazil. At the end of the day, it remains a speculation of co-factors or co-infection acting jointly with Zika virus as causing microcephaly.

#zika / #microcephaly in Colombia / Brazil

May 17th 2016

We were speculating on Colombia as a control group for microcephaly caused by Zika virus. 7 months later, we do not observe the same occurrence/prevalence for microcephaly than declared (without evidence) in NE Brazil. As of today less than 10 microcephalies has been recorded in Colombia. How explaining such a huge discrepancy between Brazil and Colombia?

  1. Lack of accurate reporting in Brazil leading to overestimation
  2. Possible non identified co-factors:
    • Poverty, poor hygiene, Vitamin deficit/malnutrition
    • chemicals:pesticides,larvicides,…
  3. Timeline of outbreaks: Dengue,Zika

During Zika summit hold in Paris, Institut Pasteur, there were some debate on the role and responsibility of immune system and microcephaly or Guillain-Barré Syndrome (GBS); We see emerging evidence for an autoimmune process as the main cause of central nervous system defects observed during Zika.

Colombia 2

Brazil and Colombia have both naive population with regards immunization for Zika. It looks as if Dengue antibodies might react with Zika virus as an enhancement of the immune response on the CNS of fetus during the first quarter of pregnancy, affecting neural cells.

The immune response to the previous infection of dengue is potentially one of the mechanisms that can make you more susceptible to Zika. It’s definitely not been 100% proven yet, but there’s a lot of work going on to investigate it.

Dr Abigail Culsh, Research Associate at Imperial College London

Recently, studies in mice are demonstrating that Zika virus is able to cross placenta barrier and to replicate, damaging the placenta by the way; same for the brain barrier.

These three reports provide conclusive evidence that Zika virus can cross the placenta and cause fetal defects in mice, and provide models to understand the biology and pathogenesis of infection.

by Vincent Racaniello,Earth’s virology Professor

More and more evidence describing physiopathogenesis of Zika virus and how it affects CNS in adult (GBS,myelitis,meningo-encephalitis) or fetus (birth defects, microcephaly or still born).

But also more and more evidence to support the key role of immunity interacting with Zika virus like Dengue antibodies, leading to neural damages and explaining microcephaly acquired during Q1 of pregnancy.

Better knowledge of Zika virus and its interactions with other substances, antibodies or environments are key elements helping to understand the gaps between Colombia and Brazil. As said before, not sure Brazil will get the capability and willingness to review and validate the entire non tested cases recorded as Zika causing microcephalies. Home State Politics and Olympics Games will now take the lead…

#zikasummit in Paris hosted by Institut Pasteur: New pathways

Zika summit ParisLucky attendee of the zika summmit in Paris hosted by Institut Pasteur, fully committed in Zika study and on the way for producing a new vaccine; but first starting by discovering Zika virus, its environment, its vector and its morbidity. Nice opening then scientific Lectures followed by some good news by presenting previews of scientific works and studies. At the end of the first day on Public Health and epidemiology of Zika, no speaker declared Zika as causative microcephaly but Zika as involved in the process of microcephaly; that makes a huge difference…

Historical then clinical review of Zika virus discovered in 1947 in Uganda then traveling worldwide, first west then moving back to east before reaching South America in 2015. A timeline of Zika in Americas compared with other outbreaks occurring at the same time or/and at the same location, like Dengue, Chikungunya.

A good reminder on the neurological damages due to CMV and feedbacks.

What are the lessons learned (from French Polynesia) and new trends about Zika virus and microcephaly or Guillain-Barré Syndrome (GBS)?

  • Ecosystem:Possible several Vectors for Zika virus
  • Zika virus among Flavivirus family including Dengue
  • Role and responsibility of immunity:
    • Ab, IgM, IgG and autoimmune system
    • enhancement of Zika virus by acquired immunity
    • Co-infection with Dengue or Chikungunya
  • Specs and conditions related to Zika in Americas:
    1. naive population
    2. several waves of outbreaks:
      • Dengue
      • Zika
      • Chikungunya
    3. to be at the wrong place at the wrong time
  • Neurotropism of Zika
  • Co-factors, aggravating factors suspected
  • Timeline for pregnancy impacting fetus
  • Zika virus crossing placental and blood brain barriers

No more but no less to be happy by attending this meeting entirely dedicated to Zika by gathering scientists working in both Research Lab or Public Health departments, what is called now Global Health and by sharing in real time critical previews of new studies and preliminary results.

Structure 3D Zika virusNo doubt, PHEIC was declared by WHO on February 1st 2016 in order to cope with microcephaly, not Zika virus, as the emergence of an unexplained neurological complications related to a Neglected Tropical Disease (NTD) like Zika. Knowing that almost 80% of Zika cases are unknown due to lack of clinical symptoms, it is a great importance for improving knowledge of pathogenicity and physiopathology. How immune system, autoimmune reaction are connected and if there are cause related to co-infection.

Far from the “politically correct” speaking but always based on evidence, the panel of speakers gave us an optimistic orientated overview with new vision and perspectives for the on coming future. Instead of focusing on what we know, it was effectively more interesting to address the questions about what we don’t know about Zika and microcephaly + GBS. If you see what I mean…

#zika as causative for #microcephaly: Has CDC jumped the gun?

April 18th 2016

Following both WHO statement and press release of NEJM, CDC declared last week that Zika virus is cause for microcephaly and other neural collateral damages. What a stress related to this short shrift by US CdC for science. In other words, Game is over and time to go back to R&D for searching and developing, producing asap new vaccine, new drugs to fight Zika, keeping an eye on vector control, more specifically Aedes aegypti and albopictus (mosquitoes carrier of DENV, CHIKV and ZIKV).

Forget the root causes analysis; don’t mind whatever co-factors are responsible for occurrence and emergence of microcephaly beside Zika virus; CDC says that Zika is cause of microcephaly and that might be enough to agree. Don’t You? But Why? US National Health Agencies are seeking for Funds (1.9 BN $) in order to cope with an outbreak preparedness plan, classified as likely; Congress is still refusing to raise and allocate this funds waiting for more conclusive evidence of Home security threat. No doubt, there is a conflicting situation between White House and Congress (Republicans) with regards the on coming presidential election. May be too far from Public/Global Health issues?….

NTD_zikaWe have to raise this question, right now: is the Zika threat overestimated? and if yes, why? Is the risk related to microcephaly over reported by exaggerating alarming numbers? Is there a link between false reporting of Zika cases (just suspected but not tested) and politics at a time where Brazilian government is facing an Impeachment procedure? The PHEIC declared by WHO is addressing unanswered questions about microcephaly observed and recorded in Brazil; surprisingly, only states of North-East regions are concerned so far, raising interest about causative of microcephaly beyond Zika virus, through co-factors or different risk factors as previously explained; mostly pointing out the role and responsibility of DENV or IgM,IgG immunization reaction following infection or co-infection with Zika virus.

Colombia appears to play the role of a control group by comparing stats with Brazil. Fortunately, a few microcephaly cases are related to Zika virus so far: only 2 cases as of today, when we are observing fewer microcephaly cases related to Zika than cases related to the other viral causes (Rubella, CMV). Surprise, surprise…

Q: What is the predictive value of Brazilian numbers? The first estimates have been reviewed and reduced from 600.000 to 200.000 cases. Do you remember the estimates for Ebola at the beginning of the outbreak in West Africa? How credible are these forecasts based on maths modeling and far away from the front line?

 It looks like Scientists and Health agencies running a race against the time to get money and budget just before publishing evidence for a multi-causal model explaining microcephaly in Brazil; budget which could not be voted without stressing on Congressmen and before a “Name and Shame” procedure for Republicans refusing to allocate the resources to fight the Tiger; knowing the race for Presidential is at its final stage. Some writers tried to compare with a terrorist threat, even if a bit rude but efficient.

Dilma RousseffWho has interests to hide  the truth in Brazil? Not to report how many People living in NE are impacted in areas outside of basic sanitation and running water? Dilma Roussef is now involved in a process leading to Impeachment following lower chamber’s decision. The increase of microcephaly cases, whatever the cause is, are reflecting the poor management of Public/Global Health concerns: lack of waste management, no access to drinkable water, black and grey waters surrounding at community level. No resources (human and equipment) to fight mosquito, except recently by committing the Army forces but pesticide is no longer available in some areas. No tests performed; just report of suspected cases based on clinical symptoms (not specific). No medico-social support for mothers of newborns with microcephaly, abandoned, without long term help and follow-up implemented. The failure and bankruptcy of a Democracy which expected to conduct a social economy but in fact corrupted at its highest level.

Definitively, it is legitimate questioning CDC who has jumped the gun by convicting Zika for microcephaly.

#Microcephaly / #Zika as Political issues?

On Feb.1st 2016, WHO declared PHEIC with regards Zika virus threats and its potential health impacts worldwide; since, we are observing  a surprising crisis management of Zika disease overwhelmed by an international political crisis.

  • Starting with WHO and the funds raisingwho-logo in order to sponsoring both studies on Zika virus in Vitro and epidemiology surveys in Vivo. More questions raised than answered so far since the arrival of the virus in South America, mid April 2015. The emergence of new neurological diseases in link with the virus like GBS, Myelitis or microcephaly which seem to be related to an autoimmune disease are responsible for fears leading to threats for Public Health/Global Health. Pictures of microcephaly posted in Newspapers and social medias are indecent but attracting to People. “Unfortunately”, Zika is responsible for less fatalities than Ebola and is less bankable, despite a urge need to fight the disease.
  • Looking at Brazil, we are focusingZikaMap on the huge amount of microcephaly cases occurring since April 2015 when the Zika virus arrived for the first time in South America. In a way, Zika is a “good opportunity” to hide some of critical points with regards Politics in Brazil including but not limited to corruption scandal with Petrobras, Impeachment procedure of Mrs President. But here are other corps in the cupboard, I mean socio-economics or environmental issues: lack of potable/drinkable water pipe system, sanitation, waste management, vector control by using toxic pesticide/larvicide, poverty leading to malnutrition. It is surprising noticing that the country where started in 1992 in Rio, The precautionary principle applied to Sustainable Development, poor Public Health policy is implemented in some areas like in NE Brazil for testing and monitoring whenever an infectious disease outbreak is emerging. No doubt that budgets have been absorbed by the Olympics Games this summer.
  • What is going on in US Capitol and White House? Congress is rejecting to vote funds for fighting mosquitoes and preventing vector borne diseases including Zika, Dengue and Chikungunya. white HousePresident Obama has decided to move Funds allocated for Ebola to Zika (600 M$). May be a political way to push Congress to feel more responsible and liable just in case of an outbreak of Zika or an increase of microcephaly and especially at the time where Republicans and its representative Donald Trump, are not in the best shape. How avoiding to think about the TV fiction House of Cards and how politicians manipulate each others to achieve their goals. But today is no longer a fiction but true real life.

We are far from Public/Global Health issues and PHEIC despite the need for sponsoring in Vitro Laboratory studies or in Vivo Epidemiology surveys in order to bring on the table some seeds to grind for a better understanding of the pathogenesis and neurotropism of Zika virus.