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**sharon sanders** · January 30, 2016, 08:15 AM

As referenced above....hat tip Crof

January 29, 2016

Is microcephaly surging in Brazil, or just efforts to find it?

Yesterday I posted about Declan Butler's Nature News & Comment article Report questions size of surge in Brazil's microcephaly cases. Today I've read the ECLAMC report on which it's based.
I did so in part because a reader asked why, if the US with 300 million people has 25,000 microcephaly cases yearly, Brazil with 200 million shouldn't have a proportionate number of cases--somewhere around 17,000 cases?

That in turn sent me on a search through various American and European health websites. I found the 25,000 number on just one site, the Foundation for Children with Microcephaly, which also says "Microcephaly affects 2-2 1/2% of the entire population." Perhaps so, but I didn't find corroboration on the 25,000 yearly statistic.

The CDC was far less specific, estimating the microcephaly rate at from 2 to 12 cases per 10,000 live births. Given the approximately 4 million births in the US in 2013, that would mean 800 to 4,800 microcephaly cases.

Brazil's annual live births in the period 2010-2015 were3,073,000. At a rate of 2 per 10,000 births, that would mean 614 yearly microcephaly cases; at 12 per 10,000 it would mean 3,684...very close to the numbers we now hear from the Brazilian Ministry of Health as an appalling increase in cases.

The ECLAMC authors argue that the growth in microcephaly numbers is a "seek and ye shall find" effect: the cases were alway there but not recorded as such. (And I recall late last year that Brazil's medical authorities were in a fuss about just how many centimeters would take a baby from microcephaly to normal.)

They also argue that if the EUROCAT numbers on microcephaly in Europe are accurate (2.85 per 10,000 live births), Pernambuco's 1,153 microcephaly cases out of 147,597 births in 2015 are 25.6 times the European baseline...meaning that 100% of pregnant Pernambuco women must have caught Zika last year to explain 1,108 of Pernambuco's cases.

I'll let you review the ECLAMC report's 13 pages at your leisure and judge whether its arguments make sense—including its proposal for a case-cohort study in some Brazilian state where Zika circulation is increasing. The authors suspect that many other fetal infections (collectively known as STORCH) may be involved, but that remains to be seen. Their arguments seem to me highly testable, and should be tested.

Acquitting Zika of causing microcephaly may cause enormous relief to pregnant women everywhere, especially in Brazil (and enormous embarrassment to Brazil's Ministry of Health and international agencies like PAHO). Latin American tourism and travel will also survive, shaken but unharmed.

But Zika doesn't get out of jail free. It's still charged with triggering unusually high numbers of Guillain-Barr? syndrome cases, and in several countries that have yet to report a spike in microcephaly.

To confirm or refute the Zika-microcephaly connection, and the Zika-Guillain-Barr? connection, we'll need to conduct an enormous surveillance and testing operation coupled with a massive Aedes-extermination program. We'll likely find more unwelcome news about mosquito-borne viruses, but also reduce the numbers of dengue, chikungunya, yellow fever, and Zika cases—not to mention identifying and reducing the causes of many other fetal deformities, around the world.

**Gert van der Hoek** · January 30, 2016, 04:27 PM

Charles Simmins ‏@CharlesSimmins

Microcephaly and Zika

January 30, 2016

Is there an outbreak of microcephaly in Brazil? That is one of the first questions that ought to be asked when examining the topic of the potential effects of a prenatal Zika viral infection. Without knowing the preexisting rates of this serious yet usually rare birth defect, any recent change is impossible to detect. Unfortunately, data from public health authorities and medical educators is so varied that a conclusion may not be possible.

Each piece of data below will have a citation number, displayed in bold red, which refers to an ordered list at the bottom of this piece.

Data

Births	[1] 2,953,597		[2] 3,988,076
SOURCE	INCIDENCE	CASES	INCIDENCE	CASES
Brazil, PER 10,000 [3]	0.5	148
CDC A, PER 10,000 [4]	1.0	295
CDC B, PER 10,000 [5]	2.0	591
ECLAMC, PER 10,000 [6]	1.98	585
CDC C, PER 10,000 [7]		591	2.0	798
CDC D, PER 10,000 [8]		3,544	12.0	4,786
Virginia DoH A, PER 10,000[9]		1,181	4	1,595
Virginia DoH B, PER 10,000[10]		1,772	6	2,393
Cleveland Clinic A, PER 10,000 [11]		347	1.18	469
Cleveland Clinic B, PER 10,000 [12]		476	1.61	643
Handbook of Toxicologic Pathology A, PER 1,000 [13]		1,772	0.6	2,393
Handbook of Toxicologic Pathology A, PER 1,000 [14]		4,726	1.6	6,381

The second table uses the above data from the United States, and its application to Brazil, to show the means and medians. I discarded the data from the highest incidence, 12:10,000 and the lowest, 0.6:1,000 before calculating.

	INCIDENCE	CASES	INCIDENCE	CASES
Mean		1,516	2.73	2,047
Median		886	1.81	1,197

Discussion

In a Jan. 26 article in Nature, Declan Butler explores the possibility that the increase in reported microcephaly cases in Brazil is unrelated to an outbreak of Zika viral illness and may even be non-existent. The article, titled Zika virus: Brazil?s surge in small-headed babies questioned by report, is based upon a report from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) [6].
In the article, Butler reports that as of Jan. 27, Brazil had ?4,180 suspected cases of microcephaly recorded since October.? The government had examined 732 of those, and had rejected 462, 63 percent, as false diagnoses. While the ratio of false diagnoses of 462:732 is unlikely to be the final result, it provides an additional set of data that can be analyzed in a limited way.
Using the 4,180 suspected cases as a starting point, the analysis suggests that 1,547 cases will be found to be properly diagnosed as microcephaly. That number is very uncertain but it is useful. If incidence rates other than those from the Brazilian government and the rates labelled CDC A and CDC B are used, 1,547 begins to look a lot like a normal number of cases.
ECLAMC notes in its report that the Brazilian authorities are using an unproven criteria for microcephaly. The government has changed the diagnostic criteria to reflect that all children with a head circumference of less than 33 cm. should be reported as a case of microcephaly.
Normal head circumference is known to vary by ethnicity. [15] Newborns in the United States have been found to have a larger head, on average, then those in the Third World. It is also noted that an exam and measurement of the skulls of a newborn?s parents is also warranted as the family may just be expressing a trait for a smaller than average skull.
More than one study has noted that the WHO charts vary from those produced by the CDC. ?For children in industrial countries, the mean OFC is larger than that indicated in the WHO standard values, which are based on measurements taken from about 8500 children in Brazil, Ghana, India, Oman, and the USA.? [16] OFC is the abbreviation for occipital-frontal circumference.

Conclusion

Data exists that suggests that the number of confirmed cases of microcephaly in Brazil will be far lower than the number of reports. In addition, the actual number of cases of microcephaly per year in Brazil prior to the arrival of the Zika viral illness is less clear than it might be. It is impossible to draw a sound conclusion that the Zika outbreak has or has not added to the number of cases of microcephaly in Brazil.
The data is suggestive that the number of microcephaly cases will range, in a given 12 months, from normal to two or three times normal. It remains an issue of great concern but the hype seems to have far exceeded the threat.

Citations and Sources

CIA World Factbook 2015 estimate
U.S. National Vital Statistics Report Births:Final Data for 2014
Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible Association Between Zika Virus Infection and Microcephaly ? Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65:59?62. (historical incidence)
ibid. (expected incidence ? low)
ibid. (expected incidence ? high)
Latin American Collaborative Study of Congenital Malformations (ECLAMC)
CDC Facts about Microcephaly (low)
ibid. (high)
Virginia Dept of Health fact sheet Microcephaly (low)
ibid. (high)
Cleveland Clinic ? Microcephaly in Children (low)
ibid. (high)
Editors Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Haschek and Rousseaux?s Handbook of Toxicologic Pathology, Third Edition, Volume One (Waltham: Elsevier, 2013) 2723. (low)
ibid. (high)
BAXTER, P. (2011), Head size: WHOse growth charts?. Developmental Medicine & Child Neurology, 53: 3?4. doi: 10.1111/j.1469-8749.2010.03847.x
von der Hagen, M., Pivarcsi, M., Liebe, J., von Bernuth, H., Didonato, N., Hennermann, J. B., B?hrer, C., Wieczorek, D. and Kaindl, A. M. (2014), Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Developmental Medicine & Child Neurology, 56: 732?741. doi: 10.1111/dmcn.12425

**sharon sanders** · January 30, 2016, 05:59 PM

Saturday, January 30, 2016

Pondering The Great Zika Unknowns

PAHO - Zika Spread Epi Week 4

#10,948

It is practically an axiom of infectious disease blogging that the first details you get on any emerging disease outbreak are nearly always wrong, or at least misleading. Rarely are all of the pieces to the puzzle immediately available, and the media's narrative is often geared more to boosting circulation than presenting the facts.

As a result, I only sparingly use media accounts in this blog and try to use official releases of information where I can. Of course, those are often wrong (or biased), as well.

I've called it the `fog of flu' before - borne of situations where there are alarming but ambiguous reports of something `bad' breaking out - but very little real information. We deal with it every winter, as we try to parse out the avian H5N1, H5N6 and H7N9 cases from the yearly cascade of seasonal flu and other respiratory outbreaks in places like Egypt and China.

Since November we've been aware of reports of elevated cases of microcephaly in Brazil which the local authorities have tentatively linked to the arrival of Zika last spring. The case numbers have been alarming, the stories of its impact tragic, and we've seen strong warnings issued by our own CDC regarding travel to the region by pregnant women.

But despite all of that, it is far from clear what is going on with Brazil's rates of microcephaly, or even if Zika is responsible.

Overnight both Crof and Dr. Ian Mackay have weighed in on this topic, and I encourage you to read both of their efforts.

First Crof, whose excellent analysis of the (admittedly sketchy) numbers to date (see Is microcephaly surging in Brazil, or just efforts to find it?), was inspired by Declan Butler's Nature News & Comment article Report questions size of surge in Brazil's microcephaly cases.

Ian took a hard look at this week's MMWR report Possible Association Between Zika Virus Infection and Microcephaly ? Brazil, 2015, and finds it wanting in:

Microcephaly in Brazil: is it occurring in greater numbers than normal or not?

A paper came out yesterday (AEST) from Morbidity and Mortality Weekly Report (MMWR) with the heading...

Possible Association Between Zika Virus Infection and Microcephaly ? Brazil, 2015

Reads as though some great data may finally show us a hint of an association between Zika virus (ZIKV) infection and microcephaly disease. Right?

Nope. There are none. At least none that could approach satisfying that title which highlights that it is not just the popular media who can generate misleading titles (headlines in their case).

(Continue. . .)

This lack of evidence doesn't mean the evidence won't be found, or that a problem doesn't exist. Only that there are an awful lot of questions yet to be answered.

CIDRAP Director Dr. Michael Osterholm, on the other hand, already finds the evidence compelling. He looks at the rise in mosquito-borne threats in the Americas - due in large part to the cutbacks in mosquito control efforts over the past couple of decades - in:

How Scared Should You Be About Zika?

By MICHAEL T. OSTERHOLM JAN. 29, 2016

Zika, or perhaps co-infection(or sequential infection) with Zika and other similar arboviruses (DENV, CHKV), may very well turn out to beresponsible for increased rates of microcephaly, spikes in Guillain-Barr? syndrome (GBS), or other serious outcomes.

Other viral infections have produced similar impacts, so it is certainly plausible. But until we know for sure, it is important not ignore other possibilities.

While it may be overstated, I find it hard to believe Brazil's reported surge in microcephaly is due entirely to observational bias, even granting that the base line numbers are suspect and most of the cases are still only suspected. Something certainly seems amiss.

But that's what epidemiological investigations are for . . . to find out.

There are other issues, other unknowns, including determining exactly what species of mosquitoes can (and cannot) transmit the virus, that will need to be nailed down by scientists before we can accurately gauge the impact Zika will have on North America.

I certainly have no inside information or special insight into all of this - but considering the potential impacts to individuals, to families, and to society - it seems only prudent to regard Zika as the most likely culprit - at least until proven otherwise.

Which means, until we know different, the smart money will be on preparing to deal with an enhanced mosquito threat this summer, and likely for many years to come.

Because if it isn't Zika, there's always WNV, Dengue, CHKV, and EEE out there, and they can all ruin your entire day.

Posted by Michael Coston at 2:10 PM

**sharon sanders** · January 30, 2016, 06:01 PM

Also please see:

DIscussion: Congenital birth defects and the Zika a virus

**Pathfinder** · January 31, 2016, 04:54 PM

Translation Google

The effects of Zika are less well known than believed

Jean-Yves Nau Science & Health 01/30/2016 - 12h 29 updated the 01/30/2016 at 12 h 29
...
No one predicted the extent of the epidemic; nobody had imagined that transported long-distance by female mosquitoes Aedes aegypti, Zika virus would progress so quickly and on such a scale in the Americas. The first case was reported in Brazil in May 2015. The epidemic now affects about twenty Latin American countries. WHO is now talking about an epidemic spread "explosive" and said the alert level is "extremely high". It will gather in Geneva an emergency committee on 1 February. US President Barack Obama called for urgent action. A few isolated cases are reported in Europe in returning traveler American countries. And France Marisol Touraine, Minister of Health, January 28, "recommended for pregnant women (or having a project of pregnancy) and had planned to travel to the Caribbean or in affected countries in Latin America, to defer their travel plans. "

These recommendations of the Minister are based on an opinion of the High Public Health Committee (HCSP) dated January 5 and translated into practical measures by Professor Beno?t Vallet, Director General of Health, January 22. US health officials from the Centers for Disease Control in Atlanta formulate similar precautions for restricting the travel of pregnant women (and those considering the future) to the infected countries. In all cases it is the risk of neurological birth defects induced by the infection of a pregnant woman who is advanced. The main of these malformations is a "microcephaly" [1].

Causality in doubt

But health officials also point each time, that if the existence of that risk seems very likely it does not mean scientifically established. The "causal link" between maternal infection and cranial malformation of the newborn is not indisputably proven. This demonstration will still require different work from sophisticated virological tools. The evidence today are made by this new emerging discipline that is the "spatial and temporal epidemiology" in the words of Prof. Eric Caumes, head of the infectious diseases in the Piti?-Salp?tri?re ( Paris); is a model for analyzing the dynamics and risks of epidemics in the absence of molecular confirmations. "It is this approach which, for example, allowed to understand the origin of the Nepalese cholera epidemic raging in Haiti in 2010," says Professor Caumes.

For now there is a beam of converging arguments in favor of the viral origin of microcephaly. These arguments are presented and analyzed in the opinion of the HCSP to the drafting of which Professor Caumes participated. Until the end of October 2015 the Zika virus had not been described as responsible for microcephaly or other birth defects. But epidemics had previously concerned only sparsely populated areas like Micronesia. In late October 2015, the Brazilian Ministry of Health stated 54 cases of microcephaly among newborns in several public and private hospitals in the northeast of the country. Quickly other cases of neurological birth defects have been reported in other Brazilian states where flows the Zika virus. Either in total 2782 suspected cases (including 40 deaths) reported mainly in the states of North-east.

Experts also report cases of rare defects (neonatal brainstem dysfunction) in newborns after an outbreak of Zika in French Polynesia from October 2013 to April 2014. The survey also showed, in the same period, an increase of the number of brain malformations that led to medical abortions. Other arguments exist that argue in favor of this hypothesis.

"How to go further in demonstrating a causal link? For obvious reasons we can never go as far as to verify the rules of the postulate of Koch and conduct an experiment of experimental infection, says Dr. Alain Goudeau, Head of Microbial virology department of University Hospital of Tours. History shows that the epidemiological evidence is sufficient. As in the case of rubella. Virus isolation in fetal tissues was only a complementary element to affirm the great danger of the virus in pregnant women. It seems to me that with Zika we are not far from this level of evidence. "
...
http://www.slate.fr/story/113349/vir...-microcephalie

---------------------------------------------------------------------
Jean-Yves Nau 725 items Journalist and medical doctor, former teacher, Jean-Yves Nau was in charge of the medical section of Monde from 1980 to 2009. He also holds the Journalism and Public Health blog. http://www.slate.fr/source/jean-yves-nau

Page introuvable | Slate.fr

http://www.slate.fr/source/jean-yves-nau

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Excerpt from France High Council of Public Health report, published online on January 22, 2016:

Full report (in French)
Avis (721 ko)

Translation Google

High Council of Public Health
REVIEWS

on updating the HCSP opinion of July 28, 2015
on the medical care of people affected by Zika

January 5, 2016
Revised January 20, 2016

...
Discussion of the hypothesis of a relationship between the increase in cases of microcephaly and

Zika virus infection in Brazil and French Polynesia

? Available data

Cases of neonatal microcephaly reported in Brazil coincide with the occurrence of
Zika epidemic. However, this increase was markedly observed in 8 states
the 18 states where flows the Zika virus (see Table 2) in 1112 and an increase in cases of
microcephaly has been reported in the Sergipe (small state located between those of Alagoas and Bahia)
where the circulation of Zika virus is not notified by the health authorities.

On 18 November 2015, the laboratory flaviviruses of the Instituto Oswaldo Cruz established the
presence of Zika virus genome by RT-PCR in samples of amniotic fluid
from two pregnant women in the state of Paraiba in whom the diagnosis intrauterine
microcephaly had been worn by ?chographie13. These observations illustrate the
Placental transfer possibility of the virus. Furthermore, the genome of Zika virus was
detected in the blood and tissues of a newborn with microcephaly and died in
hours after naissance14.

Many mothers who have children with microcephaly have reported the occurrence
of rashes during pregnancy but this type of symptom can be observed in
of dengue and chikungunya. However, dengue virus and chikungunya have
caused major epidemics for many years around the world
affecting millions of people, are not considered responsible
of embryof?thopathies.

There were no reports of other infectious or toxic known causes that can explain the
upsurge in cases of microcephaly. This is, however, being investigated by the
Brazilian health authorities.

In French Polynesia, cases of embryof?topathies also coincide with the period
probable Zika virus circulation. In 15 cases, at least a portion of the first six months of
pregnancy took place during the epidemic period.

At least three mothers reported a Zika type of episode during pregnancy, but others

Investigations are ongoing. All mothers had received a serological balance
pregnancy and no cases of CMV or rubella infection was detected. In addition, the 13 results
Available realized karyotypes were normal.

? Data analysis

The space-time approximation supports the hypothesis of a relationship between increased
cases of microcephaly and Zika virus outbreak although a number of data are
conflicting or missing.

Zika virus detection in amniotic fluid suggests that transplacental infection
is possible.

Correlation studies can be biased in that the infections are Zika
often asymptomatic.

To evaluate the causal nature of the association between Zika virus infection during the
pregnancy and congenital neurological defects, it is necessary to gather a
beam of arguments for and against the relationship of causality. Analysis
causation based on the criteria of Hill can contribute to the establishment of the causal relationship
effect [9]. Table 3 summarizes the analysis of causality.

Table 3. Analysis of the causal association between increased incidence of
congenital neurological defects and the occurrence of Zika virus infection
Hill criteria criterion Rating

Strength of the association strong statistical association: Brazil, the magnitude of the increase
affect neurological birth defects
(multiplied by 20 in some states) can not be explained by the
random grouping of those cases (Poisson cumulative probability;
p <10-12) 15. In French Polynesia, the increase of incidence of
DNTC was multiplied by 20 and that of embryofoetopathies by 10.

Coherence (repetition of
observations
different populations)
The association has been observed in Brazil and French Polynesia.

Specificity (a cause
an effect)
Not applicable

Temporal relationship
(temporality). The causes
must precede
aftermath
Brazil and French Polynesia, there is a correlation
time between the emergence of Zika virus population
increased incidence of birth defects (<9
month). Some mothers, especially in Brazil, report the
occurrence of signs suggesting Zika virus infection during
pregnancy.

Dose-response relationship Not applicable
Plausibility (plausibility
biological)
There is no formal scientific proof for a tropism
Zika of neurological prenatally. In Brazil, the presence of
virus in the amniotic fluid has been documented for two fetuses
suffering from microc?phalie16. Genome Zika virus was detected
in the blood and tissues of a newborn with microcephaly
and died within hours of naissance17.

Experimental evidence
(in animals or in
the man)
No experimental evidence available today.

Analogy (description
the same type phenomena
caused by agents
same nature)
Other viruses such as CMV or rubella virus are known
to cause similar embryofoethopathies.

In summary, major judged causal criteria are met: strength of association,
consistency and temporality. This is in favor of the causal infection Zika in
occurrence of cases malformations. However, further studies, pathophysiological
in particular, is needed to definitively establish causality.

Conclusion
The relation of cause and effect between cases of resurgence of fetal or neonatal microcephaly
and Zika virus infection in the mother during pregnancy is not, at this
day formally established. However, this assumption is likely, should be taken as soon
now and in the pending confirmation or reversal, a number of
measures. These measures are to be taken in the context of and severity of microcephaly
extension of the disease.

Based on currently available data and in a situation of risk
Serious complications (microcephaly, Guillain-Barr? syndrome, other complications in
newborn, child or adult) that could be induced during infection by the virus Zika,
HCSP makes recommendations to:
? a better understanding of Zika and its complications;
? the establishment of preventive measures by the individual and collective protection
against biting mosquitoes vectors;
? priority management of pregnant women exposed to Zika infection.
...
Avis (721 ko)

Announcement

Microcephaly in Brazil: is it occurring in greater numbers than normal or not? - January 30, 2016

Microcephaly in Brazil: is it occurring in greater numbers than normal or not? - January 30, 2016

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