Thursday, June 30, 2016

The Lancet: Two Congenital Zika Virus Studies


Although microcephaly has been the most obvious birth defect linked to maternal Zika infection, for months we've been warned by Brazilian MOH, the CDC, NIH, and WHO that Zika may cause other congenital defects that may not become apparent until the child is much older.

Cranial development is generally advanced enough by the 30th week of gestation that a 3rd trimester exposure would be unlikely to seriously impact head circumference, yet it could still cause neurological damage. 

So, while investigators have discarded 2/3rds of all suspected Zika related microcephaly cases as not meeting their criteria (see last week's chart below), it may still turn out that some of these kids have serious neurological deficits. 

Shedding new light on the effects of maternal Zika carriage for the developing fetus, we a pair of Lancet studies, published late yesterday.   

Below you'll find links, excepts from the abstracts, and some snippets from the press releases.

Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation
Giovanny V A França, PhD, Prof Lavinia Schuler-Faccini, PhD, Wanderson K Oliveira, MSc, Claudio M P Henriques, MD, Eduardo H Carmo, PhD, Vaneide D Pedi, MSc, Marília L Nunes, DVM, Marcia C Castro, PhD, Suzanne Serruya, PhD, Mariângela F Silveira, MD, Prof Fernando C Barros, MD, Prof Cesar G Victora, MD

Published online: June 29, 2016
Open Access



In November, 2015, an epidemic of microcephaly was reported in Brazil, which was later attributed to congenital Zika virus infection. 7830 suspected cases had been reported to the Brazilian Ministry of Health by June 4, 2016, but little is known about their characteristics. We aimed to describe these newborn babies in terms of clinical findings, anthropometry, and survival.


We reviewed all 1501 liveborn infants for whom investigation by medical teams at State level had been completed as of Feb 27, 2016, and classified suspected cases into five categories based on neuroimaging and laboratory results for Zika virus and other relevant infections. Definite cases had laboratory evidence of Zika virus infection; highly probable cases presented specific neuroimaging findings, and negative laboratory results for other congenital infections; moderately probable cases had specific imaging findings but other infections could not be ruled out; somewhat probable cases had imaging findings, but these were not reported in detail by the local teams; all other newborn babies were classified as discarded cases. Head circumference by gestational age was assessed with InterGrowth standards. First week mortality and history of rash were provided by the State medical teams.    


Between Nov 19, 2015, and Feb 27, 2015, investigations were completed for 1501 suspected cases reported to the Brazilian Ministry of Health, of whom 899 were discarded. Of the remainder 602 cases, 76 were definite, 54 highly probable, 181 moderately probable, and 291 somewhat probable of congenital Zika virus syndrome. Clinical, anthropometric, and survival differences were small among the four groups. 
Compared with these four groups, the 899 discarded cases had larger head circumferences (mean Z scores −1·54 vs −3·13, difference 1·58 [95% CI 1·45–1·72]); lower first-week mortality (14 per 1000 vs 51 per 1000; rate ratio 0·28 [95% CI 0·14–0·56]); and were less likely to have a history of rash during pregnancy (20·7% vs 61·4%, ratio 0·34 [95% CI 0·27–0·42]). Rashes in the third trimester of pregnancy were associated with brain abnormalities despite normal sized heads. One in five definite or probable cases presented head circumferences in the normal range (above −2 SD below the median of the InterGrowth standard) and for one third of definite and probable cases there was no history of a rash during pregnancy. The peak of the epidemic occurred in late November, 2015.   

Zika virus congenital syndrome is a new teratogenic disease. Because many definite or probable cases present normal head circumference values and their mothers do not report having a rash, screening criteria must be revised in order to detect all affected newborn babies.

You'll find a nice summation in the Journal's press release: The Lancet: Microcephaly screening alone won't detect all cases of Zika virus in newborns, study suggests 

The second study finds evidence of Zika virus infection in the brain tissue of a deceased 2-month-old microcephalic baby, in two newborns who died shortly after delivery, and in the placental tissue of two fetuses that spontaneously aborted.

While a small sample, all five mothers reported Zika-like symptoms (fever and rash) during their first trimester.  Of the three live-births, all three showed signs of microcephaly.

You'll find a summary of their findings in The Lancet: Zika virus identified in brain and placenta tissue, strengthening link to birth defects, or you can follow the link below to read the full full report (warning: PDF contains graphic autopsy photos).

Pathology of congenital Zika syndrome in Brazil: a case series

Roosecelis Brasil Martines, MD†, Julu Bhatnagar, PhD†, Prof Ana Maria de Oliveira Ramos, MD, Helaine Pompeia Freire Davi, MD, Silvia D'Andretta Iglezias, MD, Cristina Takami Kanamura, MSc, M Kelly Keating, DVM, Gillian Hale, MD, Luciana Silva-Flannery, PhD, Atis Muehlenbachs, MD, Jana Ritter, DVM, Joy Gary, DVM, Dominique Rollin, MD, Cynthia S Goldsmith, MGS, Sarah Reagan-Steiner, MD, Yokabed Ermias, MPH, Tadaki Suzuki, MD, Prof Kleber G Luz, MD, Wanderson Kleber de Oliveira, MSc, Robert Lanciotti, PhD, Amy Lambert, PhD, Wun-Ju Shieh, MD, Dr Sherif R Zaki, MDcorrespondenceemail

Published Online: 29 June 2016
Article has an altmetric score of 6
DOI: |


In this case series, formalin-fixed paraffin-embedded tissue samples from five cases, including two newborn babies with microcephaly and severe arthrogryposis who died shortly after birth, one 2-month-old baby, and two placentas from spontaneous abortions, from Brazil were submitted to the Infectious Diseases Pathology Branch at the US Centers for Disease Control and Prevention (Atlanta, GA, USA) between December, 2015, and March, 2016. Specimens were assessed by histopathological examination, immunohistochemical assays using a mouse anti-Zika virus antibody, and RT-PCR assays targeting the NS5 and envelope genes. Amplicons of RT-PCR positive cases were sequenced for characterisation of strains.


Viral antigens were localised to glial cells and neurons and associated with microcalcifications in all three fatal cases with microcephaly. Antigens were also seen in chorionic villi of one of the first trimester placentas. Tissues from all five cases were positive for Zika virus RNA by RT-PCR, and sequence analyses showed highest identities with Zika virus strains isolated from Brazil during 2015.


These findings provide strong evidence of a link between Zika virus infection and different congenital central nervous system malformations, including microcephaly as well as arthrogryposis and spontaneous abortions.

No comments: