title: Pathology of congenital Zika syndrome in Brazil: a case series.
abstract: BACKGROUND
  Zika virus is an arthropod-borne virus that is a member of the family Flaviviridae transmitted mainly by mosquitoes of the genus Aedes. Although usually asymptomatic, infection can result in a mild and self-limiting illness characterised by fever, rash, arthralgia, and conjunctivitis. An increase in the number of children born with microcephaly was noted in 2015 in regions of Brazil with high transmission of Zika virus. More recently, evidence has been accumulating supporting a link between Zika virus and microcephaly. Here, we describe findings from three fatal cases and two spontaneous abortions associated with Zika virus infection.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  None.
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Roosecelis Brasil
authors.initials: RB
authors.lastname: Martines
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Julu
authors.initials: J
authors.lastname: Bhatnagar
authors.affiliation: Department of Pathology, Federal University of Rio Grande do Norte, Natal, Brazil; Service for Ascertaining Death in the State of Rio Grande do Norte (SVO/RN), Natal/RN, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Oliveira Ramos
authors.affiliation: Service for Ascertaining Death in the State of Rio Grande do Norte (SVO/RN), Natal/RN, Brazil.
authors.forename: Helaine Pompeia Freire
authors.initials: HP
authors.lastname: Davi
authors.affiliation: Adolfo Lutz Institute, Sao Paulo, Brazil.
authors.forename: Silvia D'Andretta
authors.initials: SD
authors.lastname: Iglezias
authors.affiliation: Adolfo Lutz Institute, Sao Paulo, Brazil.
authors.forename: Cristina Takami
authors.initials: CT
authors.lastname: Kanamura
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: M Kelly
authors.initials: MK
authors.lastname: Keating
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hale
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Luciana
authors.initials: L
authors.lastname: Silva-Flannery
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Atis
authors.initials: A
authors.lastname: Muehlenbachs
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Gary
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Rollin
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Goldsmith
authors.affiliation: Immunization Services Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Reagan-Steiner
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Yokabed
authors.initials: Y
authors.lastname: Ermias
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Tadaki
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Luz
authors.affiliation: Ministry of Health, Brasilia, DF, Brazil.
authors.forename: Wanderson Kleber
authors.initials: WK
authors.lastname: de Oliveira
authors.affiliation: Arboviral Diseases Branch, Division of Vector-Borne Diseases, NCEZID, Centers for Disease Control and Prevention, Fort Collins, CO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lanciotti
authors.affiliation: Arboviral Diseases Branch, Division of Vector-Borne Diseases, NCEZID, Centers for Disease Control and Prevention, Fort Collins, CO, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lambert
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA.
authors.forename: Wun-Ju
authors.initials: WJ
authors.lastname: Shieh
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Atlanta, GA, USA. Electronic address: szaki@cdc.gov.
authors.forename: Sherif R
authors.initials: SR
authors.lastname: Zaki
mesh_terms: D000022:Abortion, Spontaneous / Q000821:virology; D000328:Adult; D000956:Antigens, Viral / Q000302:isolation & purification; D001344:Autopsy; D001921:Brain / Q000473:pathology* / Q000821:virology*; D001938:Brazil; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007223:Infant; D017880:Limb Deformities, Congenital / Q000000981:diagnostic imaging / Q000821:virology*; D008297:Male; D008831:Microcephaly / Q000473:pathology / Q000821:virology*; D009457:Neuroglia / Q000473:pathology / Q000821:virology; D010920:Placenta / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000473:pathology* / Q000821:virology*; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D012367:RNA, Viral / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D016216:Ultrasonography, Prenatal; D000071244:Zika Virus / Q000276:immunology / Q000302:isolation & purification*; D000071243:Zika Virus Infection / Q000151:congenital* / Q000473:pathology*
chemical_list: D000956:Antigens, Viral; D012367:RNA, Viral