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MMWR Pregnant Zika Patient B Matches DC ex-Central America Case


niman

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In the CDC MMWR on US citizens who were Zika confirmed after travel to a country where Zika was transmitting, one patient (case report B) who terminated her pregnancy after her fetus showed signs of microcephaly and was Zika positive, as was described.

This description matches a Washington DC case who had been infected in Central America.

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The pregnant woman was in her 30s and, like a growing number of patients at Richard Newman's practice in downtown Washington, worried about a threat the obstetrician himself had learned about only recently: Zika.

In December, during her first trimester, she'd taken a vacation to Central America. Weeks later, U.S. officials began warning pregnant women about traveling to regions where the virus was spreading rapidly. She'd gotten a mosquito bite, followed by a rash, fever and joint pain -- all potential symptoms of infection.

Newman recommended she see a specialist at Sibley Memorial Hospital and encouraged her to have her blood tested by the Centers for Disease Control and Prevention. He'd already done the same for more than a dozen anxious patients in 2016, and each time the results were negative

This time, the test came back positive.

 

The outcome was different for the expectant mother at Newman's practice.

Everything looked fine on the sonogram he'd ordered when she was 16 weeks along. But the image a month later showed distinct abnormalities with "very little brain development," Newman said. A fetal MRI confirmed severe brain atrophy, and analysis of the woman's amniotic fluid detected the presence of Zika.

Newman told his patient that the results suggested her child, if carried to term, might not survive long and almost certainly would have "no chance for a normal quality of life."

Last month, after the final tests results came in, the woman called and told him she planned to terminate the pregnancy.

"I just listened and sympathized," he said. "I can only imagine how hard this was for her. ... It was one of the saddest moments of my medical career."

http://www.chicagotribune.com/news/nationworld/ct-zika-virus-pregnant-women-20160307-story.html

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Patient B. In January 2016, a pregnant woman in her 30s underwent laboratory testing for Zika virus infection. She reported a history of travel to a Zika-affected area at approximately 11–12 weeks’ gestation. One day after returning from travel, she developed fever, eye pain, and myalgia. The next day, she developed a rash. Serologic testing confirmed recent Zika virus infection. At approximately 20 weeks’ gestation, she underwent a fetal ultrasound that suggested absence of the corpus callosum, ventriculomegaly, and brain atrophy; subsequent fetal magnetic resonance imaging demonstrated severe brain atrophy. Amniocentesis was performed, and Zika virus RNA was detected by RT-PCR testing. After discussion with her health care providers, the patient elected to terminate her pregnancy.

http://www.cdc.gov/mmwr/volumes/65/wr/mm6508e1.htm?s_cid=mm6508e1_w

 

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  • 3 weeks later...
LOCUS       KU870645               10798 bp    RNA     linear   VRL 22-MAR-2016
DEFINITION  Zika virus isolate FB-GWUH-2016, complete genome.
ACCESSION   KU870645
VERSION     KU870645.1  GI:1006593136
KEYWORDS    .
SOURCE      Zika virus
  ORGANISM  Zika virus
            Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA
            stage; Flaviviridae; Flavivirus.
REFERENCE   1  (bases 1 to 10798)
  AUTHORS   Driggers,R.W., Ho,C.-Y., Korhonen,E.M., Kuivanen,S.,
            Jaaskelainen,A.J., Smura,T., Rosenberg,A., Hill,A., DeBiasi,R.,
            Vezina,G., Timofeev,J., Rodriguez,F.J., Levanov,L., Razak,J.,
            Iyengar,P., Hennenfent,A., Kennedy,R., Lanciotti,R., du Plessis,A.
            and Vapalahti,O.
  TITLE     Zika virus infection with prolonged maternal viremia and fetal
            brain abnormalities
  JOURNAL   Unpublished
REFERENCE   2  (bases 1 to 10798)
  AUTHORS   Smura,T., Korhonen,E., Kuivanen,S. and Vapalahti,O.
  TITLE     Direct Submission
  JOURNAL   Submitted (05-MAR-2016) Department of Virology, University of
            Helsinki, Haartmaninkatu 3, Helsinki 00280, Finland
FEATURES             Location/Qualifiers
     source          1..10798
                     /organism="Zika virus"
                     /mol_type="genomic RNA"
                     /isolate="FB-GWUH-2016"
                     /isolation_source="fetal brain"
                     /host="Homo sapiens"
                     /db_xref="taxon:64320"
                     /country="USA"
                     /collection_date="02-Feb-2016"
                     /note="putative country of infection: Guatemala;
                     passage details: SK-N-SH"

http://www.ncbi.nlm.nih.gov/nuccore/KU870645

 

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Sequences producing significant alignments:

Select:AllNone Selected:0

Sequences producing significant alignments:
Select for downloading or viewing reportsDescriptionMax scoreTotal scoreQuery coverE valueIdentAccession
1852518525100%0.0100%KU870645.1
1842018420100%0.099%KU501217.1
1841718417100%0.099%KU501216.1
1837518375100%0.099%KU509998.1
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1836318363100%0.099%KU321639.1
1835718357100%0.099%KU926309.1
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1831818318100%0.099%KU922960.1
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1830018300100%0.099%KU955590.1
1829418294100%0.099%KU740184.2
1829418294100%0.099%KU761564.1
1826718267100%0.099%KU955589.1
1826718267100%0.099%KU820899.2
1815918159100%0.099%KU866423.1
1813718137100%0.099%KU744693.1
1802918029100%0.099%KU681081.3
1773217732100%0.098%KU955593.1
177301773099%0.098%JN860885.1
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1756717567100%0.098%EU545988.1
1742917429100%0.098%KU681082.3
163971639799%0.095%HQ234499.1
1328613286100%0.089%KU720415.1
132811328199%0.089%HQ234498.1
1327513275100%0.089%KF383115.1
1327213272100%0.089%KU955595.1
1327013270100%0.089%KF268949.1
1327013270100%0.089%KF268948.1
1326313263100%0.089%KU955592.1
1326313263100%0.089%LC002520.1
1326313263100%0.089%KF268950.1
1325913259100%0.089%KF383119.1
1324713247100%0.089%KU955594.1
1324513245100%0.089%KU955591.1
1324313243100%0.089%DQ859059.1
1323013230100%0.089%KF383116.1
132141321499%0.089%HQ234501.1
1320513205100%0.089%AY632535.2
1316013160100%0.088%KF383117.1
131441314499%0.088%HQ234500.1
1294513013100%0.088%KF383118.1
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108771087797%0.084%KF383120.1
4967496727%0.099%KU312314.1
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4646464625%0.099%KU646827.1
3440344018%0.099%KU312315.1
3214321417%0.099%KU740199.1
2879420695%0.071%DQ859064.1
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2042204211%0.099%KU686218.1
2021202111%0.099%KU179098.1
175217529%0.099%KM078936.1
174817489%0.099%KM078961.1
174617469%0.099%KM078930.1
174517459%0.099%KM078971.1
174517459%0.099%KM078970.1
174517459%0.099%KM078933.1
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119111916%0.099%KU232289.1
118711876%0.099%KU232299.1
118611866%0.099%KU232291.1
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Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities

Rita W. Driggers, M.D., Cheng-Ying Ho, M.D., Ph.D., Essi M. Korhonen, M.Sc., Suvi Kuivanen, M.Sc., Anne J. Jääskeläinen, Ph.D., Teemu Smura, Ph.D., Avi Rosenberg, M.D., Ph.D., D. Ashley Hill, M.D., Roberta L. DeBiasi, M.D., Gilbert Vezina, M.D., Julia Timofeev, M.D., Fausto J. Rodriguez, M.D., Lev Levanov, Ph.D., Jennifer Razak, M.G.C., C.G.C, Preetha Iyengar, M.D., Andrew Hennenfent, D.V.M., M.P.H., Richard Kennedy, M.D., Robert Lanciotti, Ph.D., Adre du Plessis, M.B., Ch.B., M.P.H., and Olli Vapalahti, M.D., Ph.D.

March 30, 2016DOI: 10.1056/NEJMoa1601824

 

SOURCE INFORMATION

From the Department of Gynecology and Obstetrics, Division of Maternal Fetal Medicine (R.W.D., J.T.), and the Department of Pathology (F.J.R.), Johns Hopkins University School of Medicine, Baltimore; the Division of Maternal Fetal Medicine, Sibley Memorial Hospital (R.W.D., J.T., J.R.), the Division of Pathology and Center for Genetic Medicine Research (C.-Y.H., A.R., D.A.H.), Division of Pediatric Infectious Diseases (R.L.D.), Department of Diagnostic Radiology and Imaging (G.V.), and the Fetal Medicine Institute, Division of Fetal and Transitional Medicine (A.P.), Children’s National Health System, the Departments of Integrative Systems Biology (C.-Y.H., D.A.H.), Pediatrics and Microbiology, Immunology and Tropical Medicine (R.L.D.B.), and Radiology and Pediatrics (G.V.), George Washington University School of Medicine and Health Sciences, the Center for Policy, Planning and Evaluation (P.I.) and Centers for Disease Control and Prevention (CDC)–Council of State and Territorial Epidemiologists (CSTE) Applied Epidemiology Fellowship (A.H.), District of Columbia Department of Health, and One Medical Group (R.K.) — all in Washington, DC; the Departments of Virology (E.M.K., S.K., T.S., L.L., O.V.) and Veterinary Biosciences (E.M.K., O.V.), University of Helsinki, and the Department of Virology and Immunology, University of Helsinki and Helsinki University Hospital (A.J.J., O.V.), Helsinki; and the Arboviral Diseases Branch, Division of Vector-Borne Diseases, National Center for Emerging Zoonotic Infectious Diseases, CDC, Atlanta (R.L.).

Address reprint requests to Dr. Driggers at , to Dr. du Plessis at , or to Dr. Vapalahti at .

http://www.nejm.org/doi/full/10.1056/NEJMoa1601824#t=article

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CASE REPORT

A 33-year-old Finnish woman who was in the 11th week of gestation was on holiday in Mexico, Guatemala, and Belize with her husband in late November 2015. (Details are provided in Section 1.0 of the Supplementary Appendix, available with the full text of this article at NEJM.org.) During their travels, she and her husband recalled being bitten by mosquitoes, particularly in Guatemala. One day after her arrival at her current residence in Washington, D.C., she became ill with ocular pain, myalgia, and mild fever (maximum, 37.5°C), which lasted for 5 days. On the second day of fever, a rash developed (Figure 1FIGURE 1nejmoa1601824_f1.gifTimeline of Symptoms and Radiographic and Laboratory Studies., and Fig. S5 in the Supplementary Appendix). Her husband was concomitantly reporting similar symptoms. Serologic analysis that was performed 4 weeks after the onset of illness while she was on a trip to her native Finland was positive for IgG antibodies and negative for IgM antibodies against dengue virus. Subsequent serologic analysis was positive for both IgG and IgM antibodies against ZIKV, findings that were compatible with acute or recent ZIKV infection. Serologic analysis for the presence of chikungunya virus was negative. The patient had been vaccinated against tick-borne encephalitis and yellow fever more than 10 years earlier.

Fetal ultrasonography that was performed at 13, 16, and 17 weeks of gestation (1, 4, and 5 weeks after the resolution of symptoms) showed no evidence of microcephaly or intracranial calcifications. However, there was a decrease in the fetal head circumference from the 47th percentile at 16 weeks to the 24th percentile at 20 weeks.

At 16 weeks of gestation, the presence of flavivirus in serum was detected on nested reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, and sequencing showed identity to Central American epidemic strains of ZIKV. The finding was confirmed with a specific ZIKV quantitative RT-PCR assay (Table S2 in the Supplementary Appendix). The Division of Vector-Borne Diseases Arbovirus Diagnostic Laboratory at the CDC reported serologic evidence of infection at 17 weeks of gestation, with serum positivity for ZIKV IgM and a titer of more than 1:2560 on a plaque-reduction neutralization test. On the basis of these results, the patient sought more thorough assessment of the fetus.

Fetal ultrasonography at 19 weeks of gestation showed abnormal intracranial anatomy (Figure 2FIGURE 2nejmoa1601824_f2.gifFetal Ultrasonography at 19 Weeks of Gestation., and Fig. S1 in the Supplementary Appendix). The cerebral mantle appeared to be thin with increased extra-axial spaces. Both frontal horns were enlarged with heterogeneous, predominantly echogenic material present in the frontal horn and body of the left lateral ventricle, a finding that raised concern about intraventricular hemorrhage. Dilation and upward displacement of the third ventricle, dilation of the frontal horns of the lateral ventricles, concave medial borders of the lateral ventricles, and the absence of the cavum septum pellucidum suggested agenesis of the corpus callosum. No parenchymal calcifications were seen. The head circumference measured in the 24th percentile for gestational age. The remainder of the fetal anatomy was normal.

Fetal MRI at 20 weeks of gestation showed diffuse atrophy of the cerebral mantle, which was most severe in the frontal and parietal lobes, with the anterior temporal lobes least affected (Figure 3FIGURE 3nejmoa1601824_f3.gifMagnetic Resonance Imaging of the Fetal Brain at 19 Weeks of Gestation.). The normal lamination pattern of the cerebral mantle was absent, and the subplate zone was largely undetectable. The corpus callosum was significantly shorter than expected for gestational age, with an anterior–posterior length of 14 mm (expected range, 18 to 22).18,19 The cavum septum pellucidum was very small. The lateral ventricles were mildly enlarged, as was the third ventricle, with a transverse diameter measuring 2.5 mm (average measurement at gestational age, 1.75 mm [range, 1.1 to 2.3]).18 The fourth ventricle was normal. The volume of the choroid plexus was unusually prominent, without evidence of hemorrhage. No focal destructive lesions were identified within the cerebral cortex or white matter. The cerebellum was normal in appearance and size. Given the grave prognosis, the patient elected to terminate the pregnancy at 21 weeks of gestation.

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Ultrasounds missed her Zika infection–until one showed serious harm to her fetus

 
   

What a new case reveals about pregnant women and the Zika virus

 
Play Video1:15
 
The case of a Washington, D.C., woman who terminated her pregnancy after contracting Zika provides new information on detecting fetal brain abnormalities. (Gillian Brockell,Claritza Jimenez/The Washington Post)

Zika successfully hid through nearly half of a District woman’s pregnancy, its damage to her fetus not showing despite a series of early ultrasounds. But suddenly at 19 weeks, another scan revealed significant abnormalities, and a more sophisticated test one week later identified even greater damage in her baby’s brain. In early February, the woman terminated the pregnancy.

The report, published Wednesday in the New England Journal of Medicine, provides troubling new information about the capacity of the virus to infect a fetus and cause serious harm. The case also indicates that Zika may remain in the blood for a long time: The 33-year-old woman still tested positive for Zika 10 weeks after she likely was infected during a trip to Guatemala – far beyond what scientists have thought is the case.

"This helps put more pieces together in the puzzle because we know so little about how this virus acts and when and how long it stays in your blood after you have symptoms," said Laura Riley, vice chair of obstetrics and gynecology at Massachusetts General Hospital in Boston, who was not part of the study. Even though the study only involves one patient, "it's very important because she was followed so closely and there is so much detailed information. "

 
 

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While the case offers important details to researchers and obstetricians-gynecologists counseling pregnant women who may have been exposed to the virus, "we're going to need to study this with a large number of patients to provide guidance for women," said Catherine Spong, acting director for the National Institute of Child Health and Human Development.

The woman and her husband traveled on vacation to Mexico, Guatemala and Belize in late November when she was 11 weeks pregnant. The couple told researchers they had been bitten by mosquitoes during their trip, particularly in Guatemala. After returning home, the woman developed eye and muscle pain, fever and a rash. A series of ultrasounds that began one week after her symptoms subsided -- at 13, 16 and 17 weeks of pregnancy -- showed none of the characteristic problems linked to Zika. The most prominent in utero are an abnormally small head and brain calcifications, bright, white spots that indicate something is amiss. Both are key to a diagnosis of a rare condition called microcephaly.

 

Yet on the ultrasound at 19 weeks, significant brain abnormalities appeared: The baby's brain was small and contained an unusual amount of fluid. The cerebral cortex, its outer layer, was very thin. By the 20th week, a fetal MRI showed severe atrophy, especially in the front and top brain areas that are involved in decision-making, learning, vision, hearing, touch and taste. The fetus did not meet the threshold to be diagnosed with microcephaly.

In the initial ultrasounds, "they only looked at the size of the head and looked for brain calcifications to make sure she didn't have microcephaly and reassured her that everything looks okay," said Rita Driggers, one of the study's lead authors and medical director of Sibley Memorial Hospital’s maternal-fetal medicine division. Driggers, an assistant professor of gynecology and obstetrics at Johns Hopkins University School of Medicine, was involved in the patient's care.

The takeaway for clinicians, she and others said, is to make sure during ultrasounds to look for other brain changes beyond microcephaly and intracranial calcifications.

Adre du Plessis, director of Children's National Health System's Fetal Medicine Institute and another study author, said Wednesday that the lack of those markers in the earlier ultrasounds may have led to "false reassurances" for the mother. What's more, he said, such delayed diagnosis of brain infection in the fetus may put women who'd opt to terminate a pregnancy "outside the legal limits" of an abortion.

 

Forty-three states prohibit abortions after a specified point in pregnancy -- most often the point of fetal viability -- except when necessary to protect the woman’s life or health.

Researchers said they are not recommending that all pregnant women infected with Zika uniformly seek out fetal MRIs, which are expensive and not readily available in many of the countries in Central and South America that have been hardest hit by the Zika epidemic. In the United States, the technology is available at most major medical centers.

It's possible that researchers might be able to develop other markers to predict whether babies will become infected and develop abnormalities, du Plessis said.

The study also provides new information about how long the virus persists in the blood of an infected person. The common thinking has been that the virus is only present for seven days to about two weeks at the outer limits. But this patient had virus in her blood from the time she became infected, when she was about 11 weeks pregnant, up until the time of her abortion, at 21 weeks.

"That's a very novel finding and important for future study," said Roberta DeBiasi, Children's chief of infectious disease division and another study author.

Have you had an experience with Zika? We'd like to hear from you.

It's possible that the woman's persistent infection was the result of the virus replicating in the fetus or placenta, the researchers said.

Researchers also found "significant" cell death of neurons in the part of the brain that plays a role in sight, hearing and language, researchers said.

https://www.washingtonpost.com/news/to-your-health/wp/2016/03/30/why-ultrasounds-may-give-mothers-with-zika-a-false-sense-of-security/

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Microcephaly and other fetal malformations potentially associated with Zika virus infection or suggestive of congenital infection have been reported in six countries (Brazil, Cabo Verde, Colombia, French Polynesia, Martinique and Panama). Two cases, each linked to a stay in Brazil, were detected in Slovenia and the United States of America. A further case, linked to a brief stay in Mexico, Guatemala and Belize, was detected in a pregnant woman in the United States of America.

http://www.who.int/emergencies/zika-virus/situation-report/21-april-2016/en/

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